KAT8/SIRT7-mediated Fascin-K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma.

Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A non-invasive artificial intelligence model for identifying axillary pathological complete response to neoadjuvant chemotherapy in breast cancer: a secondary analysis to multicenter clinical trial.

BACKGROUND: This study aims to develop a stacking model for accurately predicting axillary lymph node (ALN) response to neoadjuvant chemotherapy (NAC) using longitudinal MRI in breast cancer. METHODS: We included patients with node-positive breast cancer who received NAC following surgery from January 2012 to June 2022. We collected MRIs before and after NAC, and extracted radiomics features from the tumour, peritumour, and ALN regions. The Mann-Whitney U test, least absolute shrinkage and selection operator, and Boruta algorithm were used to select features. We utilised machine learning techniques to develop three single-modality models and a stacking model for predicting ALN response to NAC. RESULTS: This study consisted of a training cohort (n = 277), three external validation cohorts (n = 313, 164, and 318), and a prospective cohort (n = 81). Among the 1153 patients, 60.62% achieved ypN0. The stacking model achieved excellent AUCs of 0.926, 0.874, and 0.862 in the training, external validation, and prospective cohort, respectively. It also showed lower false-negative rates (FNRs) compared to radiologists, with rates of 14.40%, 20.85%, and 18.18% (radiologists: 40.80%, 50.49%, and 63.64%) in three cohorts. Additionally, there was a significant difference in disease-free survival between high-risk and low-risk groups (p < 0.05). CONCLUSIONS: The stacking model can accurately predict ALN status after NAC in breast cancer, showing a lower false-negative rate than radiologists. TRIAL REGISTRATION NUMBER: The clinical trial numbers were NCT03154749 and NCT04858529.

Noninvasive Artificial Intelligence System for Early Predicting Residual Cancer Burden during Neoadjuvant Chemotherapy in Breast Cancer.

OBJECTIVE: To develop an artificial intelligence (AI) system for the early prediction of residual cancer burden (RCB) scores during neoadjuvant chemotherapy (NAC) in breast cancer. SUMMARY BACKGROUND DATA: RCB III indicates drug resistance in breast cancer, and early detection methods are lacking. METHODS: This study enrolled 1048 patients with breast cancer from four institutions, who were all receiving NAC. Magnetic resonance images were collected at the pre- and mid-NAC stages, and radiomics and deep learning features were extracted. A multitask AI system was developed to classify patients into three groups (RCB 0-I, II, and III ) in the primary cohort (PC, n=335). Feature selection was conducted using the Mann-Whitney U- test, Spearman analysis, least absolute shrinkage and selection operator regression, and the Boruta algorithm. Single-modality models were developed followed by model integration. The AI system was validated in three external validation cohorts. (EVCs, n=713). RESULTS: Among the patients, 442 (42.18%) were RCB 0-I, 462 (44.08%) were RCB II and 144 (13.74%) were RCB III. Model-I achieved an area under the curve (AUC) of 0.975 in the PC and 0.923 in the EVCs for differentiating RCB III from RCB 0-II. Model-II distinguished RCB 0-I from RCB II-III, with an AUC of 0.976 in the PC and 0.910 in the EVCs. Subgroup analysis confirmed that the AI system was consistent across different clinical T stages and molecular subtypes. CONCLUSIONS: The multitask AI system offers a noninvasive tool for the early prediction of RCB scores in breast cancer, supporting clinical decision-making during NAC.

Tanshinone IIA attenuates osteoarthritis via inhibiting aberrant angiogenesis in subchondral bone.

Excessive angiogenesis in subchondral bone is a pathological feature of osteoarthritis (OA). Tanshinone IIA (TIIA), an active compound found in Salvia miltiorrhiza, demonstrates significant anti-angiogenic properties. However, the effect of TIIA on abnormal subchondral angiogenesis in OA is still unclear. This study aims to investigate the mechanism of TIIA in modulating subchondral bone angiogenesis during OA and assess its therapeutic potential in OA. Our findings demonstrate that TIIA attenuated articular cartilage degeneration, normalized subchondral bone remodeling, and effectively suppressed aberrant angiogenesis within subchondral bone in monosodium iodoacetate (MIA)-induced OA mice. Additionally, the angiogenesis capacity of primary CD31hiEmcnhi endothelial cells was observed to be significantly reduced after treatment with TIIA in vitro. Mechanically, TIIA diminished the proportion of hypertrophic chondrocytes, ultimately leading to a substantial reduction in the secretion of vascular endothelial growth factor A (VEGFA). The supernatant of hypertrophic chondrocytes promoted the tube formation of CD31hiEMCNhi endothelial cells, whereas TIIA inhibited this process. Furthermore, TIIA effectively suppressed the expression of vascular endothelial growth factor receptor 2 (VEGFR2) along with its downstream MAPK pathway in CD31hiEmcnhi endothelial cells. In conclusion, our data indicated that TIIA could effectively inhibit the abnormal angiogenesis in subchondral bone during the progression of OA by suppressing the VEGFA/VEFGR2/MAPK pathway. These findings significantly contribute to our understanding of the abnormal angiogenesis in OA and offer a promising therapeutic target for OA treatment.

Cocrystallization-Driven Double-Optimized Stratagem toward Directional Self-Assembly for the First Ternary Salt Cocrystal of Cardiotonic Drug Milrinone with Different Phenolic Acids Exhibits Optimal In Vitro/Vivo Biopharmaceutical Peculiarities.

The current research leverages the structural features and property superiorities along with benefits in protecting cardiovascular system of gallic acid (GLC) and gentisic acid (HGA) to optimize in vitro/vivo peculiarities of cardiotonic drug milrinone (MIL) through developing a stratagem of cocrystallization-driven double-optimized ternary salt cocrystal. This strategy assembles MIL ternary salt cocrystal by shaping a cocrystallization moiety relying on noncovalent interplays with GLC to obtain permeability advancement and molding a salt segment via the salification of proton transfer between HGA and MIL molecules to facilitate solubility enhancement. While the ameliorative in vitro properties further modulate the in vivo pharmacokinetic behaviors, thus fulfilling a dual optimization of MIL's biopharmaceutical characteristics on both in vitro and in vivo aspects. Along this line, the first MIL ternary salt cocrystal, viz., [HMIL+-GA-]-MIL-GLC-H2O (denoted as MTSC hereinafter), has been satisfactorily constructed and precisely structurally identified by diversified techniques. The single-crystal X-ray diffraction experiment validates that a molecular salt [HMIL+-GA-] species cocrystallizes with one neutral MIL, two GLC, and five solvent water molecules, among which the organic constituents compose laminated hydrogen bond networks, and then are self-assembled by water molecules to a 3D supramolecular structure. The unique structural feature and stacking pattern of MTSC make both the permeability and solubility be respectively enhanced by 9.69 times and 5.17- to 6.03-fold compared with the parent drug per se. The experimental outcomes are powerfully supported by associated calculations based on density functional theory. Intriguingly, these optimal in vitro physicochemical natures of MTSC have been potently converted into strengths of in vivo pharmacokinetics, showcasing the elevated drug plasma concentration, elongated half-life, alongside advanced bioavailability. Consequently, this presentation not just contributes a brand-new crystalline form with utility values, but ushers in a new dimension of ternary salt cocrystals for improving in vitro/vivo limitations of poor drug bioavailability.

Correction: Supramolecular self-assembly of amantadine hydrochloride with ferulic acid via dual optimization strategy establishes a precedent of synergistic antiviral drug-phenolic acid nutraceutical cocrystal.

Correction for 'Supramolecular self-assembly of amantadine hydrochloride with ferulic acid via dual optimization strategy establishes a precedent of synergistic antiviral drug-phenolic acid nutraceutical cocrystal' by Ling-Yang Wang et al., Analyst, 2021, 146, 3988-3999, https://doi.org/10.1039/D1AN00478F.

Neoadjuvant docetaxel plus carboplatin vs epirubicin plus cyclophosphamide followed by docetaxel in triple-negative, early-stage breast cancer (NeoCART): Results from a multicenter, randomized controlled, open-label phase II trial.

Previous studies have shown that the addition of carboplatin to neoadjuvant chemotherapy improved the pathologic complete response (pCR) rate in patients suffering from triple-negative breast cancer (TNBC) and patients who obtained a pCR could achieve prolonged event-free survival (EFS) and overall survival (OS). However, no studies have assessed the effects of the combination of docetaxel and carboplatin without anthracycline with taxane-based and anthracycline-based regimens. The NeoCART study was designed as a multicenter, randomized controlled, open-label, phase II trial to assess the efficacy and safety of docetaxel combined with carboplatin in untreated stage II-III TNBC. All eligible patients were randomly assigned, at a 1:1 ratio, to an experimental docetaxel plus carboplatin (DCb) for six cycles group (DCb group) or an epirubicin plus cyclophosphamide for four cycles followed by docetaxel for four cycles group (EC-D group). PCR (ypT0/is ypN0) was evaluated as the primary outcome. Between 1 September 2016 and 31 December 2019, 93 patients were randomly assigned and 88 patients were evaluated for the primary endpoint (44 patients in each group). In the primary endpoint analysis, 27 patients in the DCb group (61.4%, 95% CI 47.0-75.8) and 17 patients in the EC-D group achieved a pCR (38.6%, 95% CI 24.3-53.0; odds ratio 2.52, 95% CI 2.4-43.1; Pnoninferiority = .004). Noninferiority was met, and the DCb regimen was confirmed to be superior to the EC-D regimen (P = .044, superiority margin of 5%). At the end of the 37-month median follow-up period, OS and EFS rates were equivalent in both groups.

Paper-based sample processing for the fast and direct MS analysis of multiple analytes from serum samples.

Amino acids are closely related to human health, and their rapid determination is important for the rapid diagnosis, timely treatment, and assessment of serious diseases. In this work, we propose a novel paper-based sample-processing device combined with isotope-dilution MS for the fast analysis of 11 amino acids from blood samples. By using an isoelectric focusing electrokinetic separation method, without the aid of carrier ampholytes and the addition of inhibitors, this approach uses only the characteristic of the isoelectric point of the target amino acids to achieve separation and purification from other coexisting components in the medium; it can meet the requirements for mass spectrometry detection. Driven by a DC voltage, a stable and sharp pH gradient (pH 3-10.5 over 5 mm) can be established in a glass-fiber paper-based fluidic channel with a MS-friendly electrolyte. Amphoteric species can be well separated from the complex blood matrix and concentrated into a narrow band in the channel within 2 min, which is 20 times faster than a commercial kit method. The method can be applied to both liquid and dry spot samples, and the cleaned sample band can be simply dissolved for direct IDMS detection in ESI MRM mode. This method is a promising strategy for the rapid MS-based detection of amino acids from serum without pre-separation via liquid chromatography.

Salty Biofluidic Sample Clean-Up and Preconcentration with a Paper-Based Ion Concentration Polarization Interface.

Charged species from complex media could be separated and enriched taking advantage of ion concentration polarization (ICP) effect; thus, ICP can be used for sample purification and improvement of detection sensitivity. In this paper, a novel and reliable ICP interface was established on a paper-based analytical device (PAD) by using ion exchange membrane, and electrokinetic stacking of target analytes from salty media was successfully demonstrated. Steady ICP effect was well observed in aqueous solution with up to 400 mM NaCl as shown by a fluorescent probe, which makes it possible to directly process salty physiological samples such as blood and urine with this type of PAD. Application of this method was demonstrated by direct online stacking of total protein from urine samples and image-based colorimetric detection by a smartphone camera. The linear response was in the range of 50-350 mg/L (R2 = 0.99), with recovery rate in the range of 94.8-107.6% and relative standard deviation below 7.1%. The obtained results were consistent with that of the clinical method. As an off-line sample pretreatment method, the feasibility for rapid tandem mass spectrometry detection of amino acids from serum samples was also investigated, and promising results were obtained. This PAD method is of low cost, easy to operate, and reliable. As a disposable PAD, it is useful not only for sensitive point-of-care testing but also for direct purification and concentration of complex and highly conductive physiological samples for fast and accurate detection with advanced analytical instruments.

Prognostic Role of Nodal Skip Metastasis in Thoracic Esophageal Squamous Cell Carcinoma: A Large-Scale Multicenter Study.

BACKGROUND: Nodal-skip metastasis (NSM) is found in esophageal squamous cell carcinoma (ESCC), but its prognostic role is controversial. This study aimed to investigate the prognostic value of NSM for thoracic ESCC patients. METHODS: Categorization of NSM was according to the N groupings of Japan Esophagus Society (JES) staging system, which is dependent on tumor location. Using the Kaplan-Meier method and Cox-regression analysis, this study retrospectively analyzed the overall survival (OS) for 2325 ESCC patients after radical esophagectomy at three high-volume esophageal cancer centers. Predictive models also were constructed. RESULTS: The overall NSM rate was 20% (229/1141): 37.4% in the in upper, 12.9% in the middle, and 22.2% in the lower thoracic ESCC. The patients with NSM always had a better prognosis than those without NSM. Furthermore, NSM was an independent prognostic factor for thoracic ESCC patients (hazard ratio [HR], 0.633; 95% confidence interval [CI], 0.499-0.803; P < 0.001). By integrating the prognostic values of NSM and N stage, the authors proposed the new N staging system. The categories defined by the new N staging system were more homogeneous in terms of OS than those defined by the current N system. Moreover, the new N system was shown to be an independent prognostic factor also for thoracic ESCC patients (HR, 1.607; 95% CI, 1.520-1.700; P < 0.001). Overall, the new N system had slightly better homogeneity, discriminatory ability, and monotonicity of gradient than the current N system. CONCLUSIONS: This study emphasized the prognostic power of NSM and developed a modified node-staging system to improve the efficiency of the current International Union for Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) N staging system.

Tunable Size Dependence of Quantum Plasmon of Charged Gold Nanoparticles.

The quantum behavior of surface plasmons has received extensive attention, benefiting from the development of exquisite nanotechnology and the diverse applications. Blueshift, redshift, and nonshift of localized surface plasmon resonances (LSPRs) have all been reported as the particle size decreases and enters the quantum size regime, but the underlying physical mechanism to induce these controversial size dependences is not clear. Herein, we propose an improved semiclassical model for modifying the dielectric function of metal nanospheres by combining the intrinsic quantized electron transitions and surface electron injection or extraction to investigate the plasmon shift and LSPR size dependence of the charged Au nanoparticles. We experimentally observe that the nonmonotonic blueshift of LSPRs with size for Au nanoparticles is turned into an approximately monotonic blueshift by increasing the electron donor concentration in the reduction solution, and it can also be transformed to an approximately monotonic redshift after surface passivation by ligand molecules. Moreover, we demonstrate controlled blueshift and redshift for the electron and hole plasmons in Cu_{2-x}S@Au core-shell nanoparticles by injecting electrons. The experimental observations and the theoretical calculations clarify the controversial size dependences of LSPR reported in the literature, reveal the critical role of surface electron injection or extraction in the transformation between the different size dependences of LSPRs, and are helpful for understanding the nature of surface plasmons in the quantum size regime.

Supramolecular self-assembly of amantadine hydrochloride with ferulic acid via dual optimization strategy establishes a precedent of synergistic antiviral drug-phenolic acid nutraceutical cocrystal.

To display the capability of the phenolic acid nutraceutical ferulic acid (FLA) in optimizing the in vitro/in vivo properties of the antiviral drug amantadine hydrochloride (AMH) and achieve synergistically enhanced antiviral effects, thereby gaining some new insights into pharmaceutical cocrystals of antiviral drugs with phenolic acid nutraceuticals, a cocrystallization strategy of dual optimization was created. Based on this strategy, the first drug-phenolic acid nutraceutical cocrystal of AMH with FLA, namely AMH-FLA-H2O, was successfully assembled and completely characterized by employing single-crystal X-ray diffraction and other analytical techniques. The cocrystal was revealed to be composed of AMH, FLA, and water molecules in the ratio of 3 : 1 : 1.5, and charge-assisted hydrogen bonds containing chloride ions crucially maintained the crystal lattice together with water molecules. The in vitro/in vivo properties of the cocrystal were systematically evaluated via both theoretical and experimental methods, and the results indicate that the dissolubility of AMH is down-regulated by two-thirds in the cocrystal, resulting in its potential for sustained pharmacokinetic release and the elimination of the adverse effects of AMH. More importantly, the enhanced antiviral effects of the current cocrystal were proven against four viral strains, and the pharmaceutical synergy between AMH and FLA was realized with a combination index (CI) of less than 1. Thus, the present work provides a novel crystalline product with bright commercial prospect for the classical antiviral drug AMH and also establishes an avenue for the synergetic antiviral application of nutraceutical phenolic acids via the cocrystallization strategy of dual optimization.

Supramolecular self-assembly and perfected in vitro/vivo property of 5-fluorouracil and ferulic acid on the strength of double optimized strategy: the first 5-fluorouracial-phenolic acid nutraceutical cocrystal with synergistic antitumor efficacy.

For highlighting the predominance of phenolic acid nutraceutical ferulic acid (FR) in regulating the in vivo/vitro performances of anticancer drug 5-fluorouracil (Flu) and strengthening their cooperativity in antitumor effect, thus achieving a major breakthrough in the development of drug-nutraceutical cocrystal with synergistic antitumor action, a cocrystallization strategy of dual optimization is created, in which both the in vivo and vitro natures of Flu are improved by exploiting the FR's excellent physicochemical property. Moreover, Flu's anticancer effects were promoted by exerting the assistant antitumor peculiarity of FR. Such dual optimization of FR for Flu in physicochemical properties and anticancer activities is beneficial for realizing synergistic augmentation effect by taking the benefit of the cooperativeness of Flu and FR in the anticancer ability. Based on this idea, a novel cocrystal of Flu and FR, namely, Flu-FR-H2O, is successfully assembled as the first 5-fluorouracil-nutraceutical cocrystal with synergistic antitumor effect and its explicit structure is resolved. The single-crystal X-ray diffraction demonstrates that Flu and FR have a ratio of 1 : 1 with one equivalent of solvent water in the cocrystal, where one-dimensional hydrogen-bonding helices and FR-Flu hydrogen-bonding pairs, together construct a three-dimensional supramolecular network. By combining experimental evaluation with theoretical analysis, in vitro/vivo pharmaceutical properties are scientifically investigated. Results show that the permeability and aqueous solubility of Flu are respectively elevated by 5.08 and 1.64 folds, which has brought about ameliorated pharmacokinetics, thus providing prolonged retention time and increased oral bioavailability. More interestingly, the cocrystal shows synergistic inhibition ability of Flu and FR against tested tumor cell strains, hence laying the groundwork for reducing the dosage and even the toxic side effects of Flu. As a result of this, the present research not only provides a new strategy for Flu to optimize its physicochemical properties and antitumor activities simultaneously but also offers some opinions for the development of synergistic antitumor pharmaceutical cocrystals.

Predictive value of admission D-dimer for contrast-induced acute kidney injury and poor outcomes after primary percutaneous coronary intervention.

BACKGROUND: DD was found to be associated with acute myocardial infarction (AMI) and renal insufficiency. However, it is uncertain whether DD is an independent risk factor of CI-AKI in patients undergoing pPCI. METHODS: We prospectively enrolled 550 consecutive patients with STEMI undergoing pPCI between January 2012 and December 2016. The predictive value of admission DD for CI-AKI was assessed by receiver operating characteristic (ROC) and multivariable logistic regression analysis. CI-AKI was defined as an absolute serum creatinine increase ≥0.3 mg/dl or a relative increase in serum creatinine ≥50% within 48 h of contrast medium exposure. RESULTS: Overall, the incidence of CI-AKI was 13.1%. The ROC analysis showed that the cutoff point of DD was 0.69 µg/ml for predicting CI-AKI with a sensitivity of 77.8% and a specificity of 57.3%. The predictive value of DD was similar to the Mehran score for CI-AKI (AUCDD = 0.729 vs AUCMehran = 0.722; p = 0.8298). Multivariate logistic regression analysis indicated that DD > 0.69 µg/ml was an independent predictor of CI-AKI (odds ratio [OR] = 3.37,95% CI:1.80-6.33, p < 0.0001). Furthermore, DD > 0.69 µg/ml was associated with an increased risk of long-term mortality during a mean follow-up period of 16 months (hazard ratio = 3.41, 95%CI:1.4-8.03, p = 0.005). CONCLUSION: Admission DD > 0.69 µg/ml was a significant and independent predictor of CI-AKI and long-term mortality in patients undergoing pPCI.

Cocrystallization with syringic acid presents a new opportunity for effectively reducing the hepatotoxicity of isoniazid.

Objective: With the aim of surmounting the severe hepatotoxicity induced by antituberculosis drug isoniazid (INH), a novel cocrystal of INH with hepatoprotective nutraceutical syringic acid (SYA), namely INH-SYA, was designed and prepared through cocrystallization strategy, which is an intriguing attempt to reduce the toxic side effects of INH.Significance: The study not only provides new thinking for inhibiting toxic side effects of drugs through cocrystallization strategy, but also opens a new pathway for the application of nutraceuticals in the pharmacy.Methods: INH and SYA were successfully crystallized into the same crystal lattice through combining volatilization with solvent assisted methods. The resulting cocrystal was structurally characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC).Results: The SCXRD analysis for the present cocrystal revealed that it has a 1:1 ratio of INH to SYA with two molecules INH homodimers and two SYA molecules, in which they are arranged alternately linked by hydrogen bonds to form a six molecules ring structure (R66(40)) in crystal. The systematic evaluation of the in vitro/in vivo suggested that, owing to the formation of cocrystal, the dissolution efficiency of SYA was increased 5.85-fold compared with that of coarse SYA, and the oral bioavailability of the cocrystal in rats was enhanced by 3.66 times. As a result, the present INH-SYA cocrystal almost removed INH induced serious hepatotoxicity, which was further demonstrated by the hepatotoxicity studies in rats.Conclusion: INH-SYA cocrystal could effectively reduce the hepatotoxicity of INH.

Super-Enhancer-Driven Long Non-Coding RNA LINC01503, Regulated by TP63, Is Over-Expressed and Oncogenic in Squamous Cell Carcinoma.

BACKGROUND & AIMS: Long non-coding RNAs (lncRNAs) are expressed in tissue-specific pattern, but it is not clear how these are regulated. We aimed to identify squamous cell carcinoma (SCC)-specific lncRNAs and investigate mechanisms that control their expression and function. METHODS: We studied expression patterns and functions of 4 SCC-specific lncRNAs. We obtained 113 esophageal SCC (ESCC) and matched non-tumor esophageal tissues from a hospital in Shantou City, China, and performed quantitative reverse transcription polymerase chain reaction assays to measure expression levels of LINC01503. We collected clinical data from patients and compared expression levels with survival times. LINC01503 was knocked down using small interfering RNAs and oligonucleotides in TE7, TE5, and KYSE510 cell lines and overexpressed in KYSE30 cells. Cells were analyzed by chromatin immunoprecipitation sequencing, luciferase reporter assays, colony formation, migration and invasion, and mass spectrometry analyses. Cells were injected into nude mice and growth of xenograft tumors was measured. LINC01503 interaction with proteins was studied using fluorescence in situ hybridization, RNA pulldown, and RNA immunoprecipitation analyses. RESULTS: We identified a lncRNA, LINC01503, which is regulated by a super enhancer and is expressed at significantly higher levels in esophageal and head and neck SCCs than in non-tumor tissues. High levels in SCCs correlated with shorter survival times of patients. The transcription factor TP63 bound to the super enhancer at the LINC01503 locus and activated its transcription. Expression of LINC01503 in ESCC cell lines increased their proliferation, colony formation, migration, and invasion. Knockdown of LINC01503 in SCC cells reduced their proliferation, colony formation, migration, and invasion, and the growth of xenograft tumors in nude mice. Expression of LINC01503 in ESCC cell lines reduced ERK2 dephosphorylation by DUSP6, leading to activation of ERK signaling via MAPK. LINC01503 disrupted the interaction between EBP1 and the p85 subunit of PI3K, increasing AKT signaling. CONCLUSIONS: We identified an lncRNA, LINC01503, which is increased in SCC cells compared with non-tumor cells. Increased expression of LINC01503 promotes ESCC cell proliferation, migration, invasion, and growth of xenograft tumors. It might be developed as a biomarker of aggressive SCCs in patients.

Lymph Node Station-Based Nodal Staging System for Esophageal Squamous Cell Carcinoma: A Large-Scale Multicenter Study.

BACKGROUND: The American Joint Committee on Cancer (AJCC) nodal staging for esophageal squamous cell carcinoma (ESCC) has been defined by the number of metastatic lymph nodes (N system). However, the precise counting of individual positive lymph nodes is difficult and unreliable in some clinical settings, which calls for a more available and reliable system. This study examined the performance of a newly proposed nodal staging category, termed the S system, based on the number of metastatic lymph node stations. METHODS: Using the Kaplan-Meier method and Cox-regression analysis, this study retrospectively analyzed the overall survival (OS) of 2285 ESCC patients who underwent esophagectomy in three major China hospitals. Predictive models were constructed, and C-indices were computed to evaluate the discriminatory power of the S system, and to compare it with the N system. RESULTS: The categories defined by the S system were more homogeneous in terms of OS than those defined by the N system. Overall, the S system had a slightly better C-index (p = 0.659) than the N system ((p = 0.658). Subgroup analyses also showed that the C-index of the S system was slightly better than that of the N system for each subgroup of sex and age, but the two were comparable for each subgroup defined by the tumor location. CONCLUSION: The S system demonstrated a competing prognostic performance compared with the current AJCC N system. Due to the relatively easy accessibility of the number of metastatic lymph node stations, the S system may offer an easier option for cancer staging without a loss of discriminative power.

Investigation of hairpin DNA and chelerythrine interaction by a single bio-nanopore sensing interface.

Chelerythrine (CHE) is one of the potential drugs for cancer treatments. The interaction between hairpin DNA and CHE has been investigated by spectral and mass spectrometry methods. In this paper, the stability of hairpin DNA with different loop bases and its interaction with CHE were explored with a single α-hemolysin (α-HL) nanopore sensing interface. The results showed that the characteristic current pulses not only relate to the loop composition changes of the hairpin DNA, but also provide interaction information between CHE and the hairpin DNA molecules. The dwell time of current pulses for hairpin DNA was significantly increased (hundreds of ms) due to the addition of CHE, and two characteristic current distributions were recognized for the hairpin with T3 and C3 loops. The two characteristic current groups could be ascribed to the hairpin DNA and the ones with CHE. This study indicates that it is possible to study the interaction between single CHE and single hairpin DNA molecules by the single-nanopore sensing interface as an alternative method to conventional spectrometric methods for therapeutic mechanism and drug screening purposes.

A field amplification enhanced paper-based analytical device with a robust chemiluminescence detection module.

A sensitive detection method combined with an effective on-line concentration may improve the analytical performance of a paper-based analytical device (PAD), and its merits of low cost and portability in POCT are fully demonstrated. Here, a sensitive PAD system with chemiluminescence (CL) detection and electrokinetic preconcentration was introduced, and the performance was demonstrated by the detection of hemin. A commercially available low cost and miniaturized optical detection module was used for the CL detection. Firstly, hemin was stacked on a simple paper fluidic channel based on field amplified stacking (FAS), and then a CL reagent (luminol-H2O2) was loaded on the stacked band to initiate the CL reaction. The photons were directly detected using the detection module. With optimization of the background electrolyte (BGE), voltage and CL reagent, a limit of detection (LOD) of 0.58 nM for hemin was obtained with a linear range of 1-1000 nM (R2 = 0.995). With FAS, the signal intensity was about 13-fold enhanced. This PAD also exhibited satisfactory selectivity over possible interfering components at a 104 times higher concentration. The applicability of the PAD was demonstrated by the detection of hemin from iron supplements and human serum samples. With total manual operation, recovery rates of 84.8-115.6% were obtained with an RSD of less than 14.3%. With the introduction of the optical detection model, and together with FAS, both the LOD and dynamic range of this PAD were effectively improved.

SLC52A3 expression is activated by NF-κB p65/Rel-B and serves as a prognostic biomarker in esophageal cancer.

The human riboflavin transporter-3 (encoded by SLC52A3) plays a prominent role in riboflavin absorption. Interestingly, abnormal expression patterns of SLC52A3 in multiple types of human cancers have been recently noted. However, the molecular mechanisms underlying its dysregulation remain unclear. In this study, we find that SLC52A3 has two transcript variants that differ in the transcriptional start site, and encode different proteins: SLC52A3a and SLC52A3b. Importantly, aberrant expressions of SLC52A3 are associated with stepwise development of esophageal squamous cell carcinoma (ESCC) as well as the survival rates of ESCC patients. Functionally, SLC52A3a, but not SLC52A3b, strongly promotes the proliferation and colony formation of ESCC cells. Furthermore, SLC52A3 5'-flanking regions contain NF-κB p65/Rel-B-binding sites, which are crucial for mediating SLC52A3 transcriptional activity in ESCC cells. Chromatin immunoprecipitation and electrophoretic mobility shift assay reveal that p65/Rel-B bind to 5'-flanking regions of SLC52A3. Accordingly, NF-κB signaling upregulates SLC52A3 transcription upon TNFα stimulation. Taken together, these results elucidate the mechanisms underlying SLC52A3 overexpression in ESCC. More importantly, our findings identify SLC52A3 as both a predictive and prognostic biomarker for this deadly cancer.