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.

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.

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.

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.

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.

DNMT3B-mediated FAM111B methylation promotes papillary thyroid tumor glycolysis, growth and metastasis.

Over the past decades, the incidence of thyroid cancer (TC) rapidly increased all over the world, with the papillary thyroid cancer (PTC) accounting for the vast majority of TC cases. It is crucial to investigate novel diagnostic and therapeutic targets for PTC and explore more detailed molecular mechanisms in the carcinogenesis and progression of PTC. Based on the TCGA and GEO databases, FAM111B is downregulated in PTC tissues and predicts better prognosis in PTC patients. FAM111B suppresses the growth, migration, invasion and glycolysis of PTC both in vitro and in vivo. Furthermore, estrogen inhibits FAM111B expression by DNMT3B methylation via enhancing the recruitment of DNMT3B to FAM111B promoter. DNMT3B-mediated FAM111B methylation accelerates the growth, migration, invasion and glycolysis of PTC cells. In clinical TC patient specimens, the expression of FAM111B is inversely correlated with the expressions of DNMT3B and the glycolytic gene PGK1. Besides, the expression of FAM111B is inversely correlated while DNMT3B is positively correlated with glucose uptake in PTC patients. Our work established E2/DNMT3B/FAM111B as a crucial axis in regulating the growth and progression of PTC. Suppression of DNMT3B or promotion of FAM111B will be potential promising strategies in the estrogen induced PTC.

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.

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.

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.

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.

Regional Differences in Epidemiological and Clinical Characteristics, Treatment, and Clinical Outcomes of COVID-19 in Wuhan and Remote Areas of Hubei Province.

Background: The Coronavirus disease 2019 (COVID-19) pandemic has been a major threat to global health. Regional differences in epidemiological and clinical characteristics, treatment and outcomes of patients have not yet been investigated. This study was conducted to investigate these differences amongCOVID-19 patients in Hubei Province, China. Methods: This retrospective cross-sectional study analyzed data on 289 COVID-19 patients from designated hospitals in three regions:Urban (Wuhan Union West Hospital), Suburban areas of Wuhan (Hannan Hospital) and Enshi city, between February 8 and 20, 2020. The final date of follow-up was December 14th, 2020. The outcomes were case fatality rate and epidemiological and clinical data. Results: Urban Wuhan experienced a significantly higher case fatality rate (21.5%) than suburban Wuhan (5.23%) and rural area of Enshi (3.51%). Urban Wuhan had a higher proportion of patients on mechanical ventilation (24.05%) than suburban Wuhan (0%) and rural Enshi (3.57%). Treatment with glucocorticoids was equivalent in urban and suburban Wuhan (46.84 and 45.75%, respectively) and higher than Enshi (25.00%). Urban Wuhan had a higher proportion of patients with abnormal tests including liver function and serum electrolytes and a higher rate of pneumonia (p < 0.01 for all). Urban Wuhan also had a higher incidence of respiratory failure, heart disease, liver disease and shock, compared with the other two regions (all p < 0.05). Conclusions: Our findings revealed that there are regional differences in COVID-19. These findings provide novel insights into the distribution of appropriate resources for the prevention, control and treatment of COVID-19 for the global community.

STAT3/LINC00671 axis regulates papillary thyroid tumor growth and metastasis via LDHA-mediated glycolysis.

Lactate dehydrogenase A (LDHA), a critical component of the glycolytic pathway, relates to the development of various cancers, including thyroid cancer. However, the regulatory mechanism of LDHA inhibition and the physiological significance of the LDHA inhibitors in papillary thyroid cancer (PTC) are unknown. Long non-coding RNA (lncRNA) plays a vital role in tumor growth and progression. Here, we identified a novel lncRNA LINC00671 negatively correlated with LDHA, downregulating LDHA expression and predicting good clinical outcome in thyroid cancer. Moreover, hypoxia inhibits LINC00671 expression and activates LDHA expression largely through transcriptional factor STAT3. STAT3/LINC00671/LDHA axis regulates thyroid cancer glycolysis, growth, and lung metastasis both in vitro and in vivo. In thyroid cancer patients, LINC00671 expression is negatively correlated with LDHA and STAT3 expression. Our work established STAT3/LINC00671/LDHA as a critical axis to regulate PTC growth and progression. Inhibition of LDHA or STAT3 or supplement of LINC00671 could be potential therapeutic strategies in thyroid cancer.

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.

CD38-Targeted Theranostics of Lymphoma with 89Zr/177Lu-Labeled Daratumumab.

Lymphoma is a heterogeneous disease with varying clinical manifestations and outcomes. Many subtypes of lymphoma, such as Burkitt's lymphoma and diffuse large B cell lymphoma, are highly aggressive with dismal prognosis even after conventional chemotherapy and radiotherapy. As such, exploring specific biomarkers for lymphoma is of high clinical significance. Herein, a potential marker, CD38, is investigated for differentiating lymphoma. A CD38-targeting monoclonal antibody (mAb, daratumumab) is then radiolabeled with Zr-89 and Lu-177 for theranostic applications. As the diagnostic component, the Zr-89-labeled mAb is highly specific in delineating CD38-positive lymphoma via positron emission tomography (PET) imaging, while the Lu-177-labeled mAb serves well as the therapeutic component to suppress tumor growth after a one-time administration. These results strongly suggest that CD38 is a lymphoma-specific marker and prove that 89Zr/177Lu-labeled daratumumab facilitates immunoPET imaging and radioimmunotherapy of lymphoma in preclinical models. Further clinical evaluation and translation of this CD38-targeted theranostics may be of significant help in lymphoma patient stratification and management.

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.

Association of Premenopausal Bilateral Oophorectomy With Restless Legs Syndrome.

Importance: Restless legs syndrome is a common neurologic disorder that is more prevalent in women than in men, and it has been suggested that female hormones may be involved in the disorder's pathophysiology. Objective: To determine whether women who underwent premenopausal bilateral oophorectomy were at increased risk of restless legs syndrome. Design, Setting, and Participants: This cohort study was performed using data from the Mayo Clinic Cohort Study of Oophorectomy and Aging-2 for a population in Olmsted County, Minnesota. There were 1653 women who underwent premenopausal bilateral oophorectomy before the age of 50 years for a benign indication between 1988 and 2007 and 1653 age-matched women (of same age plus or minus 1 year) in a reference group. Follow-up was conducted until the end of the study period (ie, December 31, 2014). Data were analyzed from January to July 2020. Exposures: Undergoing bilateral oophorectomy, as shown in medical record documentation. Main Outcomes and Measures: Diagnosis of restless legs syndrome, as defined using Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria, was recorded. Results: Among 3306 women, the median (interquartile range) age at baseline was 44.0 (40.0-47.0) years. Women who underwent bilateral oophorectomy, compared with women who did not undergo this procedure, had a greater number of chronic conditions at the index date (eg, 300 women [18.1%] vs 171 women [10.3%] with ≥3 chronic conditions; overall P < .001), were more likely to have obesity (576 women [34.8%] vs 442 women [27.1%]; overall P < .001), and were more likely to have a history of anemia of any type (573 women [34.7%] vs 225 women [13.6%]; P < .001), iron deficiency anemia (347 women [21.0%] vs 135 women [8.2%]; P < .001), and restless legs syndrome before the index date (32 women [1.9%] vs 14 women [0.8%]; P = .008). Women who underwent bilateral oophorectomy prior to natural menopause had a higher risk of restless legs syndrome after the index date compared with women in the reference group (120 diagnoses vs 74 diagnoses), with an adjusted hazard ratio (HR) of 1.44 (95% CI, 1.08-1.92; P = .01). After stratification by indication for the bilateral oophorectomy, there was an increased risk of restless legs syndrome among women without a benign ovarian condition (HR, 1.52; 95% CI, 1.03-2.25; P = .04) but not among women with a benign condition (HR, 1.25; 95% CI, 0.80-1.96; P = .34). Treatment with estrogen therapy through the age of 46 years in women who underwent bilateral oophorectomy at younger ages was not associated with a difference in risk. Conclusions and Relevance: This cohort study found that risk of restless legs syndrome was increased among women who underwent bilateral oophorectomy prior to menopause, especially those without a benign ovarian indication.

Patient factors associated with oral generic olanzapine initiation and substitution among Medicaid beneficiaries: a new user cohort study.

OBJECTIVE: Generic drugs typically are less expensive than branded products; however, several factors can limit generic drug utilization. This study assesses the associations of patient factors with generic olanzapine initiation and substitution. METHODS: A retrospective new user cohort study was conducted using the 2011-2012 Medicaid administrative claims data. Beneficiaries continuously enrolled during the 6 month washout period prior to their initial oral brand or generic olanzapine prescription were included and followed up to 12 months. Among brand olanzapine new users, time to generic substitution and competing risk outcomes was estimated using the Fine-Gray cumulative incidence function. Patient demographic and health service utilization factors were assessed in the multivariate cause-specific hazards model. RESULTS: Among olanzapine new users, 70.7% patients initiated generic treatment. Beneficiaries aged ≥21, and living in the Midwest and West regions were more likely to initiate generic olanzapine. Among brand new users, 28.2% switched to generic olanzapine, 23.6% switched to an alternative atypical antipsychotic treatment and 38.0% discontinued within 12 months. Beneficiaries who resided in urban areas (adjusted hazard ratio [AHR) = 0.53, 95% CI = 0.37-0.75) and had prior hospitalizations (AHR = 0.85, 95% CI = 0.75-0.96) had lower rates of generic substitution, whereas those with emergency department (ED) visits (AHR = 1.06, 95% CI = 1.02-1.10) had a higher rate of generic substitution. In addition, beneficiaries in different age subgroups also had different rates of generic substitution in different regions. CONCLUSION: Medicaid beneficiaries' age, geographic region, prior hospitalization and ED utilization were associated with generic olanzapine initiation and substitution. Tailored educational outreach targeting these patient subgroups might improve generic olanzapine utilization.

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.