Hexokinase 2 nonmetabolic function-mediated phosphorylation of IκBα enhances pancreatic ductal adenocarcinoma progression.

Aberrant signaling in tumor cells induces nonmetabolic functions of some metabolic enzymes in many cellular activities. As a key glycolytic enzyme, the nonmetabolic function of hexokinase 2 (HK2) plays a role in tumor immune evasion. However, whether HK2, dependent of its nonmetabolic activity, plays a role in human pancreatic ductal adenocarcinoma (PDAC) tumorigenesis remains unclear. Here, we demonstrated that HK2 acts as a protein kinase and phosphorylates IκBα at T291 in PDAC cells, activating NF-κB, which enters the nucleus and promotes the expression of downstream targets under hypoxia. HK2 nonmetabolic activity-promoted activation of NF-κB promotes the proliferation, migration, and invasion of PDAC cells. These findings provide new insights into the multifaceted roles of HK2 in tumor development and underscore the potential of targeting HK2 protein kinase activity for PDAC treatment.

Risk prediction of second primary malignancies after gynecological malignant neoplasms resection with and without radiation therapy: a population-based surveillance, epidemiology, and end results (SEER) analysis.

PURPOSE: The association between post-resection radiotherapy for primary gynecological malignant neoplasms (GMNs) and the development of secondary primary malignancies (SPMs) remains a subject of debate. This study represents the first population-based analysis employing a multivariate competitive risk model to assess risk factors for this relationship and to develop a comprehensive competing-risk nomogram for quantitatively predicting SPM probabilities. MATERIALS AND METHODS: In our study, data on patients with primary GMNs were retrospectively collected from the Epidemiology, Surveillance and End Results (SEER) database from 1973 to 2015. The incidence of secondary malignant tumors diagnosed at least six months after GMN diagnosis was compared to determine potential risk factors for SPMs in GMN patients using the Fine and Gray proportional sub-distribution hazard model. A competing-risk nomogram was constructed to quantify SPM probabilities. RESULTS: A total of 109,537 patients with GMNs were included in the study, with 76,675 and 32,862 GMN patients in the training and verification sets, respectively. The competing-risk model analysis identified age, primary tumor location, tumor grade, disease stage, chemotherapy, and radiation as risk factors for SPMs in GMN patients. Calibration curves and ROC curves in both training and verification cohorts demonstrated the predictive accuracy of the established nomogram, which exhibited a good ability to predict SPM occurrence. CONCLUSIONS: This study presents the nomogram developed for quantitatively predicting SPM probabilities in GMN patients for the first time. The constructed nomogram can assist clinicians in designing personalized treatment strategies and facilitate clinical decision-making processes.

RMI2 is a novel prognostic and predictive biomarker for breast cancer.

BACKGROUND: RecQ-mediated genome instability 2 (RMI2) maintains genome stability by promoting DNA damage repair. It has been reported to accelerate the progression of several tumors. However, the functional mechanism of RMI2 in breast cancer remains unclear. METHODS: Gene expression profiles were obtained from TCGA, GTEx, and GEO databases. The expression of RMI2 and its prognostic value in breast cancer was explored. In addition, we calculated pooled standardized mean deviation (SMD) and performed a summary receiver operating characteristic (sROC) curve analysis to further determine RMI2 expression status and diagnostic significance. The functions and related signaling pathways were investigated based on GO and KEGG analyses. The PPI network was constructed by combining the STRING database and Cytoscape software. Subsequently, in vitro assays were conducted to detect the effect of RMI2 on the proliferation and migration of breast cancer cells. RESULTS: The expression of RMI2 was markedly upregulated in breast cancer tissues relative to that in normal tissues. Moreover, pooled SMD further confirmed the overexpression of RMI2 in breast cancer (SMD = 1.29, 95% confidence interval (CI): 1.18-1.41, p = 0.000). The sROC curve analysis result suggested that RMI2 had a relatively high diagnostic ability in breast cancer (AUC = 0.87, 95% CI: 0.84-0.90). High RMI2 expression was associated with poor prognosis. GO and KEGG analyses revealed that RMI2 was closely related to cell adhesion, various enzyme activities, and PI3K/AKT signaling pathway. PPI analysis showed that RMI2 had interactions with proteins involved in DNA damage repair. knockdown of RMI2 remarkably inhibited the proliferation and migration of breast cancer cells, while overexpression of RMI2 exerted the opposite effects. Furthermore, we identified that RMI2 accelerates the proliferation and migration of breast cancer cells via activation of the PI3K/AKT pathway. CONCLUSION: The results suggest that RMI2 is a potential diagnostic and prognostic biomarker associated with cell proliferation and migration, and may be used as a novel therapeutic target for breast cancer in the future.

The clinical implication of soluble PD-L1 (sPD-L1) in patients with breast cancer and its biological function in regulating the function of T lymphocyte.

This work investigated the clinical prognostic implications and biological function of plasma soluble programmed cell death ligand 1 in breast cancer patients. Plasma sPD-L1 levels of recurrent/metastatic breast cancer patients were determined, and the association of sPD-L1 levels and metastatic progression-free survival and metastatic overall survival was assessed. The PD-L1 expression on breast cancer cells was analyzed by flow cytometry, and the level of sPD-L1 in the supernatant of breast cancer cells was determined by enzyme-linked immunosorbent assay. Furthermore, the effect of sPD-L1 on the proliferation and apoptosis of T lymphocytes was detected by WST-1 assay and flow cytometry. The plasma sPD-L1 levels in 208 patients with recurrent/metastatic breast cancer before receiving first-line rescue therapy were measured. The optimal cutoff value of plasma sPD-L1 for predicting disease progression was 8.774 ng/ml. Univariate and multivariate analyses identified high sPD-L1 level (≥ 8.774 ng/ml) and visceral metastasis were independent factors associated with poor prognosis. Relevance analysis showed that the plasma sPD-L1 level was weaklyassociated with some systemic inflammation markers, including white cell count (WBC), absolute monocytecount, and absolute neutrophil count. Furthermore, we found sPD-L1 could be found in supernatant of culture with breast cancer cell line expressing PD-L1 on the cell surface and inhibit T lymphocyte function, playing a negative regulatory role in cellular immunity. sPD-L1 was a good tumor predictive maker in breast cancer and it may play a potentially important role in immune tolerance.

Ultrasensitive detection of saccharides using terahertz sensor based on metallic nano-slits.

Unambiguous identification of trace amounts of biochemical molecules in a complex background using terahertz spectroscopy is extremely challenging owing to the extremely small absorption cross sections of these molecules in the terahertz regime. Herein, we numerically propose a terahertz nonresonant nano-slits structure that serves as a powerful sensor. The structure exhibits strongly enhanced electric field in the slits (five orders of magnitude), as well as high transmittance over an extra-wide frequency range that covers the characteristic frequencies of most molecules. Fingerprint features of lactose and maltose are clearly detected using this slits structure, indicating that this structure can be used to identify different saccharides without changing its geometrical parameters. The absorption signal strengths of lactose and maltose with a thickness of 200 nm are strongly enhanced by factors of 52.5 and 33.4, respectively. This structure is very sensitive to thin thickness and is suitable for the detection of trace sample, and the lactose thickness can be predicted on the basis of absorption signal strength when the thickness is less than 250 nm. The detection of a mixture of lactose and maltose indicates that this structure can also achieve multi-sensing which is very difficult to realize by using the resonant structures.

The microRNA miR-181c enhances chemosensitivity and reduces chemoresistance in breast cancer cells via down-regulating osteopontin.

Acquired resistance to chemotherapy is a frequent challenge in cancer care and one of the leading causes for failing breast cancer therapies. There is accumulative clinical and experimental evidence indicating that microRNAs (miRNAs) play a crucial role in developing therapeutic resistance in cancer cells. We aimed to explore key miRNAs and associated mechanisms by which breast cancer develops chemoresistance. In this study, we found that a particular miRNA species, miR-181c, was significantly low-expressed in breast cancer cell line MCF-7 which developed chemoresistance towards doxorubicin (Adriamycin, ADR, subclone renamed as MCF-7/ADR) than in the wild-type MCF-7 cells. Induced overexpression of miR-181c significantly inhibited cell proliferation, reversed the chemoresistance towards doxorubicin, and reduced the growth of resistant breast cancer xenograft tumors in vitro and in vivo. Using a bioinformatics approach, we also identified osteopontin (OPN) as a direct target of miR-181c. In contrast to low miR-181c expression in MCF-7/ADR cells, OPN showed a reversely high expression in resistant MCF-7/ADR cells. Our results suggest that miR-181c may regulate chemosensitivity and chemoresistance by downregulating OPN, resulting in enhanced p53-dependent transactivation and apoptosis in resistant breast cancer cells. This study provides new insights to develop effective interventions for cancer patients with acquired resistance to chemotherapy.

A sensitive and selective terahertz sensor for the fingerprint detection of lactose.

Special recognition to molecules is essential for many biochemical processes, thus highly sensitive sensing methods for molecule recognition are strongly demanded. Recently, metamaterials present a unique platform for sensing applications owing to their exotic properties. In the current work, a metamaterial sensor for enhanced fingerprint detection of lactose based on resonant coupling of plasmonic modes of split-ring resonators (SRRs) and terahertz characteristic modes of lactose was theoretically and experimentally demonstrated. Large electric field enhancement (about 120 times) at the gap of SRRs allows for the highly sensitive detection. A narrow transmittance peak in the broader transmittance dip which corresponded to the characteristic modes of lactose was observed due to the resonant coupling, and the differential transmittance enhanced as the lactose concentration increased. The experimental result agreed well with the theoretical analysis. Moreover, the selectivity of this SRRs sensor for the target molecule was also verified by using fructose. A low amount of lactose, as small as 20 mg/mL was successfully detected in the experiment. Our study opens a new avenue to exploit new materials or devices for molecule sensing with high sensitivity and selectivity.

Knockdown of lncRNA H19 restores chemo-sensitivity in paclitaxel-resistant triple-negative breast cancer through triggering apoptosis and regulating Akt signaling pathway.

Triple negative breast cancer (TNBC) is associated with poor prognosis and systemic chemotherapy is the only treatment for TNBC. However, development of chemo-resistance remains a major obstacle for TNBC treatment. Paclitaxel-resistance is mainly related to the activation of the Akt signaling pathway and deregulation of apoptotic regulatory proteins. LncRNAs are frequently dysregulated in various malignancies, including breast cancer, facilitating cell proliferation, metastasis and drug resistance. LncRNA H19 is overexpressed in approximately 70% of breast cancer patients, and has been reported to confer chemo-resistance in breast cancer. In the present study, we investigated the expression level of lncRNA H19 in paclitaxel-resistant and paclitaxel-sensitive cell lines. The results showed that the level of lncRNA H19 expression in paclitaxel-resistant cells was significantly higher than that in paclitaxel-sensitive cells, and knockdown of lncRNA H19 might restore chemo-sensitivity in paclitaxel-resistant TNBC by mediating the AKT signaling pathway. Thus, lncRNA H19 might be an efficient therapeutic target in paclitaxel-resistant TNBC treatment.

Correlation between gastrointestinal hormones and anxiety-depressive states in irritable bowel syndrome.

The aim of this study was to investigate the mechanism(s) of action of gastrointestinal hormones in the pathogenesis of irritable bowel syndrome (IBS), and the correlation between gastrointestinal hormones and psychological factors. Patients with IBS were divided into IBS with normal emotional state ratings and IBS in anxiety-depressive states groups. The two groups were then subdivided into IBS-constipation predominant (IBS-C) and IBS-diarrhea predominant (IBS-D) groups. Non-IBS patients with normal depression and anxiety ratings were recruited as controls. The serum concentrations of somatostatin (SS) and vasoactive intestinal peptide (VIP) were measured by radioimmunoassay, and the expression of SS and VIP in the colonic mucosa was detected by immunohistochemistry and radioimmunoassay. The anxiety-depression scores of patients with IBS were significantly different from those of the control group (P<0.05). The expression levels of SS and VIP in the serum and colonic mucosa of the patients with IBS were higher compared with those of the control group. Furthermore, the expression level of SS in the IBS-C group demonstrated a significantly larger increase than that in the IBS-D group (P<0.05); however, there was no significant difference in the expression of VIP between the IBS-C and IBS-D groups (P>0.05). In addition, the expression levels of SS and VIP in the IBS groups with normal emotional state ratings were notably different from those in the IBS groups in anxiety-depressive states (P<0.05). Anxiety-depressive states may lead to changes in the secretion of SS and VIP, and subsequently to changes in gastrointestinal motility and function.