Temporal coherence in an unbalanced SU(1,1) interferometer.

In classical coherence theory, coherence time is typically related to the bandwidth of the optical field. Narrowing the bandwidth by optical filtering will result in the lengthening of the coherence time. In the case of a delayed pulse photon interference, this will lead to pulse overlap and recovery of interference, which is otherwise absent due to time delay. However, this is changed for entangled optical fields. In this Letter, we investigate how the temporal coherence of the fields in a pulse-pumped SU(1,1) interferometer changes with the bandwidth of optical filtering. We find that the effect of optical filtering is not similar to the classical coherence theory in the presence of quantum entanglement. A full quantum theory is presented and can explain the phenomena well.

LSD1-Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1-Induced p62 Transcription in HCC.

BACKGROUND AND AIMS: Oxaliplatin (OXA) is one of the most common chemotherapeutics in advanced hepatocellular carcinoma (HCC), the resistance of which poses a big challenge. Long noncoding RNAs (lncRNAs) play vital roles in chemoresistance. Therefore, elucidating the underlying mechanisms and identifying predictive lncRNAs for OXA resistance is needed urgently. METHODS: RNA sequencing (RNA-seq) and fluorescence in situ hybridization (FISH) were used to investigate the OXA-resistant (OXA-R) lncRNAs. Survival analysis was performed to determine the clinical significance of homo sapiens long intergenic non-protein-coding RNA 1134 (LINC01134) and p62 expression. Luciferase, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and chromatin isolation by RNA purification (ChIRP) assays were used to explore the mechanisms by which LINC01134 regulates p62 expression. The effects of LINC01134/SP1/p62 axis on OXA resistance were evaluated using cell viability, apoptosis, and mitochondrial function and morphology analysis. Xenografts were used to estimate the in vivo regulation of OXA resistance by LINC01134/SP1/p62 axis. ChIP, cell viability, and xenograft assays were used to identify the demethylase for LINC01134 up-regulation in OXA resistance. RESULTS: LINC01134 was identified as one of the most up-regulated lncRNAs in OXA-R cells. Higher LINC01134 expression predicted poorer OXA therapeutic efficacy. LINC01134 activates anti-oxidative pathway through p62 by recruiting transcription factor SP1 to the p62 promoter. The LINC01134/SP1/p62 axis regulates OXA resistance by altering cell viability, apoptosis, and mitochondrial homeostasis both in vitro and in vivo. Furthermore, the demethylase, lysine specific demethylase 1 (LSD1) was responsible for LINC01134 up-regulation in OXA-R cells. In patients with HCC, LINC01134 expression was positively correlated with p62 and LSD1 expressions, whereas SP1 expression positively correlated with p62 expression. CONCLUSIONS: LSD1/LINC01134/SP1/p62 axis is critical for OXA resistance in HCC. Evaluating LINC01134 expression in HCC will be effective in predicting OXA efficacy. In treatment-naive patients, targeting the LINC01134/SP1/p62 axis may be a promising strategy to overcome OXA chemoresistance.

Propagation of temporal mode multiplexed optical fields in fibers: influence of dispersion.

Exploiting two interfering fields which are initially in the same temporal mode but with the spectra altered by propagating through different fibers, we characterize how the spectral profiles of temporal modes change with the fiber induced dispersion by measuring the fourth-order interference when the order number and bandwidth of temporal modes are varied. The experiment is done by launching a pulsed field in different temporal modes into an unbalanced Mach-Zehnder interferometer, in which the fiber lengths in two arms are different. The results show that the mode mismatch of two interfering fields, reflected by the visibility and pattern of interference, is not only dependent upon the amount of unbalanced dispersion but also related to the order number of temporal mode. In particular, the two interfering fields may become orthogonal under a modest amount of unbalanced dispersion when the mode number of the fields is k ≥ 2. Moreover, we discuss how to recover the spectrally distorted temporal mode by measuring and compensating the transmission induced dispersion. Our investigation paves the way for further investigating the distribution of temporally multiplexed quantum states in fiber network.

64Cu-labeled daratumumab F(ab')2 fragment enables early visualization of CD38-positive lymphoma.

PURPOSE: Abnormal CD38 expression in some hematologic malignancies, including lymphoma, has made it a biomarker for targeted therapies. Daratumumab (Dara) is the first FDA-approved CD38-specific monoclonal antibody, enabling successfully immunoPET imaging over the past years. Radiolabeled Dara however has a long blood circulation and delayed tumor uptake which can limit its applications. The focus of this study is to develop 64Cu-labeled Dara-F(ab')2 for the visualization of CD38 in lymphoma models. METHODS: F(ab')2 fragment was prepared from Dara using an IdeS enzyme and purified with Protein A beads. Western blotting, flow cytometry, and surface plasmon resonance (SPR) were performed for in vitro assay. Probes were labeled with 64Cu after the chelation of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Small animal PET imaging and quantitative analysis were performed after injection of 64Cu-labeled Dara-F(ab')2, IgG-F(ab')2, and Dara for evaluation in lymphoma models. RESULTS: Flow cytometry and SPR assay proved the specific binding ability of Dara-F(ab')2 and NOTA-Dara-F(ab')2 in vitro. Radiolabeling yield of [64Cu]Cu-NOTA-Dara-F(ab')2 was over 90% and with a specific activity of 4.0 ± 0.6 × 103 MBq/µmol (n = 5). PET imaging showed [64Cu]Cu-NOTA-Dara-F(ab')2 had a rapid and high tumor uptake as early as 2 h (6.9 ± 1.2%ID/g) and peaked (9.5 ± 0.7%ID/g) at 12 h, whereas [64Cu]Cu-NOTA-Dara reached its tumor uptake peaked at 48 h (8.3 ± 1.4%ID/g, n = 4). In comparison, IgG-F(ab')2 and HBL-1 control groups found no noticeable tumor uptake. [64Cu]Cu-NOTA-Dara-F(ab')2 had significantly lower uptake in blood pool, bone, and muscle than [64Cu]Cu-NOTA-Dara and its tumor-to-blood and tumor-to-muscle ratios were significantly higher than controls. CONCLUSIONS: [64Cu]Cu-NOTA-Dara-F(ab')2 showed a rapid and high tumor uptake in CD38-positive lymphoma models with favorable imaging contrast, showing its promise as a potential PET imaging agent for future clinical applications.

Risk of de novo cancer after premenopausal bilateral oophorectomy.

BACKGROUND: Hysterectomy is one of the most frequent gynecologic surgeries in the United States. Women undergoing hysterectomy are commonly offered bilateral oophorectomy for ovarian and breast cancer prevention. Although bilateral oophorectomy may dramatically reduce the risk of gynecologic cancers, some studies suggested that bilateral oophorectomy may be associated with an increased risk of other types of cancer, such as lung cancer and colorectal cancer. However, the results are conflicting. OBJECTIVE: To study the association between bilateral oophorectomy and the risk of subsequent cancer of any type. STUDY DESIGN: This population-based cohort study included all premenopausal women who underwent bilateral oophorectomy for a nonmalignant indication before the age of 50, between January 1, 1988 and December 31, 2007 in Olmsted County, Minnesota, and a random sample of age-matched (±1 year) referent women who did not undergo bilateral oophorectomy. Women with cancer before oophorectomy (or index date) or within 6 months after the index date were excluded. Time-to-event analyses were performed to assess the risk of de novo cancer. Cancer diagnosis and type were confirmed using medical record review. RESULTS: Over a median follow-up of 18 years, the risk of any cancer did not significantly differ between the 1562 women who underwent bilateral oophorectomy before natural menopause and the 1610 referent women (adjusted hazard ratio, 0.82; 95% confidence interval, 0.66-1.03). However, women who underwent bilateral oophorectomy had a decreased risk of gynecologic cancers (adjusted hazard ratio, 0.15; 95% confidence interval, 0.06-0.34) but not of nongynecologic cancers (adjusted hazard ratio, 0.99; 95% confidence interval, 0.78-1.26). In particular, the risk of breast cancer, gastrointestinal cancer, and lung cancer did not differ between these 2 cohorts. Use of estrogen therapy through the age of 50 years in women who underwent bilateral oophorectomy did not modify the results. CONCLUSION: Women who underwent bilateral oophorectomy before menopause have a reduced risk of gynecologic cancer but not of other types of cancer including breast cancer. Women at average risk of ovarian cancer should not consider bilateral oophorectomy for the prevention of breast cancer or other nongynecologic cancers.

FHIR-Ontop-OMOP: Building clinical knowledge graphs in FHIR RDF with the OMOP Common data Model.

BACKGROUND: Knowledge graphs (KGs) play a key role to enable explainable artificial intelligence (AI) applications in healthcare. Constructing clinical knowledge graphs (CKGs) against heterogeneous electronic health records (EHRs) has been desired by the research and healthcare AI communities. From the standardization perspective, community-based standards such as the Fast Healthcare Interoperability Resources (FHIR) and the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) are increasingly used to represent and standardize EHR data for clinical data analytics, however, the potential of such a standard on building CKG has not been well investigated. OBJECTIVE: To develop and evaluate methods and tools that expose the OMOP CDM-based clinical data repositories into virtual clinical KGs that are compliant with FHIR Resource Description Framework (RDF) specification. METHODS: We developed a system called FHIR-Ontop-OMOP to generate virtual clinical KGs from the OMOP relational databases. We leveraged an OMOP CDM-based Medical Information Mart for Intensive Care (MIMIC-III) data repository to evaluate the FHIR-Ontop-OMOP system in terms of the faithfulness of data transformation and the conformance of the generated CKGs to the FHIR RDF specification. RESULTS: A beta version of the system has been released. A total of more than 100 data element mappings from 11 OMOP CDM clinical data, health system and vocabulary tables were implemented in the system, covering 11 FHIR resources. The generated virtual CKG from MIMIC-III contains 46,520 instances of FHIR Patient, 716,595 instances of Condition, 1,063,525 instances of Procedure, 24,934,751 instances of MedicationStatement, 365,181,104 instances of Observations, and 4,779,672 instances of CodeableConcept. Patient counts identified by five pairs of SQL (over the MIMIC database) and SPARQL (over the virtual CKG) queries were identical, ensuring the faithfulness of the data transformation. Generated CKG in RDF triples for 100 patients were fully conformant with the FHIR RDF specification. CONCLUSION: The FHIR-Ontop-OMOP system can expose OMOP database as a FHIR-compliant RDF graph. It provides a meaningful use case demonstrating the potentials that can be enabled by the interoperability between FHIR and OMOP CDM. Generated clinical KGs in FHIR RDF provide a semantic foundation to enable explainable AI applications in healthcare.

FOXO3A-induced LINC00926 suppresses breast tumor growth and metastasis through inhibition of PGK1-mediated Warburg effect.

Phosphoglycerate kinase 1 (PGK1), a critical component of the glycolytic pathway, relates to the development of various cancers. However, the mechanisms of PGK1 inhibition and physiological significance of PGK1 inhibitors in cancer cells are unclear. Long non-coding RNAs (lncRNAs) play a vital role in tumor growth and progression. Here, we identify a lncRNA LINC00926 that negatively regulates PGK1 expression and predicts good clinical outcome of breast cancer. LINC00926 downregulates PGK1 expression through the enhancement of PGK1 ubiquitination mediated by E3 ligase STUB1. Moreover, hypoxia inhibits LINC00926 expression and activates PGK1 expression largely through FOXO3A. FOXO3A/LINC00926/PGK1 axis regulates breast cancer glycolysis, tumor growth, and lung metastasis both in vitro and in vivo. In breast cancer patients, LINC00926 expression is negatively correlated with PGK1 and positively correlated with FOXO3A expression. Our work established FOXO3A/LINC00926/PGK1 as a critical axis to regulate breast cancer growth and progression. Targeting PGK1 or supplement of LINC00926 or FOXO3A could be potential therapeutic strategies in breast cancer.

ImmunoPET of CD146 in Orthotopic and Metastatic Breast Cancer Models.

The overexpression of CD146 in breast cancer is considered a hallmark of tumor progression and metastasis, particularly in triple negative breast cancer. Aimed at imaging differential CD146 expressions in breast cancer, a noninvasive method for predictive prognosis and diagnosis was investigated using a 64Cu-labeled CD146-specific monoclonal antibody, YY146. CD146 expression was screened in human breast cancer cell lines using Western blotting. Binding ability was evaluated using flow cytometry and immunofluorescent staining. YY146 was conjugated with 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with 64Cu following standard procedures. Serial PET or PET/CT imaging was performed in orthotopic and metastatic breast cancer tumor models. Biodistribution was performed after the final time point of imaging. Finally, tissue immunofluorescent staining and hematoxylin and eosin (H&E) staining were performed on tumor tissues. The MDA-MB-435 cell line showed the highest CD146 expression level, whereas MCF-7 had the lowest level at the cellular level. ImmunoPET showed that MDA-MB-435 orthotopic tumors had high and clear radioactive accumulation after the administration of 64Cu-NOTA-YY146. The tumor uptake of 64Cu-NOTA-YY146 in MDA-MB-435 was significantly higher than that in MCF-7 and nonspecific IgG control groups (P < 0.01). Biodistribution verified the PET imaging results. For metastatic models, 64Cu-NOTA-YY146 allowed for the visualization of high radioactivity accumulation in metastatic MDA-MB-435 tumors, which was confirmed by ex vivo biodistribution of lung tissues. H&E staining proved the successful building of metastatic tumor models. Immunofluorescent staining verified the differential expression of CD146 in orthotopic tumors. Therefore, 64Cu-NOTA-YY146 could be used as an immunoPET probe to visualize CD146 in the breast cancer model and is potentially useful for cancer diagnosis, prognosis prediction, and monitoring therapeutic response.

Intracellular signaling pathway in dendritic cells and antigen transport pathway in vivo mediated by an OVA@DDAB/PLGA nano-vaccine.

BACKGROUND: Poly(D, L-lactic-co-glycolic acid) (PLGA) nanoparticles have potential applications as a vaccine adjuvant and delivery system due to its unique advantages as biodegradability and biocompatibility. EXPERIMENTAL: We fabricated cationic solid lipid nanoparticles using PLGA and dimethyl-dioctadecyl-ammonium bromide (DDAB), followed by loading of model antigen OVA (antigen ovalbumin, OVA257-264) to form an OVA@DDAB/PLGA nano-vaccine. And we investigated the intracellular signaling pathway in dendritic cells in vitro and antigen transport pathway and immune response in vivo mediated by an OVA@DDAB/PLGA nano-vaccine. RESULTS: In vitro experiments revealed that the antigen uptake of BMDCs after nanovaccine incubation was two times higher than pure OVA or OVA@Al at 12 h. The BMDCs were well activated by p38 MAPK signaling pathway. Furthermore, the nano-vaccine induced antigen escape from lysosome into cytoplasm with 10 times increased cross-presentation activity than those of OVA or OVA@Al. Regarding the transport of antigen into draining lymph nodes (LNs), the nano-vaccine could rapidly transfer antigen to LNs by passive lymphatic drainage and active DC transport. The antigen+ cells in inguinal/popliteal LNs for the nano-vaccine were increased over two folds comparing to OVA@Al and OVA at 12 h. Moreover, the antigen of nano-vaccine stayed in LNs for over 7 days, germinal center formation over two folds higher than those of OVA@Al and OVA. After immunization, the nano-vaccine induced a much higher ratio of IgG2c/IgG1 than OVA@Al. It also effectively activated CD4+ T, CD8+ T and B cells for immune memory with a strong cellular response. CONCLUSION: These results indicated that DDAB/PLGA NP was a potent platform to improve vaccine immunogenicity by p38 signaling pathway in BMDCs, enhancing transport of antigens to LNs, and higher immunity response.

Direct Temporal Mode Measurement for the Characterization of Temporally Multiplexed High Dimensional Quantum Entanglement in Continuous Variables.

Field-orthogonal temporal mode analysis of optical fields has recently been developed for a new framework of quantum information science. However, so far, the exact profiles of the temporal modes are not known, which makes it difficult to achieve mode selection and demultiplexing. Here, we report a novel method that measures directly the exact form of the temporal modes. This, in turn, enables us to make mode-orthogonal homodyne detection with mode-matched local oscillators. We apply the method to a pulse-pumped, specially engineered fiber parametric amplifier and demonstrate temporally multiplexed multidimensional quantum entanglement of continuous variables in telecom wavelength. The temporal mode characterization technique can be generalized to other pulse-excited systems to find their eigenmodes for multiplexing in the temporal domain.

PURB is a positive regulator of amino acid-induced milk synthesis in bovine mammary epithelial cells.

Previous studies have implicated that purine-rich element binding protein B (PURB) is a key regulator of gene transcription and cell physiology. Whether PURB plays a regulatory role in milk synthesis in bovine mammary epithelial cells (BMECs) is not known. We observed that Met and Leu increased PURB expression and nuclear localization. Overexpression of PURB led to increased milk protein and fat synthesis as well as mTOR and SREBP-1c expression whereas PURB knockdown had the opposite effects. The PI3K inhibitor wortmannin totally abolished the stimulation of Met and Leu on PURB expression, and we further confirmed that PURB was required for Met and Leu to stimulate mTOR phosphorylation and SREBP-1c expression. We also demonstrated that PURB binds to the promoters of mTOR and SREBP-1c, and these bindings were increased by Met and Leu stimulation. In summary, our data reveal that PURB is required for amino acids to stimulate mTOR and SREBP-1c gene expression, and PURB is a positive regulator of amino acid-induced PI3K-regulated milk protein and fat synthesis in BMECs.

Pulsed entanglement measured by parametric amplifier assisted homodyne detection.

Balanced homodyne detection relies on a beam splitter to superpose the weak signal input and strong local oscillator. However, recent investigation shows that a high gain phase sensitive amplifier (PSA) can be viewed as homodyne detector, in which the strong pump of PSA serves as the local oscillator [1]. Here, we analyze a new method of measuring the continuous variable entanglement by assisting a balanced homodyne detector with the PSA and implement it experimentally. Before measuring quadrature amplitude with the balanced homodyne detectors, two entangled fields generated from a pulse pumped fiber optical parametric amplifier are simultaneously coupled into the PSA. We find that the normalized noise for both the difference and sum of the quadrature amplitudes of the two entangled fields fall below the shot noise limit by about 4.6 dB, which is the record degree of entanglement measured in optical fiber systems. The experimental results illustrate that the advantages of the new measurement method include but not limit to tolerance to detection loss and characterizing entanglement with only one homodyne detector. The influence of mode-mismatching due to multi-mode property of entanglement on the measured noise reduction can also be greatly mitigated, indicating the new method is advantageous over the traditional measurement in multi-mode case.

Optimum quantum resource distribution for phase measurement and quantum information tapping in a dual-beam SU(1,1) interferometer.

Quantum entanglement is a resource in quantum metrology that can be distributed to two conjugate physical quantities for the enhancement of their measurement sensitivity. This is demonstrated in the joint measurement of phase and amplitude modulation signals in quantum dense metrology schemes. We can also devote all the quantum resource to phase measurement only, leading to the optimum sensitivity enhancement. In this paper, we experimentally implement a dual-beam sensing scheme in an SU(1,1) interferometer for the optimum quantum enhancement of phase measurement sensitivity. We demonstrate a 3.9-dB improvement in signal-to-noise ratio over the optimum classical method, and this is 3-dB better than the traditional single-beam scheme. Furthermore, such as cheme also realizes a quantum optical tap of quantum entangled fields and has the full advantages of an SU(1,1) interferometer, such as detection loss tolerance, making it more suitable for practical applications in quantum metrology and quantum information.

Loss-tolerant quantum dense metrology with SU(1,1) interferometer.

Heisenberg uncertainty relation in quantum mechanics sets the limit on the measurement precision of non-commuting observables in one system, which prevents us from measuring them accurately at the same time. However, quantum entanglement between two systems allows us to infer through Einstein-Podolsky-Rosen correlations two conjugate observables with precision better than what is allowed by Heisenberg uncertainty relation. With the help of the newly developed SU(1,) interferometer, we implement a scheme to jointly measure information encoded in multiple non-commuting observables of an optical field with a signal-to-noise ratio improvement of about 20% over the classical limit on all measured quantities simultaneously. This scheme can be generalized to the joint measurement of information in arbitrary number of non-commuting observables.

Long-distance distribution of the telecom band intensity difference squeezing generated in a fiber optical parametric amplifier.

Using an all-fiber source of pulsed twin beams, with the record intensity difference squeezing of 6.1±0.15 dB for fiber optical parametric amplifiers, we experimentally distribute the pulsed continuous variable (CV) quantum state over a long distance. After separating the signal and idler twin beams by 26 km single-mode fibers, the measured intensity difference noise is still below the shot noise limit by 2 dB. The result shows that the distribution process is only affected by the vacuum noise originated from the fiber transmission loss. The extra noise contributed by the acoustic wave Brillouin scattering and Raman scattering in 26 km transmission fibers has not been observed. The investigation is beneficial for studying long-distance CV quantum communication.

Complementary and alternative medicine use among people with asthma and health-related quality of life.

OBJECTIVE: This study investigated the relationship between complementary and alternative medicine (CAM) use and self-reported health-related quality of life among people with asthma. METHOD: Data from the 2010 Behavioral Risk Factor Surveillance System (BRFSS) survey and the 2010 Asthma Callback Survey (ACBS) were used. Survey respondents were men and women with asthma who were 18-99 years of age who responded to both surveys. RESULTS: CAM use was associated with an increase in the number of days of poor mental health (OR = 1.02, 95% CI 1.02, 1.03) and poor physical health (OR = 1.02, 95% CI 1.01, 1.02). The odds ratios are adjusted for covariates such as asthma severity, age, sex, race/ethnicity, income, and educational attainment. CAM users report more days of poor mental health (7.2 versus 4.6) and poor physical health (9.6 versus 6.5) compared with those not using CAM therapies. CONCLUSIONS: Contrary to the hypotheses, CAM use is associated with poorer health-related quality of life. Implications for research and practice are discussed in detail.

A causal multiomics study discriminates the early immune features of Ad5-vectored Ebola vaccine recipients.

The vaccine-induced innate immune response is essential for the generation of an antibody response. To date, how Ad5-vectored vaccines are influenced by preexisting anti-Ad5 antibodies during activation of the early immune response remains unclear. Here, we investigated the specific alterations in GP1,2-specific IgG-related elements of the early immune response at the genetic, molecular, and cellular levels on days 0, 1, 3, and 7 after Ad5-EBOV vaccination. In a causal multiomics analysis, distinct early immune responses associated with GP1,2-specific IgG were observed in Ad5-EBOV recipients with a low level of preexisting anti-Ad5 antibodies. This study revealed the correlates of the Ad5-EBOV-induced IgG response and provided mechanistic evidence for overcoming preexisting Ad5 immunity during the administration of Ad5-vectored vaccines.

Lumichrome from the photolytic riboflavin acts as an electron shuttle in microbial photoelectrochemical systems.

Riboflavin has been proposed to serve as an electron shuttle in photoelectrochemical systems. However, riboflavin was also observed for abiotic photolysis under illumination. Such conflicting reports raise the necessity for further investigation. In this study, riboflavin secreted by Rhodopseudomonas palustris was studied to clarify its stability and electron shuttle function under illumination. The data of high-performance liquid chromatography-mass spectrometry showed that the riboflavin was photolyzed to lumichrome in microbial photoelectrochemical systems. In addition, the anodic current increased by 75% after adding lumichrome compared with that of the control; it further demonstrated that lumichrome, not riboflavin, as an electron shuttle could facilitate microbial electron transfer. This study clarifies the mechanism of the interface process in microbial photoelectrochemical systems.

Hsa-LINC02418/mmu-4930573I07Rik regulated by METTL3 dictates anti-PD-L1 immunotherapeutic efficacy via enhancement of Trim21-mediated PD-L1 ubiquitination.

BACKGROUND: Limited response to programmed death ligand-1 (PD-L1)/programmed death 1 (PD-1) immunotherapy is a major hindrance of checkpoint immunotherapy in non-small cell lung cancer (NSCLC). The abundance of PD-L1 on the tumor cell surface is crucial for the responsiveness of PD-1/PD-L1 immunotherapy. However, the negative control of PD-L1 expression and the physiological significance of the PD-L1 inhibition in NSCLC immunotherapy remain obscure. METHODS: Bioinformatics analysis was performed to profile and investigate the long non-coding RNAs that negatively correlated with PD-L1 expression and positively correlated with CD8+T cell infiltration in NSCLC. Immunofluorescence, in vitro PD-1 binding assay, T cell-induced apoptosis assays and in vivo syngeneic mouse models were used to investigate the functional roles of LINC02418 and mmu-4930573I07Rik in regulating anti-PD-L1 therapeutic efficacy in NSCLC. The molecular mechanism of LINC02418-enhanced PD-L1 downregulation was explored by immunoprecipitation, RNA immunoprecipitation (RIP), and ubiquitination assays. RIP, luciferase reporter, and messenger RNA degradation assays were used to investigate the m6A modification of LINC02418 or mmu-4930573I07Rik expression. Bioinformatics analysis and immunohistochemistry (IHC) verification were performed to determine the significance of LINC02418, PD-L1 expression and CD8+T cell infiltration. RESULTS: LINC02418 is a negative regulator of PD-L1 expression that positively correlated with CD8+T cell infiltration, predicting favorable clinical outcomes for patients with NSCLC. LINC02418 downregulates PD-L1 expression by enhancing PD-L1 ubiquitination mediated by E3 ligase Trim21. Both hsa-LINC02418 and mmu-4930573I07Rik (its homologous RNA in mice) regulate PD-L1 therapeutic efficacy in NSCLC via Trim21, inducing T cell-induced apoptosis in vitro and in vivo. Furthermore, METTL3 inhibition via N6-methyladenosine (m6A) modification mediated by YTHDF2 reader upregulates hsa-LINC02418 and mmu-4930573I07Rik. In patients with NSCLC, LINC02418 expression is inversely correlated with PD-L1 expression and positively correlated with CD8+T infiltration. CONCLUSION: LINC02418 functions as a negative regulator of PD-L1 expression in NSCLC cells by promoting the degradation of PD-L1 through the ubiquitin-proteasome pathway. The expression of LINC02418 is regulated by METTL3/YTHDF2-mediated m6A modification. This study illuminates the underlying mechanisms of PD-L1 negative regulation and presents a promising target for improving the effectiveness of anti-PD-L1 therapy in NSCLC.

Sex Differences in the Association Between Midlife Cardiovascular Conditions or Risk Factors With Midlife Cognitive Decline.

BACKGROUND AND OBJECTIVES: The prevalence of midlife cardiovascular conditions and risk factors is higher in men than women. Associations between midlife cardiovascular conditions or risk factors and midlife cognitive decline have been reported, but few studies have assessed sex differences in these associations. METHODS: We included 1,857 participants enrolled in the population-based Mayo Clinic Study of Aging who were 50 to 69 years of age at baseline. Participants were evaluated every 15 months by a coordinator, including neurologic evaluation and neuropsychological testing. The neuropsychological testing used 9 tests to calculate global cognitive and domain-specific (memory, language, executive function, and visuospatial skills) z scores. Nurse abstractors reviewed participant medical records to determine the presence of cardiovascular conditions (coronary heart disease, arrhythmias, congestive heart failure) and risk factors (hypertension, diabetes, dyslipidemia, obesity, ever smoking). Linear mixed-effect models evaluated the association between baseline cardiovascular conditions or risk factors and global and domain-specific cognitive decline. Multivariable models adjusted for demographics, APOE genotype, depression, and other medical conditions. Interactions between sex and each cardiovascular condition or risk factor were examined, and results were stratified by sex. RESULTS: Overall, 1,465 (78.9%) participants had at least 1 cardiovascular condition or risk factor; the proportion of men was higher than women (767 [83.4%] vs 698 [74.5%], p < 0.0001). Cross-sectionally, coronary heart disease and ever smoking were associated with a lower visuospatial z score in multivariable models. Longitudinally, several cardiovascular conditions and risk factors were associated with declines in global and domain-specific z scores but not visuospatial z scores. Most cardiovascular conditions were more strongly associated with cognition among women: coronary heart disease and other cardiovascular conditions were associated with global cognitive decline only in women (all p < 0.05). In addition, diabetes, dyslipidemia, and coronary heart disease were associated with language z score decline only in women (all p < 0.05). However, congestive heart failure was associated with language z score decline only in men (all p < 0.05). DISCUSSION: Midlife cardiovascular conditions and risk factors are associated with midlife cognitive decline. Moreover, specific cardiovascular conditions and risk factors have stronger associations with cognitive decline in midlife for women than men despite the higher prevalence of those conditions in men.