Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2.

COVID-19 has spread worldwide since 2019 and is now a severe threat to public health. We previously identified the causative agent as a novel SARS-related coronavirus (SARS-CoV-2) that uses human angiotensin-converting enzyme 2 (hACE2) as the entry receptor. Here, we successfully developed a SARS-CoV-2 hACE2 transgenic mouse (HFH4-hACE2 in C3B6 mice) infection model. The infected mice generated typical interstitial pneumonia and pathology that were similar to those of COVID-19 patients. Viral quantification revealed the lungs as the major site of infection, although viral RNA could also be found in the eye, heart, and brain in some mice. Virus identical to SARS-CoV-2 in full-genome sequences was isolated from the infected lung and brain tissues. Last, we showed that pre-exposure to SARS-CoV-2 could protect mice from severe pneumonia. Our results show that the hACE2 mouse would be a valuable tool for testing potential vaccines and therapeutics.

A pneumonia outbreak associated with a new coronavirus of probable bat origin.

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1-4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5-7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.

TNFAIP3 Derived from Skeletal Stem Cells Alleviated Rat Osteoarthritis by Inhibiting the Necroptosis of Subchondral Osteoblasts.

Recent investigations have shown that the necroptosis of tissue cells in joints is important in the development of osteoarthritis (OA). This study aimed to investigate the potential effects of exogenous skeletal stem cells (SSCs) on the necroptosis of subchondral osteoblasts in OA. Human SSCs and subchondral osteoblasts isolated from human tibia plateaus were used for Western blotting, real-time PCR, RNA sequencing, gene editing, and necroptosis detection assays. In addition, the rat anterior cruciate ligament transection OA model was used to evaluate the effects of SSCs on osteoblast necroptosis in vivo. The micro-CT and pathological data showed that intra-articular injections of SSCs significantly improved the microarchitecture of subchondral trabecular bones in OA rats. Additionally, SSCs inhibited the necroptosis of subchondral osteoblasts in OA rats and necroptotic cell models. The results of bulk RNA sequencing of SSCs stimulated or not by tumor necrosis factor α suggested a correlation of SSCs-derived tumor necrosis factor α-induced protein 3 (TNFAIP3) and cell necroptosis. Furthermore, TNFAIP3-derived from SSCs contributed to the inhibition of the subchondral osteoblast necroptosis in vivo and in vitro. Moreover, the intra-articular injections of TNFAIP3-overexpressing SSCs further improved the subchondral trabecular bone remodeling of OA rats. Thus, we report that TNFAIP3 from SSCs contributed to the suppression of the subchondral osteoblast necroptosis, which suggests that necroptotic subchondral osteoblasts in joints may be possible targets to treat OA by stem cell therapy.

Multiplexed Fluoro-electrochemical Single-Molecule Counting Enabled by SiC Semiconducting Nanofilm.

A major challenge for ultrasensitive analysis is the high-efficiency determination of different target single molecules in parallel with high accuracy. Herein, we developed a quantitative fluoro-electrochemical imaging approach for direct multiplexed single-molecule counting with a SiC-nanofilm-modified indium tin oxide transparent electrode. The nanofilm could control local pH through proton-coupled electron transfer in a lower potential range and further induce direct electrochemical oxidation of the dye molecules with a higher applied potential. The fluoro-electrochemical responses of immobilized single molecules with different pH values and redox behaviors could thus be distinguished within the same fluorescence channels. This method yields nonamplified direct counting of single molecules, as indicated by excellent linear responses in the picomolar range. The successful distinction of seven different randomly mixed dyes underscores the versatility and efficacy of the proposed method in the highly accurate determination of single dye molecules, paving the way for highly parallel single-molecule detection for diverse applications.

Three-Dimensionally Nanometallic Superstructure Synthesized via a Single-Particle Soft-Enveloping Strategy.

Three-dimensionally (3D) integrated metallic nanomaterials composed of two or more different types of nanostructures make up a class of advanced materials due to the multidimensional and synergistic effects between different components. However, designing and synthesizing intricate, well-defined metallic 3D nanomaterials remain great challenges. Here, a novel single-particle soft-enveloping strategy using a core-shell Au NP@mSiO2 particle as a template was proposed to synthesize 3D nanomaterials, namely, a Au nanoparticle@center-radial nanorod-Au-Pt nanoparticle (Au NP@NR-NP-Pt NP) superstructure. Taking advantage of the excellent plasmonic properties of Au NP@NR-NP by the synergistic plasmonic coupling of the outer Au NPs and inner Au nanorods, we can enhance the catalytic performance for 4-nitrophenol hydrogenation using Au NP@NR-NP-Pt NP as a photocatalyst with plasmon-excited hot electrons from Au NP@NR-NP under light irradiation, which is 2.76 times higher than in the dark. This process opens a door for the design of a new generation of 3D metallic nanomaterials for different fields.

Dual-Mode Imaging of Dynamic Interaction between Bubbles and Single Nanoplates during the Electrocatalytic Hydrogen Evolution Process.

Gas bubble formation at electrochemical interfaces can significantly affect the efficiency and durability of electrocatalysts. However, obtaining comprehensive details on bubble evolution dynamics, particularly their dynamic interaction with high-performance structured electrocatalysts, poses a considerable challenge. Herein, dual-mode interference/total internal reflection fluorescence microscopy is introduced, which allows for the simultaneous capture of the evolution pathway of bubbles and the 3D motion of nanoplate electrocatalysts, providing high-resolution and accurate spatiotemporal information. During the hydrogen evolution reaction, the dynamics of hydrogen bubble generation and their interactions with single nanoplate electrocatalysts at the electrochemical interface are observed. The results unveiled that, under constant potential, bubbles initially manifest as fast-moving nanobubbles, transforming into stationary microbubbles subsequently. The morphology of stationary nanoplates regulates the trajectories of these moving nanobubbles while the pinned microbubbles induce the motion of the electrocatalysts. The dual-mode microscopy can be employed to scrutinize numerous multiphase electrochemical interactions with high spatiotemporal resolution, which can facilitate the rational design of high-performance electrocatalysts.

Isolation of ACE2-dependent and -independent sarbecoviruses from Chinese horseshoe bats.

While the spike proteins from severe acute respiratory syndrome coronaviruses-1 and 2 (SARS-CoV and SARS-CoV-2) bind to host angiotensin-converting enzyme 2 (ACE2) to infect cells, the majority of bat sarbecoviruses cannot use ACE2 from any species. Despite their discovery almost 20 years ago, ACE2-independent sarbecoviruses have never been isolated from field samples, leading to the assumption these viruses pose little risk to humans. We have previously shown how spike proteins from a small group of ACE2-independent bat sarbecoviruses may possess the ability to infect human cells in the presence of exogenous trypsin. Here, we adapted our earlier findings into a virus isolation protocol and recovered two new ACE2-dependent viruses, RsYN2012 and RsYN2016A, as well as an ACE2-independent virus, RsHuB2019A. Although our stocks of RsHuB2019A rapidly acquired a tissue-culture adaption that rendered the spike protein resistant to trypsin, trypsin was still required for viral entry, suggesting limitations on the exogenous entry factors that support bat sarbecoviruses. Electron microscopy revealed that ACE2-independent sarbecoviruses have a prominent spike corona and share similar morphology to other coronaviruses. Our findings demonstrate a broader zoonotic threat posed by sarbecoviruses and shed light on the intricacies of coronavirus isolation and propagation in vitro. IMPORTANCE Several coronaviruses have been transmitted from animals to people, and 20 years of virus discovery studies have uncovered thousands of new coronavirus sequences in nature. Most of the animal-derived sarbecoviruses have never been isolated in culture due to cell incompatibilities and a poor understanding of the in vitro requirements for their propagation. Here, we built on our growing body of work characterizing viral entry mechanisms of bat sarbecoviruses in human cells and have developed a virus isolation protocol that allows for the exploration of these understudied viruses. Our protocol is robust and practical, leading to successful isolation of more sarbecoviruses than previous approaches and from field samples that had been collected over a 10-year longitudinal study.

Discrepancy of coordinate system selection in backscattering Mueller matrix polarimetry: exploring photon coordinate system transformation invariants.

In biomedical studies, Mueller matrix polarimetry is gaining increasing attention because it can comprehensively characterize polarization-related vectorial properties of the sample, which are crucial for microstructural identification and evaluation. For backscattering Mueller matrix polarimetry, there are two photon coordinate selection conventions, which can affect the following Mueller matrix parameters calculation and information acquisition quantitatively. In this study, we systematically analyze the influence of photon coordinate system selection on the backscattering Mueller matrix polarimetry. We compare the Mueller matrix elements in the right-handed-nonunitary and non-right-handed-unitary coordinate systems, and specifically deduce the changes of Mueller matrix polar decomposition, Mueller matrix Cloude decomposition and Mueller matrix transformation parameters widely used in backscattering Mueller matrix imaging as the photon coordinate system varied. Based on the theoretical analysis and phantom experiments, we provide a group of photon coordinate system transformation invariants for backscattering Mueller matrix polarimetry. The findings presented in this study give a crucial criterion of parameters selection for backscattering Mueller matrix imaging under different photon coordinate systems.

Experimental study of laser spot tracking for underwater optical wireless communication.

In this paper, a novel laser spot tracking algorithm that incorporates the Kalman filter with the continuously adaptive Meanshift algorithm (Cam-Kalm) is proposed and employed in an underwater optical wireless communication (UOWC) system. Since the Kalman filter has the advantage of predicting the state information of the target spot based on its spatial motion features, the proposed algorithm can improve the accuracy and stability of the moving laser spot tracking. A 2 m optical wireless communication experimental system with auto-tracking based on a green laser diode (LD) is built to evaluate the tracking performance of different algorithms. Experimental results verify that the proposed algorithm outperforms conventional tracking algorithms in aspects of tracking accuracy, interference resistance, and response time. With the proposed Cam-Kalm algorithm, the experimental system can establish an effective communication link, while the maximum tracking speed is 20 mm/s given the forward-error-correction (FEC) threshold.

Polarization feature fusion and calculation of birefringence dynamics in complex anisotropic media.

As a complex anisotropic medium, variation in birefringence within biological tissues is closely associated with numerous physiological behaviors and phenomena. In this Letter, we propose a polarization feature fusion method and corresponding polarimetric parameters, which exhibit excellent performance of capturing the birefringence dynamic variation process in complex anisotropic media. By employing the feature fusion method, we combine and transform polarization basis parameters (PBPs) to derive fused polarization feature parameters (FPPs) with explicit expressions. Subsequently, we conduct Monte Carlo (MC) simulation to demonstrate the effectiveness of the proposed FPPs from two variation dimensions of birefringence direction θ and modulus Δn. Leveraging mathematical modeling and linear transformations, we investigate and abstract their response patterns concerning θ and Δn. Finally, the experiments confirm that the FPPs show superior adaptability and interpretability in characterizing the birefringence dynamic process of turbid media. The findings presented in this study provide new, to the best of our knowledge, methodological insights of information extraction for computational polarimetry in biomedical research.

Advances in the study of the influence of photoreceptors on the development of myopia.

This review examines the pivotal role of photoreceptor cells in ocular refraction development, focusing on dopamine (DA) as a key neurotransmitter. Contrary to the earlier view favoring cone cells, recent studies have highlighted the substantial contributions of both rod and cone cells to the visual signaling pathways that influence ocular refractive development. Notably, rod cells appeared to play a central role. Photoreceptor cells interact intricately with circadian rhythms, color vision pathways, and other neurotransmitters, all of which are crucial for the complex mechanisms driving the development of myopia. This review emphasizes that ocular refractive development results from a coordinated interplay between diverse cell types, signaling pathways, and neurotransmitters. This perspective has significant implications for unraveling the complex mechanisms underlying myopia and aiding in the development of more effective prevention and treatment strategies.

25-Hydroxy vitamin D deficiency is an inferior predictor of peripheral T-cell lymphomas.

The aim of the study was to explore the significance and prognostic value of 25-hydroxy vitamin D (25-(OH) D) deficiency in peripheral T-cell lymphomas (PTCLs). One hundred fifty-six patients of newly diagnosed PTCLs were enrolled in the study. Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic (ROC) curves were plotted, and corresponding areas under the curve (AUC) were calculated to estimate the accuracy of International Prognostic Index (IPI) plus 25-(OH) D deficiency and Prognostic Index for T-cell lymphoma (PIT) plus 25-(OH) D deficiency respectively in PTCL risk stratification. Our results showed that the 25-(OH) D deficiency was an independent inferior prognostic factor for both PFS (P = 0.0019) and OS (P = 0.005) for PTCLs, especially for AITL and PTCL-not otherwise specified (PTCL-NOS). Additionally, adding 25-(OH) D deficiency to PIT indeed has a superior prognostic significance than PIT alone for PFS (P = 0.043) and OS (P = 0.036). Multivariate COX regression analysis revealed that PIT 2‒4, albumin (ALB) ≤ 35 g/L, and 25-(OH) D deficiency were regarded as independent risk factors of PFS and OS. Our results showed that 25-(OH) D deficiency was associated with inferior survival outcome of PTCLs, especially for AITL and PTCL-NOS. PIT plus 25-(OH) D deficiency could better indicate the prognosis for PFS and OS of PTCLs than PIT.

NOTCH pathway mutation contributes to inferior prognosis in HBV-infected chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) patients with hepatitis B virus (HBV) infection have a poor prognosis, underlying mechanism remains unclear. NOTCH mutations are frequent in CLL and associated with disease progression and drug resistance. It is also reported to be associated with hepatitis infection in lymphoid malignancies. In order to investigate the relation between the NOTCH pathway and HBV-associated CLL, we studied 98 previously untreated HBV-positive CLL patients and 244 HBV-negative CLL. NOTCH mutations were more frequent in HBV-positive CLL subgroup (p = 0.033). By survival analysis, HBV infection was associated with disease progression and poor survival (p = 0.0099 for overall survival (OS) and p = 0.0446 for time-to-treatment (TTT)). Any lesions of the NOTCH pathway (NOTCH1, NOTCH2, and SPEN) aggravated prognosis. In multivariate analysis, NOTCH mutation retained an independent significance for HBV-infected patients (p = 0.016 for OS and p = 0.023 for TTT). However, HBV positive with NOTCH unmutated had no statistical difference in prognosis compared with HBV-negative patients (p = 0.1706 for OS and p = 0.2387 for TTT), which indicated that NOTCH pathway mutation contributed to inferior prognosis in HBV-infected CLL. In conclusion, a cohort of CLL patients with HBV positive displayed a worse clinical outcome and the status of the NOTCH signaling pathway might play a crucial role.

Analysis of CCND3 mutations in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL), accounts for 30-40% of newly diagnosed lymphomas, has an overall cure rate of approximately 60%. Despite previous reports suggesting a negative prognostic association between CCND3 mutations and Burkitt lymphoma, their prognostic implications in DLBCL remain controversial. To investigate this, we evaluated CCND3 mutation status in 2059 DLBCL patient samples from four database (integrated cohort) and additional 167 DLBCL patient samples in our center (JSPH cohort). The mutation was identified in 5.5% (113/2059) of the cases in the integrated cohort, with 86% (97/113) found in exon 5. Furthermore, P284, R271, I290 and Q276 are described as CCND3 mutation hotspots. CCND3 mutation was associated with decreased overall survival (OS) in the integrated cohort (P = 0.0407). Further subgroup analysis revealed that patients diagnosed as EZB subtype DLBCL by LymphGen algorithm with CCND3 mutations had poorer OS than patients diagnosed as EZB subtype without CCND3 mutations (P = 0.0140). Using the next-generation sequencing (NGS) in the JSPH cohort, it was found that both cell cycle and DNA replication pathways were highly upregulated in patients with CCND3 mutations. Our results suggest that CCND3 mutations can serve as a novel prognostic factor in DLBCL pathogenesis. Consequently, the development of personalized therapeutic strategies for DLBCL patients with CCND3 mutations might enhance their prognosis.

Cause-specific mortality in a population-level cohort of diffuse large B-cell lymphoma following chemotherapy in the early 21st century.

Diffuse large B-cell lymphoma (DLBCL) is a severe non-Hodgkin's lymphoma. Life expectancy has improved with rituximab, but cause-specific mortality data is lacking. Using the Surveillance, Epidemiology, and End Results (SEER) database to study 27,449 individuals aged 20-74 years diagnosed with primary DLBCL who received chemotherapy between 2000 and 2019, we calculated standardized mortality rate (SMR) and excess absolute risk (EAR) and examined the connection between age, sex, time after diagnosis, and cause of death. Based on 12,205 deaths, 68.7% were due to lymphoma, 20.1% non-cancer causes, and 11.2% other cancers. Non-cancer mortality rates (SMR 1.2; EAR, 21.5) increased with DLBCL compared to the general population. The leading non-cancer death causes were cardiovascular (EAR, 22.6; SMR, 1.6) and infectious (EAR, 9.0; SMR, 2.9) diseases with DLBCL. Risks for non-cancer death and solid neoplasms are highest within the first diagnosis year, then decrease. Among socioeconomic factors, being white, being married, and having a higher income were favorable factors for reducing non-cancer mortality. To improve survival, close surveillance, assessment of risk factors, and early intervention are needed.

Identify truly high-risk TP53-mutated diffuse large B cell lymphoma patients and explore the underlying biological mechanisms.

TP53 mutation (TP53-mut) correlates with inferior survival in many cancers, whereas its prognostic role in diffuse large B-cell lymphoma (DLBCL) is still in controversy. Therefore, more precise risk stratification needs to be further explored for TP53-mut DLBCL patients. A set of 2637 DLBCL cases from multiple cohorts, was enrolled in our analysis. Among the 2637 DLBCL patients, 14.0% patients (370/2637) had TP53-mut. Since missense mutations account for the vast majority of TP53-mut DLBCL patients, and most non-missense mutations affect the function of the P53 protein, leading to worse survival rates, we distinguished patients with missense mutations. A TP53 missense mutation risk model was constructed based on a 150-combination machine learning computational framework, demonstrating excellent performance in predicting prognosis. Further analysis revealed that patients with high-risk missense mutations are significantly associated with early progression and exhibit dysregulation of multiple immune and metabolic pathways at the transcriptional level. Additionally, the high-risk group showed an absolutely suppressed immune microenvironment. To stratify the entire cohort of TP53-mut DLBCL, we combined clinical characteristics and ultimately constructed the TP53 Prognostic Index (TP53PI) model. In summary, we identified the truly high-risk TP53-mut DLBCL patients and explained this difference at the mutation and transcriptional levels.

MRI evaluation of cranial nerve abnormalities and extraocular muscle fibrosis in duane retraction syndrome and congenital extraocular muscle fibrosis.

PURPOSE: To investigate the alterations in extraocular muscles (EOMs) by magnetic resonance imaging (MRI) among patients diagnosed with Duane retraction yndrome (DRS) and congenital fibrosis of the extraocular muscles (CFEOM), who present with various cranial nerve anomalies in an attempt to enhance the clinical diagnostic process. METHODS: A case-control study was conducted to evaluate 27 patients with DRS and 14 patients with CFEOM. All patients underwent MRI scans of the brainstem and orbital examination. Neurodevelopmental assessments were conducted through MRI, and maximum cross-sectional area and volumes of EOMs were obtained. Three types of models were constructed using machine learning decision tree algorithms based on EOMs to predict disease diagnosis, cranial nerve abnormalities, and clinical subtypes. RESULTS: Patients with bilateral CN VI abnormalities had smaller volumes of LR, MR, and IR muscles compared to those with unilateral involvement (P < 0.05). Similarly, patients with CFEOM and unilateral third cranial nerve abnormalities had a smaller maximum cross-section of the affected eye's SR compared to the contralateral eye (P < 0.05). In patients with both CN III and CN VI abnormalities, the volume of SR was smaller than in patients with CN III abnormalities alone (P < 0.05). The prediction model using EOMs volume showed a diagnostic precision of 82.5% for clinical cases and 60.1% for predicting cranial nerve abnormalities. Nonetheless, the precision for identifying clinical subtypes was relatively modest, at only 41.7%. CONCLUSION: The distinctive volumetric alterations in EOMs among individuals exhibiting distinct cranial nerve anomalies associated with DRS or CFEOM provide valuable diagnostic insights into to Congenital Cranial Neurodevelopmental Disorders (CCDDs). MRI analysis of EOMs should thus be regarded as a crucial diagnostic modality.

Role of plasma fatty acid in age-related macular degeneration: insights from a mendelian randomization analysis.

BACKGROUND: An imbalance in lipid metabolism has been linked to the development of AMD, but the causal relationship between AMD and plasma fatty acids (FAs) remains controversial. Using a two-sample Mendelian randomization (MR) approach, we sought to evaluate the impact of specific FA plasma levels on the risk of different AMD subtypes. METHODS: We analysed genome-wide association data of circulating FAs from 115,006 European-descended individuals in the UK Biobank. These data were used in a two-sample MR framework to assess the potential role of circulating FAs in developing wet and dry AMD. Sensitivity analyses were conducted to ensure the robustness of our findings. Additional multivariable and locus-specific MR analyses were conducted to evaluate direct effects of FA on AMD subtypes, minimizing biases from lipoprotein-related traits and triglycerides. RESULTS: Mendelian randomization revealed associations of omega-3 was associated with decreased wet (OR 0.78, 95%CI 0.66-0.92) and dry AMD (0.85, 0.74-0.97) risk, showed a protective effect on AMD. Notably, the omega-6 to omega-3 ratio showed potential causal effects on both wet (1.27, 1.03-1.56) and dry AMD (1.18, 1.02-1.37). Multivariable MR suggested that the causal relationship of omega-3, omega-6 to omega-3 ratio on wet AMD persists after conditioning on HDL, LDL and triglycerides, albeit with slightly diminished evidence strength. Locus-specific MR linked to omega-3(FADS1, 0.89, 0.82-0.98; FADS2, 0.88, 0.81-0.96) and omega-6 to omega-3 ratio (FADS1, 1.10, 1.02-1.20; FADS2, 1.11, 1.03-1.20) suggests causal effects of these factors on wet AMD. CONCLUSIONS: The associations between plasma FA concentrations and AMD, suggest potential causal role of omega-3, and the omega-6 to omega-3 ratio in wet AMD. These results underscore the impact of an imbalanced circulating omega-3 and omega-6 FA ratio on AMD pathophysiology from MR perspective.

Comprehensive analysis of strabismus reoperations: clinical insights and progression factors.

BACKGROUND: To compare and analyze clinical characteristics of patients undergoing two surgeries and multiple surgeries and explore relevant factors to lay the foundation for clinical prediction. METHODS: A retrospective analysis was conducted on clinical data from all patients who underwent twice and multiple strabismus surgeries at Tianjin Eye Hospital between October 2012 and September 2021. Patients were divided into Group A (two surgeries) and Group B (more than two surgeries) based on the cumulative number of surgeries performed. Clinical details at the first recurrence, including sex, age, native place, overall medical history, onset time, visual acuity, affected muscle(s), etc., were documented. Non-parametric tests and chi-square tests were used to analyze clinical characteristics in each group. Binary and ordered logistic regression analysis assessed parameters associated with multiple reoperations. A linear mixed-term model observed factors impacting affected muscle(s) during surgery. Researchers examined clinical traits related to secondary strabismus variables. RESULTS: Among the 910 included patients, 840 required two surgeries (Group A) and 70 underwent more than two surgeries (Group B). Significant differences were found in age, onset time, interval time, and secondary factors. Regression analysis highlighted the significant impact of interval time on the reoperation rate, effectively predicting outcomes in patients with concomitant strabismus. Other ophthalmoplegia and secondary factors significantly influenced reoperation rates in patients with non-concomitant strabismus. Interval time, esotropia, and exotropia were linked to concomitant secondary strabismus patients, while the number of surgeries, DVD, esotropia, exotropia, and esotropia V-pattern were associated with non-concomitant secondary strabismus patients. In a longitudinal study, patients with multiple surgeries showed a correlation between the vertical deviation angle magnitude and the number of involved extraocular muscles. Regression analysis revealed that in patients with concomitant strabismus, interval time, exotropia, and esotropia influenced the total number of muscles during surgery. For patients with non-concomitant strabismus, interval time, secondary factors, and SOP impacted the total number of muscles during surgery. CONCLUSIONS: Interval time in patients with concomitant strabismus, as well as secondary and other ophthalmoplegia in non-concomitant strabismus, are the main factors for multiple reoperations.

Selective and effective suppression of pancreatic cancer through MNK inhibition.

OBJECTIVE: The study aimed to explore the role of the Wnt/ß-catenin signaling pathway in pancreatic cancer progression and chemoresistance, with a focus on identifying specific factors that distinguish between normal and tumor cells, thereby offering potential therapeutic targets. MATERIALS AND METHODS: We analyzed levels of total and phosphorylated eukaryotic translation initiation factor 4E (eIF4E) and ß-catenin in pancreatic cancer and normal pancreatic tissues. Functional assays were used to assess the impact of eIF4E phosphorylation on ß-catenin signaling, cell proliferation, and chemoresistance, with MNK kinase involvement determined through gene depletion studies. The MNK kinase inhibitor eFT508 was evaluated for its effects on eIF4E phosphorylation, ß-catenin activation, and cell viability in both in vitro and in vivo models of pancreatic cancer. RESULTS: Both total and phosphorylated eIF4E, along with ß-catenin, were significantly elevated in pancreatic cancer tissues compared to normal tissues. Phosphorylation of eIF4E at serine 209 was shown to activate ß-catenin signaling, enhance cell proliferation, and contribute to chemoresistance in pancreatic cancer. Importantly, these effects were dependent on MNK kinase activity. Depletion of eIF4E reduced cell viability in both pancreatic cancer and normal cells, while depletion of MNK selectively decreased viability in pancreatic cancer cells. Treatment with eFT508 effectively inhibited eIF4E phosphorylation, suppressed ß-catenin activation, and reduced pancreatic cancer cell growth and survival in vitro and in vivo, with minimal impact on normal cells.Conclusions: The MNK-eIF4E-ß-catenin axis plays a critical role in pancreatic cancer progression and chemoresistance, distinguishing pancreatic cancer cells from normal cells. Targeting MNK kinases with inhibitors like eFT508 presents a promising therapeutic strategy for pancreatic cancer, with potential for selective efficacy and reduced toxicity.