Factors Associated With Adherence of Cervical Cancer Screening in Women With Systemic Lupus Erythematosus.

OBJECTIVE: The objective is to determine cervical cancer screening rates and factors associated with decreased cervical cancer screening in women with systemic lupus erythematosus (SLE). METHODS: We conducted a cross-sectional study that enrolled consecutive women (age 21-64 years) with SLE. We collected demographics, clinical characteristics, constructs of the Health Beliefs Model (HBM) (ie, susceptibility, severity, barriers, benefits, cues to action, and self-efficacy), and self-reported cervical cancer screening (confirmed with the electronic medical record). The primary outcome was adherence to cervical cancer screening according to current guidelines. Multivariable logistic regression models were used to examine the association between SLE disease activity and cervical cancer screening and explore mediation effects from HBM constructs. RESULTS: We enrolled 130 women with SLE. The median age was 42 years (interquartile range 32-52 years). The cervical cancer screening adherence rate was 61.5%. Women with high SLE disease activity were less likely to have cervical cancer screening versus those with low disease activity (odds ratio 0.59, 95% confidence interval [CI] 0.39-0.89; P = 0.01), which remained statistically significant after adjusting for baseline demographics and drug therapy in a multivariable model (odds ratio 0.25, 95% CI 0.08-0.79; P = 0.02). Regarding the HBM constructs, increased perceived barriers to cervical cancer screening (r = -0.30, P < 0.01) and decreased self-efficacy (r = -0.21, P = 0.02) correlated with decreased cervical cancer screening. CONCLUSION: Patients with SLE with high disease activity undergo cervical cancer screening less frequently than those with low disease activity. Perceived barriers to cervical cancer screening are moderately correlated with decreased screening. These data highlight the need to develop strategies to increase cervical cancer screening in this high-risk patient population.

Janus adhesive microneedle patch loaded with exosomes for intrauterine adhesion treatment.

Intrauterine adhesions (IUAs) are common sequelae of cervical mucosa damage caused by uterine curettage. Establishing an anti-adhesion barrier between the damaged endometrium with a sustained-release drug capability and hence promoting endogenous regeneration of the endometrium is an available treatment for IUA. However, current therapy lacks long-term intracavitary residence, drug-delivery permeability, and tissue anti-adhesion to the endometrium. Here, we report the design of a Janus microneedle patch consisting of two layers: an adhesive inner layer with an exosomes-loaded microneedle, which endows the patch with a tissue adhesive capability as well as transdermal drug-delivery capability; and an anti-adhesion outer layer, which prevents the intrauterine membrane from postoperative adhesion. This Janus adhesive microneedle patch firmly adhered to uterine tissue, and sustainedly released ∼80% of the total loaded exosomes in 7 days, hence promoting the expression of vascular- and endothelial-related cell signals. Furthermore, the anti-adhesive layer of the microneedle patch exhibited low cell and protein adhesion performance. In rats, the microneedle patch successfully prevented uterine adhesions, improved endometrial angiogenesis, proliferation, and hormone response levels. This study provides a stable anti-adhesion barrier as well as efficient drug-release capability treatment for intrauterine adhesion treatment.

Risk of incident cardiovascular events with disease-modifying anti-rheumatic drugs among adults with rheumatoid arthritis: a nested case-control study.

OBJECTIVE: This study examined the risk of cardiovascular disease (CVD) associated with the disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA). METHOD: This nested case-control study used the MarketScan database (2012-2014), involving adult RA patients (aged ≥18 years) initiating either a conventional synthetic (cs) DMARD, biologic DMARD, or targeted synthetic (ts) DMARD between January 1, 2013 and December 31, 2014 (cohort entry) and had no CVD history. Cases were individuals with incident CVD identified using diagnosis codes or procedure codes from medical claims. For each case, 10 age- and sex-matched controls were selected using the incident density sampling with replacement. Prescriptions of DMARDs were measured 90 days before the event date. Conditional logistic regression examined the association of risk of CVD with DMARDs in combination treatment or individual use, with reference to methotrexate (MTX) monotherapy, adjusting for baseline confounders. Subgroup analyses were performed separately in DMARD combination therapy users or individual DMARD users, respectively. RESULTS: In total, 270 cases of incident CVD and 2700 controls were included (mean [standard deviation (SD)] age: 54 [1]; 75.6% women). The commonly prescribed DMARD therapies were csDMARD monotherapy (n = 795, 27.04%), followed by  tumor necrosis factor inhibitors (TNFi) monotherapy (n = 367, 12.48%), and TNFi in combination with MTX (n = 314, 10.68%). Compared with MTX monotherapy, overall use of DMARD agents was not associated with the differential risk of CVD, including various types of DMARD combination regimens. The findings were similar across subgroup analyses. CONCLUSIONS: The study found no differential risk of CVD with DMARDs in combination therapy or monotherapy compared to MTX monotherapy in patients with RA. Key Points • This study evaluated the risk of cardiovascular disease (CVD) associated with the disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA). • Findings suggest no differential CVD risk with DMARDs in combination with MTX or used individually compared with MTX monotherapy in patients with early RA. • Further efforts should focus on a better understanding of the mechanism of DMARD combination treatments with MTX in modifying CV risk.

Application of machine learning in predicting survival outcomes involving real-world data: a scoping review.

BACKGROUND: Despite the interest in machine learning (ML) algorithms for analyzing real-world data (RWD) in healthcare, the use of ML in predicting time-to-event data, a common scenario in clinical practice, is less explored. ML models are capable of algorithmically learning from large, complex datasets and can offer advantages in predicting time-to-event data. We reviewed the recent applications of ML for survival analysis using RWD in healthcare. METHODS: PUBMED and EMBASE were searched from database inception through March 2023 to identify peer-reviewed English-language studies of ML models for predicting time-to-event outcomes using the RWD. Two reviewers extracted information on the data source, patient population, survival outcome, ML algorithms, and the Area Under the Curve (AUC). RESULTS: Of 257 citations, 28 publications were included. Random survival forests (N = 16, 57%) and neural networks (N = 11, 39%) were the most popular ML algorithms. There was variability across AUC for these ML models (median 0.789, range 0.6-0.950). ML algorithms were predominately considered for predicting overall survival in oncology (N = 12, 43%). ML survival models were often used to predict disease prognosis or clinical events (N = 27, 96%) in the oncology, while less were used for treatment outcomes (N = 1, 4%). CONCLUSIONS: The ML algorithms, random survival forests and neural networks, are mainly used for RWD to predict survival outcomes such as disease prognosis or clinical events in the oncology. This review shows that more opportunities remain to apply these ML algorithms to inform treatment decision-making in clinical practice. More methodological work is also needed to ensure the utility and applicability of ML models in survival outcomes.

EGR1 Promotes Ovarian Hyperstimulation Syndrome Through Upregulation of SOX9 Expression.

Angiogenesis is strongly associated with ovarian hyperstimulation syndrome (OHSS) progression. Early growth response protein 1 (EGR1) plays an important role in angiogenesis. This study aimed to investigate the function and mechanism of EGR1 involved in OHSS progression. RNA-sequencing was used to identify differentially expressed genes. In vitro OHSS cell model was induced by treating KGN cells with human chorionic gonadotropin (hCG). In vivo OHSS model was established in mice. The expression levels of EGR1, SOX1, and VEGF were determined by Quantitative Real-Time polymerase chain reaction (qRT-PCR), Western blot, immunofluorescence staining, and immunochemistry assay. The content of VEGF in the culture medium of human granulosa-like tumor cell line (KGN) cells was accessed by the ELISA assay. The regulatory effect of EGR1 on SRY-box transcription factor 9 (SOX9) was addressed by luciferase reporter assay and chromatin immunoprecipitation. The ERG1 and SOX9 levels were significantly upregulated in granulosa cells from OHSS patients and there was a positive association between EGR1 and SOX9 expression. In the ovarian tissues of OHSS mice, the levels of EGR1 and SOX9 were also remarkedly increased. Treatment with hCG elevated the levels of vascular endothelial growth factor (VEGF), EGR1, and SOX9 in KGN cells. Silencing of EGR1 reversed the promoting effect of hCG on VEGF and SOX9 expression in KGN cells. EGR1 transcriptionally regulated SOX9 expression through binding to its promoter. In addition, administration of dopamine decreased hCG-induced VEGF in KGN cells and ameliorated the progression of OHSS in mice, which were companied with decreased EGR1 and SOX9 expression. EGR1 has a promoting effect on OHSS progression and dopamine protects against OHSS through suppression of EGR1/SOX9 cascade. Our findings may provide new targets for the treatment of OHSS.

Real-world Comparative Effectiveness of Methotrexate-based Combinations for Rheumatoid Arthritis: A Retrospective Cohort Study.

PURPOSE: Guidelines recommend using disease-modifying antirheumatic drugs (DMARDs) in combination with methotrexate (MTX) for patients with rheumatoid arthritis (RA) after monotherapy. Little is known about the real-world comparative effectiveness of these MTX-DMARD combinations. This study compared the effectiveness of various MTX-based DMARD combinations for patients with RA initiating MTX-DMARD combination therapy using administrative claims database. METHODS: This retrospective cohort study included adults (aged ≥18 years) with RA who initiated MTX combination treatment with conventional synthetic DMARDs (csDMARDs), tumor necrosis factor inhibitor (TNFi) biologic DMARDs (bDMARDs), non-TNFi bDMARDs, or targeted synthetic DMARDs (tsDMARDs) between July 1, 2012, and December 31, 2013 (index date), from the MarketScan Commercial Claims Data. Patients had continuous enrollment from the 6 months of preindex period until the 12 months of postindex period. The MTX-based DMARD combination therapy cohort was defined as ≥1 MTX prescription in the first 30 days from the index date and ≥14 days overlapping use of the prescription fills of the MTX and the index DMARD. Effectiveness was measured by using the claims algorithm (dosing, switching, addition, oral glucocorticoid use, or multiple glucocorticoid injection). Propensity score analysis with the inverse probability of treatment weighting (PS-IPTW), estimated by using the generalized boosted machine learning method, was used to balance the distribution of baseline variables between the combination groups. Multivariable logistic regression using PS-IPTW was conducted to compare the effectiveness of the combination groups. Sensitivity analysis evaluated the modified effectiveness algorithms or the time to the first treatment failure. FINDINGS: A total of 3174 adult patients with RA starting an MTX-DMARD combination therapy were identified (mean [SD] age, 50 [9] years), including 1568 (49%) initiating a csDMARD + MTX, 1343 (42%) initiating TNFi + MTX, and 240 (8%) initiating non-TNFi bDMARD + MTX, and 23 (1%) initiating tsDMARD + MTX. Owing to the small sample, the tsDMARD combination group was not included in the comparative analysis. Algorithm-based therapy effectiveness was found in 9.95% of the csDMARD + MTX, 20.48% of the TNFi + MTX, and 20.83% of the non-TNFi + MTX groups. PS-IPTW showed that the csDMARD combination is less effective (adjusted odds ratio, 0.422; 95% CI, 0.341-0.524) than the TNFi combination; however, the non-TNFi biologic combination had similar effectiveness (aOR, 1.063; 95% CI, 0.680-1.662) compared to the TNFi combination. Sensitivity analyses confirmed the main results. IMPLICATIONS: Among RA patients initiating MTX-DMARD combinations, both non-TNFi biologics and TNFi-based combinations with MTX were equally effective, but csDMARD + MTX was less effective than the TNFi plus MTX.

Factors influencing prescribing the first add-on disease-modifying antirheumatic drugs in patients initiating methotrexate for rheumatoid arthritis.

Background: Advances in Disease-Modifying Antirheumatic Drugs (DMARDs) have expanded the treatment landscape for Rheumatoid Arthritis (RA). Guidelines recommend adding either conventional synthetic (cs), biologic (b), or targeted synthetic (ts) DMARDs to methotrexate (MTX) for managing RA. Limited evidence exists regarding the factors that contribute to adding a DMARD agent to the MTX regimen. This study examined the factors associated with adding the first DMARD in RA patients initiating MTX. Methods: This retrospective cohort study utilized the MarketScan data (2012-2014) involving adults (aged ≥18) with RA initiating an MTX (index date) between Jul 1, 2012 and Dec 30, 2013, and with continuous enrollment for the 6-month pre-index period. The combination therapy users received the first treatment addition of DMARD starting from day 30 after the index MTX over one year period. The study focused on the addition of csDMARDs, Tumor Necrosis Factor Inhibitors (TNFi) bDMARDs, non-TNFi bDMARDs, or tsDMARDs. Baseline covariates were measured in the 6-month pre-index and grouped into predisposing, enabling, and need factors, as per the Andersen Behavior Model. Multivariable logistic regression examined the factors associated with the addition of TNFi compared to adding a csDMARD. An additional regression model evaluated the factors associated with adding any biologic (combining TNFi and non-TNFi biologics). Results: Among 8350 RA patients starting MTX, 31.92% (n = 2665) initiated any DMARD within the 1-year post-index period. Among RA patients initiating a DMARD prescription after starting MTX, 945 (11.32%) received combination therapy with treatment addition of a DMARD to MTX regimen; majority added TNFi (550, 58%), followed by csDMARD (352, 37%); non-TNF biologic (40, 4%), or tsDMARD (3, 0.3%). The tsDMARD group was limited and was not included for further analysis. The multivariable model found Preferred Provider Organization insurance coverage (odds ratio [OR], 1.43; 95% confidence interval (CI), 1.06-1.93), chronic pulmonary disease (OR, 1.98; 95% CI, 1.14-3.44), liver disease (OR, 5.24; 95% CI, 1.77-15.49), and Elixhauser score (OR, 0.91; 95% CI, 0.86-0.97) were significantly associated with the addition of TNF-α inhibitors. The separate multivariable model additionally found that patients from metropolitan areas (OR, 1.50; 95% CI, 1.04-2.16) were positively associated with adding any biological agent. Conclusions: TNFi are often added to MTX for managing RA. Enabling and need factors contribute to the prescribing of a TNFi add-on therapy in RA. Future research should examine the impact of these combination therapies on RA management.

miR-145 inhibits aerobic glycolysis and cell proliferation of cervical cancer by acting on MYC.

Nearly half a million women are diagnosed with cervical cancer (CC) each year, with the incidence of CC stabilizing or rising in low-income and middle-income countries. Cancer cells use metabolic reprogramming to meet the needs of rapid proliferation, known as the Warburg effect, but the mechanism of the Warburg effect in CC remains unclear. microRNAs (miRNAs) have a wide range of effects on gene expression and diverse modes of action, and they regulate genes for metabolic reprogramming. Dysregulation of miRNA expression leads to metabolic abnormalities in tumor cells and promotes tumorigenesis and tumor progression. In this study, we found that miR-145 was negatively correlated with metabolic reprogramming-related genes and prevented the proliferation and metastasis of CC cell lines by impeding aerobic glycolysis. A dual-luciferase reporter assay showed that miR-145 can bind to the 3'-untranslated region (3'-UTR) of MYC. Chromatin Immunoprecipitation-quantitative real-time PCR indicated that MYC was involved in the regulation of glycolysis-related genes. In addition, miR-145 mimics significantly suppressed the growth of CC cell xenograft tumor, prolonged the survival time of mice, and dramatically silenced the expression of tumor proliferation marker Ki-67. Therefore, the results suggested that miR-145 affects aerobic glycolysis through MYC, which may be a potential target for the treatment of CC.

HPV E6/E7 promotes aerobic glycolysis in cervical cancer by regulating IGF2BP2 to stabilize m6A-MYC expression.

Enhanced aerobic glycolysis constitutes an additional source of energy for tumor proliferation and metastasis. Human papillomavirus (HPV) infection is the main cause of cervical cancer (CC); however, the associated molecular mechanisms remain poorly defined, as does the relationship between CC and aerobic glycolysis. To investigate whether HPV 16/18 E6/E7 can enhance aerobic glycolysis in CC, E6/E7 expression was knocked down in SiHa and HeLa cells using small interfering RNA (siRNA). Then, glucose uptake, lactate production, ATP levels, reactive oxygen species (ROS) content, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were evaluated. RNA-seq was used to probe the molecular mechanism involved in E6/E7-driven aerobic glycolysis, and identified IGF2BP2 as a target of E6/E7. The regulatory effect of IGF2BP2 was confirmed by qRT-PCR, western blot, and RIP assay. The biological roles and mechanisms underlying how HPV E6/E7 and IGF2BP2 promote CC progression were confirmed in vitro and in vivo. Human CC tissue microarrays were used to analyze IGF2BP2 expression in CC. The knockdown of E6/E7 and IGF2BP2 attenuated the aerobic glycolytic capacity and growth of CC cells, while IGF2BP2 overexpression rescued this effect in vitro and in vivo. IGF2BP2 expression was higher in CC tissues than in adjacent tissues and was positively correlated with tumor stage. Mechanistically, E6/E7 proteins promoted aerobic glycolysis, proliferation, and metastasis in CC cells by regulating MYC mRNA m6A modifications through IGF2BP2. We found that E6/E7 promote CC by regulating MYC methylation sites via activating IGF2BP2 and established a link between E6/E7 and the promotion of aerobic glycolysis and CC progression. Blocking the HPV E6/E7-related metabolic pathway represents a potential strategy for the treatment of CC.

Preparation of antibodies against TXR1 and construction of a new DNA tumor vaccine.

BACKGROUND: Taxol-resistance gene 1 (TXR1) is closely correlated with the paclitaxel resistance in the cancer chemotherapy. However, due to the lack of monoclonal antibodies (mAbs) with strong specificity and high sensitivity, little information is found about TXR1 target-related tumor therapy. METHODS: We developed an TXR1 recombinant DNA vaccine by inserting TXR1 DNA sequence into lysosome-associated membrane protein 1 (LAMP1). Adaptive immune responses were assessed by indirect enzyme-linked immunosorbent assay (ELISA), Enzyme-linked immunospot test (ELISpot), and cytotoxic T-lymphocyte (CTL) cytotoxicity. RESULTS: The pGEX4T-1-TXR1 reconstructed prokaryotic expression plasmid was constructed for producing high-purity TXR1 protein. Subsequently, a total of four mAbs for TXR1 and two PcAbs were successfully constructed and identified. We further found that TXR1 was highly expressed in breast cancer tissue than normal controls. Therefore, we constructed four tumor vectors, pVAX1-LAMP/TXR1, pVAX1-LAMP, pVAX1/TXR1 and pVAX1, for immunization. After three times of immunization, ELISpot data showed that single peptide 6,9,11 could stimulate T cells secreting IFN-γ in pVAX1-LAMP/TXR1 group. Moreover, the number of specific T cells and immune response effects significantly increased comparing to the pVAX1-LAMP control group. In addition, cytotoxicity showed that when the effect to target ratio was 40:l the killing effect of pVAX1-LAMP/TXR1 group was significantly higher than the pVAX1-TXR1 group. CONCLUSION: Our results provides new evidence for the TXR1 related tumor immunology and aids the early prevention of cancer.

Value of Contrast-Enhanced Ultrasonography in Evaluating Rheumatoid Arthritis: Preliminary Research Based on an Animal Model.

BACKGROUND The aim of this study was to evaluate the effectiveness of grayscale ultrasound (GSUS), power Doppler imaging (PDI), and contrast-enhanced ultrasonography (CEUS) in early rheumatoid arthritis (RA) diagnosis through animal experiments. MATERIAL AND METHODS A rabbit RA model was constructed. The animals were randomly divided into 2 groups, namely, the RA model group and the control group. GSUS, PDI, and CEUS were performed in the model group during early RA and were compared with pathology of synovial biopsies. The consistency of 3 types of ultrasonography was evaluated in tandem with pathological grading. RESULTS 23 rabbits in the RA model group completed the experiment. GSUS showed that the synovial thickening of grades 1, 2 and 3 occurred in 12, 19, and 15 joints, respectively. The sensitivity, specificity, and accuracy of PDI in the diagnosis of knee joint synovitis in RA grades 1, 2, and 3 were 80.56% (29/36), 60.00% (6/10), and 76.09% (35/46), respectively, while those with CEUS were 94.44% (34/36), 90.00% (9/10), and 93.47% (43/46), respectively. The differences in diagnostic sensitivity, specificity, and accuracy of the 2 methods were statistically significant. Additionally, the thickness of the synovium measured with GSUS precontrast was greater than that of postcontrast. CONCLUSIONS RA evaluated with GSUS is often more hypertrophied than when evaluated with CEUS, while evaluation by PDI is less hypertrophied than that by CEUS. However, from a practical view point, GSUS and PDI are of sufficient practical value, except for in a few special cases.

Directly Patterning Conductive Polymer Electrodes on Organic Semiconductor via In Situ Polymerization in Microchannels for High-Performance Organic Transistors.

Conductive polymers are considered promising electrode materials for organic transistors, but the reported devices with conductive polymer electrodes generally suffer from considerable contact resistance. Currently, it is still highly challenging to pattern conductive polymer electrodes on organic semiconductor surfaces with good structure and interface quality. Herein, we develop an in situ polymerization strategy to directly pattern the top-contacted polypyrrole (PPy) electrodes on hydrophobic surfaces of organic semiconductors by microchannel templates, which is also applicable on diverse hydrophobic and hydrophilic surfaces. Remarkably, a width-normalized contact resistance as low as 1.01 kΩ·cm is achieved in the PPy-contacted transistors. Both p-type and n-type organic field-effect transistors (OFETs) exhibit ideal electrical characteristics, including almost hysteresis-free, low threshold voltage, and good stability under long-term test. The facile patterning method and high device performance indicate that the in situ polymerization strategy in confined microchannels has application prospects in all-organic, transparent, and flexible electronics.

Extra-Thyroid Extension Prediction by Ultrasound Quantitative Method Based on Thyroid Capsule Response Evaluation.

BACKGROUND The aim of this study was to assess the interaction between thyroid malignancies and thyroid anterior capsule by ultrasound quantification to determine extra-capsular invasion. MATERIAL AND METHODS A total of 145 patients preoperatively diagnosed with malignant nodules under the thyroid anterior capsule were selected and routinely examined by ultrasound. The length of the nodules (from the junction of the nodule capsule to the deepest point of the nodule, vertical diameter, V) and the distance between the nodule protruding from thyroid capsule and the highest protruding (ledge length, L) nodule were used to obtain the L/V ratio. These parameters where then used to compare the efficacy of predicting extra-thyroid extension (ETE) between L/V, the aspect ratio of the tumor, and manual judgment. RESULTS Out of 145 nodules, there were 63 ETEs and 82 non-ETEs determined by ultrasound. Extra-capsular invasion was associated with L//V ratio, but there was no significant correlation between capsular invasion and AR (aspect ratio), age, location, or presence of clustered calcification. The ability of the ratio of L/V to predict extra-capsular invasion was superior to the predictive ability of the AR ratio. With a Youden index of 0.593, the L/V ratio was 0.2325. The use of the L/V ratio to determine the presence of ETE was superior to subjective visual judgment. CONCLUSIONS The calculation of L/V ratio by ultrasound could more precisely predict the ETE compared with manual judgment, which indirectly reflects the interaction between thyroid capsule and malignant nodules. The above conclusions need to be confirmed by a range of cases.

Ultrasonographic evaluation of extracapsular vascular invasion for subcapsular nodules of the thyroid.

BACKGROUND: Ultrasound provides a high-frequency spatial resolution. In this study, we used the combined pathological features of extrathyroid extension (ETE) measured by ultrasound to evaluate the vascular manifestations of subcapsular differentiated thyroid cancer. Our study aims to explore the value of high-frequency ultrasonography in the evaluation of extracapsular vascular invasion for the evaluation of both benign and malignant nodules and the prediction of ETE. METHODS: A total of 167 thyroid nodules were enrolled in this study. High-frequency ultrasonography was used to observe the relationship between the blood flow of the nodules and the capsules. The blood flow was divided into two types according to the relationship: non-extracapsular invasive blood flow and extracapsular invasive blood flow. Non-extracapsular blood flow was defined as any flow seen inside or around the nodule that did not extend beyond the thyroid gland. Extracapsular invasive blood flow was defined as any blood flow seen inside or around the nodule that flowed across the capsule and extended beyond the thyroid gland. A comparison of the different types of blood flow to judge the nature of thyroid nodules for predicting ETE was performed. RESULTS: Out of 167 nodules, 81 cases of nodules were the non-extracapsular invasive blood flow type, while the remaining 86 cases of nodules were classified as the extracapsular invasive blood flow type. Nodules with distinct types of blood flow were significantly different in malignancy rates between the nodules (P<0.001). The incidence rate of ETE was also significantly different between the malignant nodules with distinct types of blood flows. CONCLUSIONS: Extracapsular vascular invasion is a good indicator for the evaluation of benign and malignant nodules. Using it as an indicator provides physicians with a potential tool for the prediction of ETE.

Nucleolin mediates the binding of cancer cells to L-selectin under conditions of lymphodynamic shear stress.

Head and neck squamous cell carcinoma (HNSCC) cells bind to lymphocytes via L-selectin in a shear-dependent manner. This interaction takes place exclusively under low-shear stress conditions, such as those found within the lymph node parenchyma. This represents a novel functional role for L-selectin-selectin ligand interactions. Our previous work has characterized as-of-yet unidentified L-selectin ligands expressed by HNSCC cells that are specifically active under conditions of low shear stress consistent with lymph flow. Using an affinity purification approach, we now show that nucleolin expressed on the surface of HNSCC cells is an active ligand for L-selectin. Parallel plate chamber flow-based experiments and atomic force microscopy (AFM) experiments show that nucleolin is the main functional ligand under these low-force conditions. Furthermore, AFM shows a clear relationship between work of deadhesion and physiological loading rates. Our results reveal nucleolin as the first major ligand reported for L-selectin that operates under low-shear stress conditions.