Outcomes in non-small cell lung cancer with uncommon epidermal growth factor receptor L858 substitutions under first-line epidermal growth factor receptor tyrosine kinase inhibitors: A large real-world cohort study.

Atypical L858R or other L858X mutations in the epidermal growth factor receptor (EGFR) gene, beyond the classical EGFRL858R mutation caused by c.2573 T > G, have been identified in non-small cell lung cancer (NSCLC), yet their genomic features and survival benefits with EGFR tyrosine kinase inhibitor (TKI) treatment have not been fully explored. We retrospectively enrolled 489 NSCLC patients with baseline tumor tissue/plasma samples carrying uncommon EGFRL858R (N = 124), EGFRL858Q/M (N = 17), or classical EGFRL858R mutations (N = 348). The comparison of molecular features was performed using treatment-naïve tumor tissues. Survival benefits and resistance mechanisms of first-line EGFR TKI treatment were studied in an advanced disease subcohort. NSCLCs harboring uncommon EGFRL858R had lower TP53 mutation prevalence (p = 0.04) and chromosome instability scores (p = 0.02) than those with classical EGFRL858R. Concomitant EGFRL861Q mutations were enriched in NSCLCs with EGFRL858Q/M (p < 0.01), with cooccurrence in those carrying EGFRL858M. Patients with uncommon EGFRL858R experienced improved progression-free survival (PFS) compared to those with classical EGFRL858R (median: 13.0 vs. 10.0 months, hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.41-0.80). The association remained significant when adjusting for sex, age, histological subtype, TKI category, and anti-vascular therapy (HR: 0.55, 95% CI: 0.39-0.77). Furthermore, EGFRL858Q/M patients showed enhanced first-line PFS (vs. classical EGFRL858R, HR: 0.26, 95% CI: 0.10-0.67), potentially benefiting more from afatinib. Additionally, NSCLCs with uncommon EGFRL858R and classical EGFRL858R had similar resistance profiles to EGFR TKIs. In conclusion, NSCLCs carrying atypical EGFR L858 aberrations, which had fewer TP53 mutations and higher chromosome stability, exhibited improved PFS under first-line EGFR TKIs than those with the classical EGFRL858R.

Inhibition of PI3K p110δ rebalanced Th17/Treg and reduced macrophages pyroptosis in LPS-induced sepsis.

Sepsis is a systemic inflammatory response syndrome caused by trauma or infection, which can lead to multiple organ dysfunction. In severe cases, sepsis can also progress to septic shock and even death. Effective treatments for sepsis are still under development. This study aimed to determine if targeting the PI3K/Akt signaling with CAL-101, a PI3K p110δ inhibitor, could alleviate lipopolysaccharide (LPS)-induced sepsis and contribute to immune tolerance. Our findings indicated that CAL-101 treatment improved survival rates and alleviated the progression of LPS-induced sepsis. Compared to antibiotics, CAL-101 not only restored the Th17/regulatory T cells (Treg) balance but also enhanced Treg cell function. Additionally, CAL-101 promoted type 2 macrophage (M2) polarization, inhibited TNF-α secretion, and increased IL-10 secretion. Moreover, CAL-101 treatment reduced pyroptosis in peritoneal macrophages by inhibiting caspase-1/gasdermin D (GSDMD) activation. This study provides a mechanistic basis for future clinical exploration of targeted therapeutics and immunomodulatory strategies in the treatment of sepsis.

Boundary-Rich Carbon-Based Electrocatalysts with Manganese(II)-Coordinated Active Environment for Selective Synthesis of Hydrogen Peroxide.

Coordinated manganese (Mn) electrocatalysts owing to their electronic structure flexibility, non-toxic and earth abundant features are promising for electrocatalytic reactions. However, achieving selective hydrogen peroxide (H2 O2 ) production through two electron oxygen reduction (2e-ORR) is a challenge on Mn-centered catalysts. Targeting this goal, we report on the creation of a secondary Mn(II)-coordinated active environment with reactant enrichment effect on boundary-rich porous carbon-based electrocatalysts, which facilitates the selective and rapid synthesis of H2 O2 through 2e-ORR. The catalysts exhibit nearly 100 % Faradaic efficiency and H2 O2 productivity up to 15.1 mol gcat -1 h-1 at 0.1 V versus reversible hydrogen electrode, representing the record high activity for Mn-based electrocatalyst in H2 O2 electrosynthesis. Mechanistic studies reveal that the epoxide and hydroxyl groups surrounding Mn(II) centers improve spin state by modifying electronic properties and charge transfer, thus tailoring the adsorption strength of *OOH intermediate. Multiscale simulations reveal that the high-curvature boundaries facilitate oxygen (O2 ) adsorption and result in local O2 enrichment due to the enhanced interaction between carbon surface and O2 . These merits together ensure the efficient formation of H2 O2 with high local concentration, which can directly boost the tandem reaction of hydrolysis of benzonitrile to benzamide with nearly 100 % conversion rate and exclusive benzamide selectivity.

Multi-biomarker combination detection system for diagnosis and classification of dry eye disease by imaging of a multi-channel metasurface.

Dry eye disease (DED) is one of the most common ocular surface diseases, characterized by unstable tear film and ocular inflammation, affecting hundreds of millions of people worldwide. Currently, the clinical diagnosis of DED mainly relies on physical methods such as optical microscopy and ocular surface interferometric imaging, but classifying DED is still difficult. Here, we propose a compact and portable immune detection system based on the direct imaging of a nanophotonic metasurface with gradient geometry, for fast and ultra-sensitive detection of multiple biomarkers (i.e. Matrix metalloproteinase-9 (MMP-9), Lipocalin-1 (LCN-1), Lactoferrin (LTF)) in tears for the diagnosis and classification of DED. This centimeter-scale concentric nanophotonic metasurface, which consists of millions of unique metallic nanostructures, was fabricated through a cost-effective nanoimprint lithography (NIL) process. The immune detection system based on the antibody-modified metasurface shows favorable detection selectivity, an ultra-high sensitivity (3350 pixels/Refractive Index Unit (RIU)) and low limit of detection (LOD) (0.3 ng/mL for MMP-9, 1 ng/mL for LTF, and 0.5 ng/mL for LCN-1). Further clinical sampling and detection results demonstrated that this multi-biomarker detection system enabled accurate determination and symptom classification of DED, manifesting high correlation and consistency with clinical diagnosis results. The advantages such as low sample consumption, one-step detection, simple operation, and simultaneous detection of multiple biomarkers make the platform promising for screening and detecting a broader range of biomarker combinations in clinical practice.

Field investigation combined with modeling uncovers the ecological heterogeneity of Aedes albopictus habitats for strategically improving systematic management during urbanization.

BACKGROUND: Aedes albopictus is an invasive vector of serious Aedes-borne diseases of global concern. Habitat management remains a critical factor for establishing a cost-effective systematic strategy for sustainable vector control. However, the community-based characteristics of Ae. albopictus habitats in complex urbanization ecosystems are still not well understood. METHODS: A large-scale investigation of aquatic habitats, involving 12 sites selected as representative of four land use categories at three urbanization levels, was performed in Guangzhou, China during 2015-2017. The characteristics and dynamics of these Ae. albopictus habitats were assessed using habitat-type composition, habitat preference, diversity indexes and the Route index (RI), and the temporal patterns of these indexes were evaluated by locally weighted scatterplot smoothing models. The associations of RI with urbanization levels, land use categories and climatic variables were inferred using generalized additive mixed models. RESULTS: A total of 1994 potential habitats and 474 Ae. albopictus-positive habitats were inspected. The majority of these habitats were container-type habitats, with Ae. albopictus showing a particularly higher habitat preference for plastic containers, metal containers and ceramic vessels. Unexpectedly, some non-container-type habitats, especially ornamental ponds and surface water, were found to have fairly high Ae. albopictus positivity rates. Regarding habitats, the land use category residential and rural in Jiangpu (Conghua District, Guangzhou) had the highest number of Ae. albopictus habitats with the highest positive rates. The type diversity of total habitats (H-total) showed a quick increase from February to April and peaked in April, while the H-total of positive habitats (H-positive) and RIs peaked in May. RIs mainly increased with the monthly average daily mean temperature and monthly cumulative rainfall. We also observed the accumulation of diapause eggs in the winter and diapause termination in the following March. CONCLUSIONS: Ecological heterogeneity of habitat preferences of Ae. albopictus was demonstrated in four land use categories at three urbanization levels. The results reveal diversified habitat-type compositions and significant seasonal variations, indicating an ongoing adaptation of Ae. albopictus to the urbanization ecosystem. H-positivity and RIs were inferred as affected by climatic variables and diapause behavior of Ae. albopictus, suggesting that an effective control of overwintering diapause eggs is crucial. Our findings lay a foundation for establishing a stratified systematic management strategy of Ae. albopictus habitats in cities that is expected to complement and improve community-based interventions and sustainable vector management.

Clinical characteristics and risk factors of acute acquired concomitant esotropia in last 5 years: a retrospective case-control study.

OBJECTIVES: A remarkable increase in the number and proportion of surgical patients with acute acquired concomitant esotropia (AACE) has been noted in our hospital in recent years. We aimed to analyse the clinical characteristics and associated risk factors of this increasing number of strabismus in last 5 years. METHODS: Medical information was obtained in 62 AACE patients and 73 orthotropic patients as control group completed questionnaires and examination items from March 2017 to May 2020. Data included age at onset, refractive error, angle of deviation, binocular vision, eye care habits, and optical quality of spectacles. RESULTS: Of the 62 AACE patients, the mean ± standard deviation age at onset was 25.3 ± 8.5 years, with 47 (75.8%) cases showing myopia, 9 (14.5%) showing emmetropia, and 6 (9.7%) showing hypermetropia. Among the AACE patients, 35 (56.5%) performed >8 h of close work daily and 36 (58.1%) reported late-night use of digital devices. When compared with the control group, the risk factors identified for AACE included long durations of close work (odds ratio [OR], 11.72; 95% confidence interval [CI], 3.53-38.91; P < 0.001) and immoderate late-night use of digital devices (OR, 14.29; 95% CI, 4.10-49.72; P < 0.001). CONCLUSION: Our study demonstrated that young adults accounted for the majority of the growing number of individuals affected by AACE in last 5 years, and excessive close visual activities and immoderate late-night use of digital devices were found to be associated with the onset of AACE.

Changes in Retinal Vessel Flow after Small Incision Lenticule Extraction.

Objective: In order to analyze changes in retinal vessel flow after small incision lenticule extraction (SMILE). Methods: A total of 32 patients (62 eyes) who underwent SMILE were enrolled in this prospective study. Optical parameters, including vessel density (VD), and perfusion density (PD) of foveal, parafoveal, and perifoveal regions, respectively, were measured before surgery and at 1 day, 1 week, 1 month, and 3 months postoperation. Preoperative parameters and surgical parameters were recorded. Results: Significant decreases in VD and PD on postoperative day 1 were detected in all quadrants, both in 3 mm and in 6 mm regions (P < 0.001). One month after surgery, VD returned to preoperative levels. None of the preoperative and surgical parameters were significantly correlated with the VD and PD fluctuations (all P > 0.05). Conclusion. VD may decrease significantly with regional disparity 1 day after SMILE while recovering at 1 month. Elevation of intraocular pressure due to suction may account for such changes.

Recharacterization of superior limbic keratoconjunctivitis via a subdividing grading method in 236 Chinese patients.

PURPOSE: Superior limbic keratoconjunctivitis (SLK) is an uncommon and often overlooked chronic ocular surface disease. This retrospective consecutive case series study on Chinese patients aimed to characterize the features of this disease, including those undescribed in previous literature. METHODS: Two hundred thirty-six patients diagnosed with SLK were enrolled into this consecutive case study from 2016 to 2019. The demographics, symptoms, Ocular Surface Disease Index, and ocular signs were collected and analyzed. A scoring system (SLK scale index, SSI) that integrated five major sign scores was applied to evaluate SLK severity. RESULTS: Of the 236 SLK patients, dryness was the most common complaint (59.3%). Of 459 SLK eyes, superior limbus/conjunctival staining (SCS) was present in 98% eyes, followed by the superior tarsal conjunctival alterations (85.2%) and superior bulbar conjunctiva hyperemia (80.8%). Approximately 63% of eyes were accompanied by corneal staining. Superior bulbar conjunctivochalasis was a relatively rare sign (41.6%). Among the five major signs, only the prevalence of SCS gradually increased with its severity. In addition, fluorescein staining at the inferior limbus and adjacent conjunctiva (ICS) was found positive in 163 eyes of 84 patients (36%) who had significantly higher SSI than those without ICS (p = 0.013). CONCLUSIONS: We found that SCS is the most common out of the 5 typical signs of SLK. ICS, a new sign, occurred in one-third of patients. SCS, a simple marker of SLK, as well as SSI, an integrated evaluation system, had the advantage of evaluating the severity and objectively characterizing SLK in clinical practice.

MicroRNA-873 inhibits colorectal cancer metastasis by targeting ELK1 and STRN4.

MicroRNAs (miRNAs) are a group of small non-coding RNAs that directly bind to the 3'-untranslated-region (3'UTR) of mRNA, thereby blocking gene expression post-transcriptionally. Accumulating evidence prove that microRNA-873 (miR-873) functions as a promoter or suppressor in various cancers, while whether it affects the progression of colorectal cancer (CRC) is yet unknown. Here we found that miR-873 was downregulated in human CRC clinical samples, mouse CRC specimens and cell lines with high metastatic potential. We also demonstrated that low miR-873 expression was closely associated with poor prognosis of CRC. Overexpressing miR-873 suppressed proliferation and metastasis of CRC cells both in vitro and in vivo, while inhibiting miR-873 expression promoted the proliferation, migration and invasion in vitro. Moreover, miR-873 exerted its function by perturbing the ERK-CyclinD1 pathway and the epithelial-mesenchymal transition (EMT) process. Furthermore, we revealed that miR-873 acted as a tumor-suppressive microRNA by directly binding to the 3'UTRs of ELK1 and STRN4 and suppressed their expression. Our study uncovered an inhibitory role of miR-873 in CRC progression and might provide a promising marker for CRC diagnosis and prognosis.

Quantitative Analysis of the Bacteria in Blepharitis With Demodex Infestation.

Bacterial infection or Demodex infestation has been reported to contribute to chronic blepharitis. The association between Demodex mites and bacterial flora in this disease remains to be elucidated. Fifty-six consecutive patients diagnosed with chronic blepharitis and 46 healthy volunteers were recruited for this study. Using specimens of three epilated eyelashes and lid margin swabs, Demodex were identified microscopically and bacteria were determined by cultures, followed by colony counting and mass spectrometry. We found 191 Demodex mites, 161 D. folliculorum and 30 D. brevis, in 45 patients. Correspondingly, 101 Demodex, 63 D. folliculorum and 38 D. brevis, were found in 21 controls (p < 0.05, both). Bacterial culture-positivity was obtained in samples (eyelashes, lid margins, or both) from 54 patients and in eyelashes from 37 controls. The total colony counts and the incidences and colony counts of Propinibacterium acnes and Staphylococcus aureus from patients' eyelashes were significantly higher than that of the controls. Furthermore, bacterial colony counts in blepharitis patients' eyelashes with D. folliculorum were higher than that of controls with D. folliculorum (p < 0.01). Similarly, P. acnes colonies increased significantly in patients' eyelashes with D. folliculorum (p < 0.05). These results suggest that D. folliculorum and P. acnes have a role in the occurrence of the chronic blepharitis. Further studies are required to reveal the relationship between these two organisms in blepharitis.