Machine learning in the prediction of in-hospital mortality in patients with first acute myocardial infarction.

BACKGROUND: Persistent efforts are required to further reduce the in-hospital mortality of patients suffering from acute myocardial infarction (AMI), even in the face of a global trend of declining AMI-related fatalities. We investigated deep machine learning models for in-hospital death prediction in patients on their first AMI. METHOD: In this 2-center retrospective analysis, first AMI patients from Hospital I and Hospital II were included; 4783 patients from Hospital 1 were split in a 7:3 ratio between the training and testing sets. Data from 1053 AMI patients in Hospital II was used for further validation. 70 clinical information and laboratory examination parameters as predictive indicators were included. Logistic Regression Classifier (LR), Random Forests Classifier (RF), eXtreme Gradient Boosting (XGB), Support Vector Machine Classifier (SVM), Multilayer Perceptron (MLP), Gradient Boosting Machine (GBM), Bootstrapped Aggregation (Bagging) models with AMI patients were developed. The importance of selected variables was obtained through the Shapley Additive exPlanations (SHAP) method. The performance of each model was shown using the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (Average Precision; AP). RESULT: The in-hospital mortality for AMI in the training, testing, and validation sets were 5.7 %, 5.6 %, and 6.0 %, respectively. The top 8 predictors were D-dimer, brain natriuretic peptide, cardiogenic shock, neutrophil, prothrombin time, blood urea nitrogen, cardiac arrest, and phosphorus. In the testing cohort, the models of LR, RF, XGB, SVM, MLP, GBM, and Bagging yielded AUROC values of 0.929, 0.931, 0.907, 0.868, 0.907, 0.923, and 0.932, respectively. Bagging has good predictive value and certain clinical value in external validation with AUROC 0.893. CONCLUSION: In order to improve the forecasting accuracy of the risk of AMI patients, guide clinical nursing practice, and lower AMI inpatient mortality, this study looked into significant indicators and the optimal models for predicting AMI inpatient mortality.

ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade.

Despite advances in cancer treatment, immune checkpoint blockade (ICB) only achieves complete response in some patients, illustrating the need to identify resistance mechanisms. Using an ICB-insensitive tumor model, here we discover cisplatin enhances the anti-tumor effect of PD-L1 blockade and upregulates the expression of Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) in tumors. Arih1 overexpression promotes cytotoxic T cell infiltration, inhibits tumor growth, and potentiates PD-L1 blockade. ARIH1 mediates ubiquitination and degradation of DNA-PKcs to trigger activation of the STING pathway, which is blocked by the phospho-mimetic mutant T68E/S213D of cGAS protein. Using a high-throughput drug screen, we further identify that ACY738, less cytotoxic than cisplatin, effectively upregulates ARIH1 and activates STING signaling, sensitizing tumors to PD-L1 blockade. Our findings delineate a mechanism that tumors mediate ICB resistance through the loss of ARIH1 and ARIH1-DNA-PKcs-STING signaling and indicate that activating ARIH1 is an effective strategy to improve the efficacy of cancer immunotherapy.

The construction and analysis of a prognostic assessment model based on P53-related multi-genes in breast carcinoma.

BACKGROUND: Breast cancer ranks second in female tumor mortality, with an estimation of 2 million new cases diagnosed each year worldwide. METHODS: In our current study, we screened 13 genes highly distributed on the P53 phenotype which were significantly expressed and had a strong correlation with survival in the Cancer Genome Atlas breast cancer dataset. Least absolute shrinkage and selection operator Cox regression was conducted to construct the risk assessment model. Based on bioinformatics and statistical methods, we confirmed the credibility and validity of the model by training set and testing set. RESULTS: The result of comparing the other two previous hypoxia models was also satisfying. We also verified the model on one of the Gene Expression Omnibus datasets-GSE20685. Using clinical data from patients in the Cancer Genome Atlas, we acknowledged the risk score as an independent influence on breast cancer survival prognosis, and strong relevance was suggested between risk signature and age, lymphatic metastasis, tumor size and clinical stage by performing univariate and multivariate analysis. Immunology analysis demonstrated that the macrophages subset was positively associated with a risk score and other immune cell types had a negative effect with the risk score increases. The risk score was also emerging as a valuable prognostic factor for the prediction of chemotherapy drug curative effect because Gemcitabine, vinorelbine, paclitaxel and cisplatin known as a generic drug for breast cancer had more pleasing sensitivity in high-scored patients than low-scored patients. CONCLUSION: The P53-related risk assessment model is promising to be a potential predictor for the prognosis of patients with breast cancer and a powerful guide for the selection of therapeutic strategies.

Novel LncRNA AK023507 inhibits cell metastasis and proliferation in Papillary Thyroid Cancer through ß-catenin/Wnt Signaling Pathway.

INTRODUCTION: Papillary Thyroid Cancer (PTC) represents a commonly encountered type of thyroid malignancy whose occurrence and development is influenced by long non-coding RNA (LncRNA). A novel lncRNA (LncRNA AK023507), known to have tumor suppressive functions, was shown to prevent breast cancer cells from proliferating and metastasizing, but its mechanism in PTC is unclear. METHODS: Using PTC tissues and cell lines, the expression of LncRNA AK023507 was investigated by quantitative Real-time Polymerase Chain Reaction (qRT-PCR). The effects of knockdown or overexpression of LncRNA AK023507 on cell growth and movement were investigated through various cell experiments in vitro. The presence of important functional proteins was determined by Western blotting, with the recovery experiment used for verification. RESULTS: LncRNA AK023507 was found to have low expression in both the PTC cell lines and tissue samples. Knockdown of LncRNA AK023507 in PTC cells significantly promoted cell proliferation, migration, and invasion, while overexpression of LncRNA AK023507 resulted in the opposite effects. Furthermore, LncRNA AK023507 could regulate the expression of ß-catenin/Wnt signaling pathway as confirmed by recovery experiment. CONCLUSION: By acting through the ß-catenin/Wnt signaling pathway, LncRNA AK023507 prevented PTC cells from proliferating and metastasizing. These novel findings indicate that LncRNA AK023507 could be of prognostic and diagnostic value as a potential biomarker of PTC.

Relationship between COVID-19 vaccine hesitancy and willingness to pay for the booster dose of COVID-19 vaccine of oncology patients in Taizhou, China.

OBJECTIVE: This population-based study aimed to determine the hesitancy and willingness to pay (WTP) for the booster dose of a coronavirus disease (COVID-19) vaccine among patients with cancer in Taizhou, China. PATIENTS AND METHODS: A self-administered online questionnaire was administered to patients with cancer in Taizhou, China. The chi-square test, binary logistic regression model were used to evaluate the WTP for the booster dose of a COVID-19 vaccine. The minimum sample size was 218, determined by G*Power software (latest ver. 3.1.9.7). A total of 354 patients received the survey, and 256 (72.3%) patients responded. RESULTS: Overall, 69.9% (179/256) of respondents were willing to pay for the booster dose, and 78.8% (141/179) of these patients were willing to pay 1-99 CNY. Furthermore, 50.4% (129/256) of respondents were hesitant to receive a COVID-19 vaccine. Being unhesitant was significantly associated with WTP for the booster dose (aOR: 3.040; 95% CI: 1.669-5.540). CONCLUSION: Hesitant patients with cancer had a lower WTP for the booster dose against COVID-19 than non-hesitant participants. These results imply that further health education programmes are essential to decrease the hesitancy of patients with cancer and enhance booster dose vaccination rates for public health improvements.KEY MESSAGESOur research showed that 70% of patients with cancer are willing to pay for the booster dose of the COVID-19 vaccine, and most are willing to pay less than 100 CNY, and this result reflects the economic value and affordability of the third dose of vaccination.COVID-19 vaccine-hesitant patients with cancer had a lower willingness to pay for a booster dose against COVID-19 than non-hesitant participants and few patients are still unwilling to pay among patients do not hesitate to receive the third dose.Therefore, promoting willingness to pay among oncology patients and addressing vaccine hesitancy remains key.

Delphian lymph node metastasis predicts occult contralateral carcinoma for unilateral papillary thyroid carcinoma patients with contralateral benign nodules.

BACKGROUND: For unilateral PTC patients with benign nodules in the contralateral lobe evaluated preoperatively, the necessity of total thyroidectomy remains controversial. This study aimed to investigate the predictive factors for occult contralateral carcinoma and whether DLN metastasis could predict it. METHODS: A total of 148 patients with unilateral PTC and contralateral benign nodules who were treated with a near-total thyroidectomy or TT at a single institution between August 2018 and April 2020 were enrolled. Clinicopathological features such as age, sex, TgAb or TPOAb level, primary tumor location, nodule number in contralateral lobe, carcinoma number in primary lobe, tumor size, capsular invasion, central lymph node metastasis, DLN metastasis were analyzed to investigate the rate and predictive factors of occult contralateral carcinoma. RESULTS: 44.6% patients were diagnosed with occult contralateral thyroid carcinoma. Univariate analysis showed that sex (P = 0.008), mulifocality of primary carcinoma (P < 0.001), tumor size (P = 0.033), capsular invasion (P = 0.042), CLN metastasis (P = 0.004), DLN metastasis (P = 0.001) were associated with occult contralateral carcinoma. Multivariate analysis showed that multifocality of primary carcinoma (p = 0.000, OR = 9.729), DLN metastasis (p = 0.042, OR = 4.701), capsular invasion (p = 0.022, OR = 2.909), and male patients (p = 0.006, OR = 3.926) were all independent predictive factors. CONCLUSION: For unilateral PTC patients with benign nodules in the contralateral lobe evaluated preoperatively, multifocality of primary carcinoma, DLN metastasis, capsular invasion, and male patients are independent predictors of occult contralateral carcinoma. We suggest separate excision and frozen section of DLN intraoperatively, if DLNs were confirmed metastasized, a TT was highly recommended.

The utility of sentinel Lymph node biopsy in the lateral neck in papillary thyroid carcinoma.

Background: Regional lymph node metastases (LNMs) are very common in papillary thyroid carcinoma (PTC) and associate with locoregional recurrence. The appropriate management of cervical lymph nodes is very important. Therefore, this study evaluated the application of sentinel lymph node biopsy (SLNB) in the lateral neck in PTC patients. Methods: This prospective study was conducted from 1 November 2015 to 31 December 2017 and recruited 78 PTC patients treated with SLNB in the lateral neck and prophylactic lateral neck dissection (compartments II-IV) followed by thyroidectomy or lobectomy and central neck dissection. Results: There were 78 PTC patients enrolled and sentinel lymph nodes (SLNs) were detected among 77 patients. A total of 30 patients were diagnosed with SLN metastases (SLNMs). The remaining 47 patients were pathologically negative of SLN, whereas 4 patients were found with metastases in the non-SLN samples. The detection rate, sensitivity, specificity, and accuracy rate of SLNB in the lateral neck were 98.7%, 87.1%, 98.7%, and 93.6%, respectively. However, the values varied greatly in each specific compartment of the lateral neck, and all of them were no more than 80%. These 34 PTC patients diagnosed with lateral compartment LNM (LLNM) were more likely to be younger (41.38 vs. 48.95 years old, p = 0.002) and exhibit extrathyroidal extension (56.8% vs. 31.7%, p = 0.026) and central compartment LNM (66.7% vs. 12.1%, p < 0.001). Tumors located in the upper third of the thyroid lobe also had a significantly higher probability of LLNM compared with those in middle or inferior location (66.7% vs. 35.3% vs. 34.8%, p = 0.044). At last, age (OR=0.912, p = 0.026), tumor location (upper vs inferior, OR=17.478, p = 0.011), and central compartment LNM (OR=25.364, p < 0.001) were independently predictive of LLNM. Conclusions: SLNB can help surgeons to identify some PTC patients who may benefit from therapeutic lateral neck dissection and protect some patients from prophylactic lateral neck dissection. However, it cannot accurately indicate specific lateral compartment-oriented neck dissection. Meanwhile, LLNM is more likely to occur in PTC patients with younger age or upper pole tumors or central compartment LNM.

Treatment patterns, effectiveness, and patient-reported outcomes of palbociclib therapy in Chinese patients with advanced breast cancer: A multicenter ambispective real-world study.

BACKGROUND: Palbociclib was the only available cyclin-dependent kinase 4/6 inhibitor in China until very recently, and its effect has not been systemically evaluated among Chinese patients. This study aims to assess the efficacy, safety and patient-reported outcomes (PROs) of palbociclib plus endocrine therapy (ET) in real-world China. METHODS: An ambispective cohort study was conducted on patients with advanced HR+HER2- breast cancer who received palbociclib between July 2018, and November 2020 and were enrolled from 12 hospitals. Treatment patterns, survival outcomes, and safety events were documented, and PROs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items [EORTC QLQ-C30] and EuroQoL 5 dimensions [EQ-5D]) were analyzed. The Kaplan-Meier method was used to visualize and estimate the median progression-free survival (mPFS). Log-rank tests, Cox regressions, t tests, and chi-square tests were performed for comparison. RESULTS: A total of 190 patients (median follow-up of 18.0 months) were enrolled. Palbociclib was mostly combined with aromatase inhibitors (66.3%), fulvestrant (32.6%), and tamoxifen (1.1%). The mPFS values were 21.0, 14.0, and 7.0 months with palbociclib administered in first- (n = 83), second- (n = 41) and subsequent-line settings (n = 66), respectively. Endocrine sensitivity was significantly associated with patient prognosis (mPFS: 23.0, 12.0, and 6.0 months for endocrine naïve, acquired, and primary resistant patients, respectively, p < 0.01). The outcome was worse for patients who failed to meet the inclusion criteria of PALOMA-3 than for those who met the criteria (later-line: 6.0 months vs. 9.0 months). The most common adverse events (AEs) were neutropenia (74.2%; grade 3/4: 30.0%), fatigue (48.4%), anemia (32.6%), and thrombocytopenia (22.1%). PRO data suggested that palbociclib plus ET significantly improved cognitive and emotional function, pain symptoms, and overall quality of life. CONCLUSIONS: Palbociclib is effective for front-line use and for treating endocrine-sensitive patients in real-world China and is generally well tolerated. The prevalence of AEs in the Chinese population is different from that reported in the PALOMA-2/3 trials.

Fascin enhances the vulnerability of breast cancer to erastin-induced ferroptosis.

Ferroptosis, which is characterized by intracellular iron accumulation and lipid peroxidation, is a newly described form of regulated cell death that may play a key role in tumour suppression. In the present study, we investigated the expression profiles and biological effects of fascin actin-bundling protein 1 (Fascin, gene name FSCN1) in breast cancer. In addition, bioinformatics analysis of the TCGA cancer database and gain- and loss-of-function studies showed that Fascin enhances sensitivity to erastin-induced ferroptosis. Mechanistically, Fascin directly interacts with cysteine/glutamate transporter (xCT, gene name SLC7A11) and decreases its stability via the ubiquitin-mediated proteasome degradation pathway. Furthermore, we observed that Fascin is substantially upregulated in tamoxifen-resistant breast cancer cell lines, and drug-resistant cells were also more vulnerable to erastin-induced ferroptosis. Taken together, our findings reveal a previously unidentified role of Fascin in ferroptosis by regulating xCT. Thus, ferroptosis activation in breast cancer with high Fascin level may serve as a potential treatment.

Prophylactic Central Neck Dissection for cN1b Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: The value of prophylactic central neck dissection (PCND) for papillary thyroid carcinoma (PTC) with clinically evident lateral cervical lymph node metastases (cN1b) remains unclear. Therefore, a systematic review and meta-analysis was conducted to assess the efficacy and safety of PCND. METHODS: A comprehensive systematic search was conducted on PubMed, Web of Science, Cochrane library and Embase databases up to September 2021 to identify eligible studies. Controlled clinical trials assessing therapeutic effects and safety of PCND for cN1b PTC patients were included. The risk of bias for each cohort study was assessed using the Newcastle-Ottawa Scale (NOS). The primary outcomes were indexes related to the locoregional recurrence (LRR) and surgical complications. Review Manager software V5.4.0 was used for statistical analysis. A fixed effects model was adopted for the data without heterogeneity, otherwise a random effects model was used. RESULTS: We included 4 retrospective cohort studies, which comprised 483 PTC patients. There was no statistically significant difference in the central neck recurrence (CNR) (10.2% vs. 3.8%, relative risk (RR) = 1.82; 95%CI 0.90-3.67; P = 0.09), lateral neck recurrence (LNR) (5.1% vs. 7.7%, RR = 0.47; 95% CI 0.13-1.74; P = 0.26), and overall recurrence (OR) (18.9% vs. 16.9%, RR = 0.77; 95%CI 0.34-1.76; P = 0.54), between LND + PCND group and LND group. Simultaneously, PCND increased the risk of permanent hypoparathyroidism (11.4% vs. 4.5%, RR = 2.70, 95%CI 1.05-6.94; P = 0.04) and overall complications (17.0% vs. 5.3%, RR = 3.28; 95%CI 1.37-7.86; P = 0.008). CONCLUSIONS: This meta-analysis showed that PCND did not have any advantage in preventing LRR for cN1b PTC. Meanwhile, PCND may result in the increased rate of surgical complications. However, the current evidence is limited and more clinical trials are still needed to further clarify the true role of PCND. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, CRD42021281825.

Naringenin Regulates FKBP4/NR3C1/NRF2 Axis in Autophagy and Proliferation of Breast Cancer and Differentiation and Maturation of Dendritic Cell.

NRF2 is an important regulatory transcription factor involved in tumor immunity and tumorigenesis. In this study, we firstly identified that FKBP4/NR3C1 axis was a novel negative regulator of NRF2 in human breast cancer (BC) cells. The effect of FKBP4 appeared to be at protein level of NRF2 since it could not suppress the expression of NRF2 at mRNA level. Bioinformatics analysis and in vitro experiments further demonstrated that FKBP4 regulated NRF2 via regulating nuclear translocation of NR3C1. We then reported that naringenin, a flavonoid, widely distributed in citrus and tomato, could suppress autophagy and proliferation of BC cells through FKBP4/NR3C1/NRF2 signaling pathway in vitro and in vivo. Naringenin was also found to promote dendritic cell (DC) differentiation and maturation through FKBP4/NR3C1/NRF2 axis. Therefore, our study found that naringenin could induce inhibition of autophagy and cell proliferation in BC cells and enhance DC differentiation and maturation, at least in part, though regulation of FKBP4/NR3C1/NRF2 signaling pathway. Identification of FKBP4/NR3C1/NRF2 axis would provide insights for novel anti-tumor strategy against BC among tumor microenvironment.

Retroperitoneal metastasis synchronous with brain and mediastinal lymph nodes metastasis from breast invasive ductal carcinoma as the first site of distant metastasis: a case report and review of literature.

Breast carcinoma retroperitoneal metastasis is rare. The clinical symptoms of this disease are always non-specific. Laboratory tests are not always helpful for diagnosis and evaluation. We reported a case of a 52 year old Chinese patient who was diagnosed with retroperitoneal metastasis from breast invasive ductal carcinoma as the first site of distant metastasis synchronous with brain and mediastinal lymph nodes metastasis 4 years after modified radical mastectomy. Second-line chemotherapy of docetaxel and capecitabine was recommended. The response evaluation every two to three months was good. Unfortunately, the metastasis in the brain advanced. The patient was transferred to a radiotherapy department to receive radiotherapy and died 10 months later. We also review the related literature.

H19/let­7/Lin28 ceRNA network mediates autophagy inhibiting epithelial­mesenchymal transition in breast cancer.

Long non­coding RNA (lncRNA) H19 and Lin28 protein have been shown to participate in various pathophysiological processes, including cellular proliferation, autophagy and epithelial­mesenchymal transition (EMT). A number of studies have investigated lncRNAs, microRNAs and mRNAs, and their roles in the initiation and progression of cancer, in doing so identifying competitive endogenous RNA (ceRNA) networks, including the H19/let­7/Lin28 network. However, whether the H19/let­7/Lin28 ceRNA network is involved in autophagy and EMT in breast cancer (BC) remains unclear. The present study demonstrated that the H19/let­7/Lin28 loop was required for the downregulation of autophagy in BC cells via western blot analysis, reverse transcription­quantitative PCR and autophagy flux monitoring. Using wound healing, migration and invasion assays, and morphological assays, the H19/let­7/Lin28 loop was revealed to promote EMT in BC cells. Moreover, the H19/let­7/Lin28 network was found to contribute to autophagy by inhibiting EMT in BC cells. To the best of our knowledge, the present study is the first to suggest the important roles of the H19/let­7/Lin28 ceRNA network in BC autophagy and EMT, thus providing insight for the use of these molecules as prognostic biomarkers and therapeutic targets in BC metastasis.

Increased Expression of Exosomal AGAP2-AS1 (AGAP2 Antisense RNA 1) In Breast Cancer Cells Inhibits Trastuzumab-Induced Cell Cytotoxicity.

BACKGROUND Trastuzumab therapy is important for patients with HER2-positive breast cancer, but more and more patients have experienced trastuzumab resistance during recent years. Accumulating evidence from recent studies showed that long non-coding RNAs (lncRNAs) play essential roles in chemoresistance of various cancer types, but the precise role of lncRNAs in trastuzumab resistance is unclear. In the present study, we aimed to identify the biofunction of lncRNA APAP2-AS1 in tranastuzumab resistance and to reveal the underlying regulatory mechanism. MATERIAL AND METHODS By culturing HER2-positive SKBR-3 and BT474 cells with transtuzumab-containing medium, we built trastuzumab-resistant cells. Quantitative real-time PCR was used to test the expression of AGAP2-AS1 in the built trastuzumab-resistant cells. Cell viability assay and TUNEL assay were used to test the cell viability and apoptosis in each group. Exosomes were purified from cells cultured in exosomes-depleted FBS and identified by transmission electron microscopy. RESULTS qRT-PCR assay suggested that AGAP2-AS1 was upregulated in the built trastuzumab-resistant cells when compared with parental sensitive cells. Cell viability assay showed that silencing of AGAP2-AS1 enhanced the cytotoxicity induced by trastuzumab treatment. Mechanistically, we revealed that AGAP2-AS1 was secreted outside cells by incorporation into exosomes in an hnRNPA2B1-dependent manner. More importantly, co-culture AGAP2-AS1-containing exosomes with sensitive cells reduced the trastuzumab-induced cell death, and silencing of AGAP2-AS1 from exosomes reversed this effect. In summary, AGAP2-AS1 promotes trastuzumab resistance of breast cancer cells through packaging into exosomes. CONCLUSIONS Knockdown of AGAP2-AS1 may be helpful for improving the clinical outcome for HER2+ breast cancer patients and could serve as a therapeutic target.

Immunotherapy for gastric cancer: dilemmas and prospect.

Gastric cancer remains the second most common cause of cancer-related death worldwide. Because of the poor prognosis of late-stage gastric cancer patients, it is imperative to develop new strategies to improve the survival rate of this disease. Currently, immunotherapy is considered as an innovative approach for cancers such as lung cancer, gastric cancer and breast cancer. In fact, previous works have revealed promising results in this field. With further understanding of immunogenomics of gastric cancer, new immune checkpoint regulators could become more important. In addition, whole-genome sequencing and genome editing provide us with more information on the heterogeneity of gastric cancer, showing helpful tools to identify new predictive biomarkers and to achieve personalized treatment. Further research and better understanding of the functions of immune system will enhance immunotherapy treatment in the future.

Cytotoxicity of Tanshinone IIA combined with Taxol on drug-resist breast cancer cells MCF-7 through inhibition of Tau.

Drug resistance represents a major obstacle to improving the overall response and survival of cancer patients. Taxol is one of the most commonly used chemotherapy agents in breast cancer. As with many cancer therapeutic agents, resistance remains a significant problem when using Taxol to treat malignancies. In this study, estrogen receptor positive breast cancer cells MCF-7 were induced Taxol resistance. And Tanshinone IIA combined with Taxol was chosen to treat it. The drugs combination showed additive effect in most drug concentrations. Drug resistance cancer cells showed a higher microtubule associated protein (Tau) expression, which was considered as one of the reasons for Taxol resistance. Tanshinone IIA inhibited the expression of Tau in MCF-7 cells and resulted in higher sensibility of Taxol. Moreover, Tanshinone IIA also showed cytotoxicity to MCF-7, which might be related to its estrogenicity effect. In conclusion, the combination of Tanshinone IIA and Taxol showed higher cytotoxicity to Taxol resistant MCF-7 cells, which might be related to the inhibition of Tau.

Direct binding of microRNA-21 pre-element with Regorafenib: An alternative mechanism for anti-colorectal cancer chemotherapy?

The Regorafenib is a broad-spectrum kinase inhibitor that has been approved to treat colorectal cancer (CRC). However, evidences have shown that the agent is also implicated in drug interaction with microRNA-21 (miR-21), an oncogenic miRNA which plays a key role in resisting programmed cell death in CRC cells. Here, we supposed that, instead of kinase inhibition, Regorafenib can directly bind to and then stabilize miR-21 pre-element, thus preventing RNase Dicer-meditated cleavage of the pre-element to mature miR-21. In order to verify the notion, an in silico-in vitro integrated investigation of the direct intermolecular interaction between Regorafenib and miR-21 pre-element was performed by using active pocket identification, RNA-ligand docking, molecular dynamics (MD) simulation, binding energetic analysis, and fluorescence-based assay. It was revealed that the Regorafenib can bind at the major groove-like stem region of miR-21 pre-element through three geometrically satisfactory hydrogen bonds (H-bonds) as well as a number of hydrophobic forces and π-π stacking, conferring strong specificity and high stability to the RNA-ligand complex system (Kd=0.73µM). Separate inversion mutation of two base pairs (G6C, C12G) and (A13U, U4A) that are involved in the H-bonding can considerably impair the affinity of Regorafenib to miR-21 pre-element, with Kd increase to 27 and 96µM, respectively. All these supported that Regorafenib can directly bind to miR-21 pre-element at molecular level and the binding mode can be properly modeled by using the proposed integrated strategy. This study would provide a potential, alternative mechanism for anti-colorectal cancer chemotherapy with Regorafenib.

A systematic analysis of the resistance and sensitivity of HER2YVMA receptor tyrosine kinase mutant to tyrosine kinase inhibitors in HER2-positive lung cancer.

Human epidermal growth factor receptor 2 (HER2) has become a well-established target for the treatment of HER2-positive lung cancer. However, a frequently observed in-frame mutation that inserts amino acid quadruplex Tyr776-Val777-Met778-Ala779 at G776 (G776(YVMA)) in HER2 kinase domain can cause drug resistance and sensitivity, largely limiting the application of reversible tyrosine kinase inhibitors in lung cancer therapy. A systematic investigation of the intermolecular interactions between the HER2(YVMA) mutant and clinical small-molecule inhibitors would help to establish a complete picture of drug response to HER2 G776(YVMA) insertion in lung cancer, and to design new tyrosine kinase inhibitors with high potency and selectivity to target the lung cancer-related HER2(YVMA) mutant. Here, we combined homology modeling, ligand grafting, structure minimization, molecular simulation and binding affinity analysis to profile a number of tyrosine kinase inhibitors against the G776(YVMA) insertion in HER2. It is found that the insertion is far away from HER2 active pocket and thus cannot contact inhibitor ligand directly. However, the insertion is expected to induce marked allosteric effect on some regions around the pocket, including A-loop and hinges connecting between the N- and C-lobes of HER2 kinase domain, which may exert indirect influence to inhibitor binding. Most investigated inhibitors exhibit weak binding strength to both wild-type and mutant HER2, which can be attributed to steric hindrance that impairs ligand compatibility with HER2 active pocket. However, the cognate inhibitor lapatinib and the non-cognate inhibitor bosutinib were predicted to have low affinity for wild-type HER2 but high affinity for HER2(YVMA) mutant, which was confirmed by subsequent kinase assay experiments; the inhibitory potencies of bosutinib against wild-type and mutant HER2 were determined to be IC(50) > 1000 and =27 nM, respectively, suggesting that the bosutinib might be exploited as a selective inhibitor for mutant over wild-type HER2. Structural examination revealed that formation of additional non-bonded interactions such as hydrogen bonds and hydrophobic contacts with HER2 A-loop region due to G776(YVMA) insertion is the primary factor to improve bosutinib affinity upon the mutation.

Transcriptional profiling of differentially expressed long non-coding RNAs in breast cancer.

Long non-coding RNAs (lncRNAs) are subclass of noncoding RNAs that have been recently shown to play critical roles in cancer biology. However, little is known about their mechanistic role in breast cancer pathogenesis, especially in triple-negative breast carcinomas (TNBC) that have particular poor outcomes. This study was specifically designed to identify the signatures relevant lncRNAs in breast cancer and characterize lncRNAs that modulate the phenotype. Here we provide detailed methods and analysis of microarray data, which is deposited in the Gene Expression Omnibus (GEO) with the accession number GSE64790. The basic analysis as contained in the manuscript published in Oncotarget with the PMID 26078338. These data can be used to further elucidate the mechanisms of breast cancer.

Identification of novel long non-coding RNAs in triple-negative breast cancer.

Triple-negative breast carcinomas (TNBC) are characterized by particularly poor outcomes, and there are no established markers significantly associated with prognosis. Long non-coding RNAs (lncRNAs) are subclass of noncoding RNAs that have been recently shown to play critical roles in cancer biology. However, little is known about their mechanistic role in TNBC pathogenesis. In this report, we investigated the expression patterns of lncRNAs from TNBC tissues and matched normal tissues with Agilent Human lncRNA array. We identified 1,758 lncRNAs and 1,254 mRNAs that were differentially expressed (≥ 2-fold change), indicating that many lncRNAs are significantly upregulated or downregulated in TNBC. Among these, XR_250621.1 and NONHSAT125629 were the most upregulated and downregulated lncRNAs respectively. qRT-PCR was employed to validate the microarray analysis findings, and results were consistent with the data from the microarrays. GO and KEGG pathway analysis were applied to explore the potential lncRNAs functions, some pathways including microtubule motor activity and DNA replication were identified in TNBC pathogenesis. Our study revealed that a set of lncRNAs were differentially expressed in TNBC tissues, suggesting that they may play role in TNBC. These results shed light on lncRNAs' biological functions and provide useful information for exploring potential therapeutic targets for breast cancer.