Evaluation of a New All-in-One Optical Biometer and Comparison With a Validated Swept-source OCT Biometer.

PURPOSE: To assess agreement between a new all-in-one non-contact optical biometer based on optical low coherence reflectometry (SW-9000 µm Plus; Suoer) and a swept-source optical coherence tomography biometer (OA-2000; Tomey). METHODS: Each eye was scanned three times in a row by each device at random. The measured ocular parameters included central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), axial length (AL), flat keratometry (Kf), steep keratometry (Ks), mean keratometry (Km), astigmatism, corneal diameter (CD), and pupil diameter (PD). The paired t test was used to show the differences between the SW-9000 and OA-2000. Bland-Altman plots and the 95% limits of agreement (LoA) were applied to assess the consistency of the measurements. RESULTS: Sixty eyes from 60 healthy participants were examined, with a mean spherical equivalent refraction of -5.58 ± 2.31 diopters and a mean age of 30.40 ± 6.07 years. The Bland-Altman plots showed high agreement for AL, ACD, LT, Kf, Ks, Km, astigmatism, and CD measurements (95% LoA: -0.06 to 0.04 mm, -0.10 to 0.06 mm, -0.12 to 0.11 mm, -0.30 to 0.29 D, -0.35 to 0.38 D, -0.29 to 0.30 D, -0.30 to 0.34 D, and -0.50 to 0.06 mm, respectively), whereas the agreement for CCT and PD were moderate (95% LoA: 7.12 to 20.43 µm, -0.75 to 1.19 mm, respectively). CONCLUSIONS: The new all-in-one non-contact biometer had high agreement with the OA-2000 biometer on the AL, ACD, LT, Kf, Ks, Km, astigmatism, and CD measurements. For most of the ocular parameters assessed, they were clinically interchangeable. [J Refract Surg. 2023;39(12):825-830.].

Inter-examiner and intra-examiner reliability of optical coherence tomography angiography in vascular density measurement of retinal and choriocapillaris plexuses in healthy children aged 6-15 years.

Objective: This study aimed to test the inter-examiner and intra-examiner reliability of macular vascular density (VD) measurement of retinal and choriocapillaris plexuses in healthy children using optical coherence tomography angiography (OCTA). Materials and methods: Ninety-two school children were prospectively recruited. Macular OCTA images (6 × 6 mm2) were obtained thrice by two examiners using the RTVue-XR Avanti OCT system. The coefficient of variation (COV), intraclass correlation coefficient (ICC), and Bland-Altman plots were used to evaluate the repeatability and reproducibility. Results: Ninety participants aged 6-15 years were enrolled; two participants were excluded because of low-quality images. In the retina, the reproducibility and repeatability of VD became poorer from superficial to deep retinal capillary plexus (superficial: COV = 4.61-11.11%; intermediate: COV = 7.73-14.15%; deep: COV = 14.60-32.28%). For both reproducibility and repeatability, the ICC ranged from moderate to high (superficial plexus: ICC = 0.570-0.976; intermediate plexus: ICC = 0.720-0.968; deep plexus: ICC = 0.628-0.954). In the choroid, the inter-examiner reproducibility and intra-examiner repeatability of the VD measurement of choriocapillaris were excellent in the macula, fovea, parafovea, and perifovea (COV = 1.00-6.10%; ICC = 0.856-0.950). The parameters of the foveal avascular zone (FAZ) also showed significant reproducibility and repeatability (COV = 0.01-0.21%; ICC = 0.743-0.994). Conclusion: The VD measurements of the choriocapillaris and FAZ parameters using OCTA showed excellent inter-examiner and intra-examiner reliability in school children. The reproducibility and repeatability of the VD of three retinal capillary plexuses depended on the depth of the retinal capillary plexus.

Precision (repeatability and reproducibility) of papillary and peripapillary vascular density measurements using optical coherence tomography angiography in children.

Importance: Optical coherence tomography angiography (OCTA) has been widely applied into children, however, few studies have assessed the repeatability and reproducibility of papillary and peripapillary VD in healthy children. Objective: To assess the precision of papillary and peripapillary vascular density (VD) measurements using optical coherence tomography angiography (OCTA) and analyze the effects of the signal strength index (SSI) and axial length (AL) on precision estimates. Design setting and participants: This was a prospective observational study. Seventy-eight children aged 6-16 years underwent 4.5 × 4.5 mm OCTA (RTVue XR Avanti) disc scans: two scans by one examiner (repeatability) and two additional scans by another examiner (reproducibility). Within-subject standard deviation (Sw), test-retest reproducibility (TRT), within-subject coefficient of variation (CoV), intraclass correlation coefficient (ICC), and Bland-Altman analysis were performed. Main outcomes and measures: In repeatability measurement, the fluctuation ranges (minimum to maximum) of VD between intraexaminer A/B in Sw, TRT, CoV, and ICC were (1.05-2.17)% / (1.16-2.32)%, (2.9-6)% / (3.21-6.44)%, (1.9-4.47)% / (2.08-5)%, and (0.588-0.783)% / (0.633-0.803)%, respectively. In reproducibility measurement, the fluctuation ranges of VD in Sw, TRT, CoV, and ICC were 1.11-2.13%, 3.07-5.91%, 1.99-4.41%, and 0.644-0.777%, respectively. VD was negatively correlated with SSI in most sectors of the peripapillary (e.g., inferior nasal, temporal inferior, temporal superior, superior temporal, and superior nasal). AL was positively correlated with inferior temporal VD and negatively correlated with superior nasal VD. Conclusion and relevance: Optical coherence tomography angiography showed moderate-to-good repeatability and reproducibility for papillary and peripapillary perfusion measurements in healthy children. The SSI value affects most of the peripapillary VD, while AL affects only the temporal inferior and nasal superior peripapillary VD.

Enhancement and Repair of Degenerative Intervertebral Disc in Rats Using Platelet-Rich Plasma/Ferulic Acid Hydrogel.

BACKGROUND: Intervertebral degenerative disc (IDD) disease is one of the most common clinical conditions causing low back pain. The main objective of this study was to investigate the repair effect of platelet-rich plasma (PRP) and ferulic acid (FA) hydrogel compound on degenerative discs in rats in combination with bioengineering technology, which may provide a strong theoretical basis for the future treatment of IDD. METHODS: Forty-five male Sprague-Dawley rats were randomly divided into groups A-F; MRI was performed in each group at 0, 4, and 8 weeks after injection; and disc tissues were obtained after executing the animals. The histomorphology, apoptosis, and protein synthesis of intervertebral discs in each group were observed by hematoxylin-eosin, Masson, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and Western blot. RESULTS: The release concentration of all groups reached the peak at 12 hours, and the highest concentration was found in the hydrogel/PRP/FA group at the same time. The MTT assay showed that hydrogel/PRP/FA is well-cytocompatible. The results of animal experiments show that hydrogel/PRP/FA has a good effect on degenerative intervertebral disc in rats. CONCLUSION: PRP/FA-rich hydrogel compound plays an active role in promoting extracellular matrix synthesis, strengthening and repairing degenerated intervertebral discs in rats.

The pro-tumorigenic activity of p38γ overexpression in nasopharyngeal carcinoma.

It is urgent to identify and validate biomarkers for early diagnosis and efficient treatment of nasopharyngeal carcinoma (NPC). Recent studies have proposed p38 gamma (p38γ) as a cyclin-dependent kinase (CDK)-like kinase that phosphorylates retinoblastoma (Rb) to promote cyclins expression and tumorigenesis. Here the Gene Expression Profiling Interactive Analysis (GEPIA) database and results from the local NPC tissues demonstrate that p38γ is significantly upregulated in NPC tissues, correlating with poor overall survival. Furthermore, p38γ mRNA and protein expression is elevated in established NPC cell lines (CNE-1 HONE-1 and CNE-2) and primary human NPC cells, but low expression detected in human nasal epithelial cells. In established and primary NPC cells, p38γ depletion, using the shRNA strategy or the CRISPR/Cas9 gene-editing method, largely inhibited cell growth, proliferation and migration, and induced significant apoptosis activation. Contrarily, ectopic p38γ overexpression exerted opposite activity and promoted NPC cell proliferation and migration. Retinoblastoma (Rb) phosphorylation and cyclin E1/A expression were decreased in NPC cells with p38γ silencing or knockout, but increased after p38γ overexpression. Moreover, mitochondrial subcellular p38γ localization was detected in NPC cells. Significantly, p38γ depletion disrupted mitochondrial functions, causing mitochondrial depolarization, reactive oxygen species production, oxidative injury and ATP depletion in NPC cells. In vivo, intratumoral injection of adeno-associated virus-packed p38γ shRNA potently inhibited primary human NPC xenograft growth in nude mice. In p38γ shRNA virus-injected NPC xenograft tissues, p38γ expression, Rb phosphorylation, cyclin E1/A expression and ATP levels were dramatically decreased. Taken together, we conclude that p38γ overexpression is required for NPC cell growth, acting as a promising therapeutic target of NPC.

GNE-493 inhibits prostate cancer cell growth via Akt-mTOR-dependent and -independent mechanisms.

GNE-493 is a novel PI3K/mTOR dual inhibitor with improved metabolic stability, oral bioavailability, and excellent pharmacokinetic parameters. Here GNE-493 potently inhibited viability, proliferation, and migration in different primary and established (LNCaP and PC-3 lines) prostate cancer cells, and provoking apoptosis. GNE-493 blocked Akt-mTOR activation in primary human prostate cancer cells. A constitutively-active mutant Akt1 restored Akt-mTOR activation but only partially ameliorated GNE-493-induced prostate cancer cell death. Moreover, GNE-493 was still cytotoxic in Akt1/2-silenced primary prostate cancer cells. Significant oxidative stress and programmed necrosis cascade activation were detected in GNE-493-treated prostate cancer cells. Moreover, GNE-493 downregulated Sphingosine Kinase 1 (SphK1), causing ceramide accumulation in primary prostate cancer cells. Daily single dose GNE-493 oral administration robustly inhibited the growth of the prostate cancer xenograft in the nude mice. Akt-mTOR inactivation, SphK1 downregulation, ceramide level increase, and oxidative injury were detected in GNE-493-treated prostate cancer xenograft tissues. Together, GNE-493 inhibited prostate cancer cell growth possibly through the Akt-mTOR-dependent and -independent mechanisms.

Joint Learning of Multiple Latent Domains and Deep Representations for Domain Adaptation.

In domain adaptation, the automatic discovery of multiple latent source domains has succeeded by capturing the intrinsic structure underlying the source data. Different from previous works that mainly rely on shallow models for domain discovery, we propose a novel unified framework based on deep neural networks to jointly address latent domain prediction from source data and deep representation learning from both source and target data. Within this framework, an iterative algorithm is proposed to alternate between 1) utilizing a new probabilistic hierarchical clustering method to separate the source domain into latent clusters and 2) training deep neural networks by using the domain membership as the supervision to learn deep representations. The key idea behind this joint learning framework is that good representations can help to improve the prediction accuracy of latent domains and, in turn, domain prediction results can provide useful supervisory information for feature learning. During the training of the deep model, a domain prediction loss, a domain confusion loss, and a task-specific classification loss are effectively integrated to enable the learned feature to distinguish between different latent source domains, transfer between source and target domains, and become semantically meaningful among different classes. Trained in an end-to-end fashion, our framework outperforms the state-of-the-art methods for latent domain discovery, as validated by extensive experiments on both object classification and human action-recognition tasks.

Poly(N-isopropylacrylamide)-Based Thermoresponsive Composite Hydrogels for Biomedical Applications.

Poly(N-isopropylacrylamide) (PNIPAM)-based thermosensitive hydrogels demonstrate great potential in biomedical applications. However, they have inherent drawbacks such as low mechanical strength, limited drug loading capacity and low biodegradability. Formulating PNIPAM with other functional components to form composited hydrogels is an effective strategy to make up for these deficiencies, which can greatly benefit their practical applications. This review seeks to provide a comprehensive observation about the PNIPAM-based composite hydrogels for biomedical applications so as to guide related research. It covers the general principles from the materials choice to the hybridization strategies as well as the performance improvement by focusing on several application areas including drug delivery, tissue engineering and wound dressing. The most effective strategies include incorporation of functional inorganic nanoparticles or self-assembled structures to give composite hydrogels and linking PNIPAM with other polymer blocks of unique properties to produce copolymeric hydrogels, which can improve the properties of the hydrogels by enhancing the mechanical strength, giving higher biocompatibility and biodegradability, introducing multi-stimuli responsibility, enabling higher drug loading capacity as well as controlled release. These aspects will be of great help for promoting the development of PNIPAM-based composite materials for biomedical applications.

Crystal structure of EGFR T790M/C797S/V948R in complex with EAI045.

Lung cancer is the leading cause of cancer deaths. Epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small cell lung cancers (NSCLCs), a major subtype of lung cancers. Patients harboring most of these mutations respond well to the anti-EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib initially, but soon develop resistance to them in about half of the cases due to the emergence of the gatekeeper mutation T790M. The third-generation TKIs such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to the EGFR kinase through Cys 797, but ultimately lose their efficacy upon emergence of the C797S mutation that abolishes the covalent bonding. Therefore to develop new TKIs to overcome EGFR drug-resistant mutants harboring T790M/C797S is urgently demanded. EAI001 and EAI045 are a new type of EGFR TKIs that bind to EGFR reversibly and not relying on Cys 797. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR L858R/T790M and L858R/T790M/C797S. Here we report the crystal structure of EGFR T790M/C797S/V948R in complex with EAI045, and compare it to EGFR T790M/V948R in complex with EAI001. The complex structure reveals why EAI045 binds tighter to EGFR than does EAI001, and why EAI001 and EAI045 prefer binding to EGFR T790M. The knowledge may facilitate future drug development studies targeting this very important cancer target.

Structural pharmacological studies on EGFR T790M/C797S.

Drug-resistance is a major challenge in targeted therapy of EGFR mutated non-small cell lung cancers (NSCLCs). The third-generation irreversible inhibitors such as AZD9291, CO-1686 and WZ4002 can overcome EGFR T790M drug-resistance mutant through covalent binding through Cys 797, but ultimately lose their efficacy upon emergence of the new mutation C797S. To develop new reversible inhibitors not relying on covalent binding through Cys 797 is therefore urgently demanded. Gö6976 is a staurosporine-like reversible inhibitor targeting T790M while sparing the wild-type EGFR. In the present work, we reported the complex crystal structures of EGFR T790M/C797S + Gö6976 and T790M + Gö6976, along with enzyme kinetic data of EGFR wild-type, T790M and T790M/C797S. These data showed that the C797S mutation does not significantly alter the structure and function of the EGFR kinase, but increases the local hydrophilicity around residue 797. The complex crystal structures also elucidated the detailed binding mode of Gö6976 to EGFR and explained why this compound prefers binding to T790M mutant. These structural pharmacological data would facilitate future drug development studies.

Effect of volatile-char interaction on the NO emission from coal combustion.

To clarify the effects of volatile-char interaction on the redistribution of fuel-N to N2 during devolatilization and the reduction of NO through gas-solid reactions during combustion, two types of experiments were performed on a novel reactor. The separate combustion of volatile and char and the combustion of entrained pulverized coal, and the formation of NO was examined between 800 and 1100 degrees C by using four typical Chinese coals with different ranks. The effect of volatile-char interaction on fuel-N conversion to NO during combustion was elucidated through comparing the NO emissions from the two types of combustion experiments. The results show that the volatile-char interaction is more important in the redistribution of fuel-N to N2 during devolatilization than in the reduction of NO over 900 degrees C, and a contrary conclusion is obtained below 850 degrees C for all used coals. A specific parameter has been proposed to characterize the relative importance of the volatile-char interaction in the redistribution of fuel-N to N2 during devolatilization to the interaction in the reduction of NO to N2 during simulataneous combustion of volatile and char. The results are of significance for minimizing the NO formation in industrial combustion processes.