The deubiquitinase BRCC3 increases the stability of ZEB1 and promotes the proliferation and metastasis of triple-negative breast cancer cells.

Triple negative breast cancer (TNBC) has a high recurrence rate, metastasis rate and mortality rate. The aim of this study is to identify new targets for the treatment of TNBC. Clinical samples are used for screening deubiquitinating enzymes (DUBs). MDA-MB-231 cells and a TNBC mouse model are used for in vitro and in vivo experiments, respectively. Western blot analysis is used to detect the protein expressions of DUBs, zinc finger E-box binding homeobox 1 (ZEB1), and epithelial-mesenchymal transition (EMT)-related markers. Colony formation and transwell assays are used to detect the proliferation, migration and invasion of TNBC cells. Wound healing assay is used to detect the mobility of TNBC cells. Immunoprecipitation assay is used to detect the interaction between breast cancer susceptibility gene 1/2-containing complex subunit 3 (BRCC3) and ZEB1. ZEB1 ubiquitination levels, protein stability, and protein degradation are also examined. Pathological changes in the lung tissues are detected via HE staining. Our results show a significant positive correlation between the expressions of BRCC3 and ZEB1 in clinical TNBC tissues. Interference with BRCC3 inhibits TNBC cell proliferation, migration, invasion and EMT. BRCC3 interacts with ZEB1 and interferes with BRCC3 to inhibit ZEB1 expression by increasing ZEB1 ubiquitination. Interference with BRCC3 inhibits TNBC cell tumorigenesis and lung metastasis in vivo. In all, this study demonstrates that BRCC3 can increase the stability of ZEB1, upregulate ZEB1 expression, and promote the proliferation, migration, invasion, EMT, and metastasis of TNBC cells, providing a new direction for cancer therapy.

Vasculogenic mimicry regulates immune infiltration and mutational status of the tumor microenvironment in breast cancer to influence tumor prognosis.

BACKGROUND: Vasculogenic mimicry (VM) refers to the direct formation of microcirculatory ducts by invasive malignant tumors via cellular phenotypic transformation. However, there is a lack of VM-based biomarkers for breast cancer. METHODS: We obtained transcriptomic expression data, single cell sequencing data, and clinical data of patients from The Cancer Genome Atlas Program (TCGA) database and GEO database, performed single cell analysis to obtain specific type annotations of breast cancer cells and analyzed their spatial expression analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analyses as well as Gene Set Enrichment Analysis (GSEA) analyses were performed to clarify the biological pathways and tumor functional enrichment relationships of the major expressed genes of VM in the breast cancer bulk data specimens. VM biomarkers were constructed. Meanwhile, the relationship between VM scores and tumor immune infiltration in breast cancer was analyzed using MCPcounter and ssGSEA methods. In addition, we assessed the specific relationship between NDRG1, a key VM gene in breast cancer, and tumor colonization, adhesion and invasion by biological experiments in breast cancer cell lines. RESULTS: The main cell types of breast cancer (BRCA) samples were annotated by single cell transcriptome analysis. Most of the VM-high group was present in epithelial cells, whereas the VM-low group was present in immune and stromal cells. Multiple tumor pathways such as TGFß p53 and MAPK were closely associated with VM-mediated breast cancer infiltration and invasion. A prognostic model of breast cancer based on VM key genes was constituted. Prognostic stratification of breast cancer was successfully achieved for the TCGA-BRCA and GSE58812 datasets. Through immune infiltration analysis, we found that differential expression of VM markers was associated with multiple immune cell regulation. In MDA-MB-231 and MDA-MB-453 cell lines, we found that the NDRG1 gene significantly promoted colony formation of breast cancer cells. CONCLUSION: Our constructed VM-related gene-based model of breast cancer biology holds promise for prognostic prediction and patient stratification of breast cancer. This may provide a potentially clinically valuable aid in promoting a deeper understanding of the biological regulation of VM in breast cancer and exploring the specific mechanisms of tumor angiogenesis and breast cancer development.

LncRNA PRKCQ-AS1 regulates paclitaxel resistance in triple-negative breast cancer cells through miR-361-5p/PIK3C3 mediated autophagy.

Paclitaxel (PTX) resistance is a key cause of chemotherapy failure in patients with triple negative breast cancer (TNBC). The aim of this study is to investigate the effect and mechanism of long non-coding RNA (lncRNA) on the PTX resistance of TNBC cells through autophagy. MDA-MB-231 cells are used to induce the PTX-resistant TNBC cell line MDA-MB-231.PR (MDR) by increasing dose intermittently. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the mRNA levels of phosphoinositide-3-kinase class 3 (PIK3C3), miR-361-5p and lncRNA PRKCQ-AS1 in the cells, and Western blot analysis was used to detect the protein expressions of PIK3C3, autophagy-related, drug-resistant and apoptosis-related genes. MDC staining detected the formation of autophagic vacuoles. The interactions between miR-361-5p and PIK3C3 and between lncRNA PRKCQ-AS1 and miR-361-5p were verified by dual-luciferase assay. Cell viability, apoptosis, migration and invasion were assessed by performing MTT, flow cytometry assay, and transwell assay. The mRNA level of miR-361-5p and the autophagy and drug resistance levels of TNBC PTX-resistant cells were significantly up-regulated. miR-361-5p could target autophagy-related gene PIK3C3, and overexpression of miR-361-5p could down-regulate PIK3C3 protein expression and autophagy level and PTX resistance of MDR cells. LncRNA PRKCQ-AS1 was selected through bioanalysis, and miR-361-5p could target lncRNA PRKCQ-AS1. In addition, lncRNA PRKCQ-AS1 level was up-regulated in TNBC PTX-resistant cells, and knockdown of lncRNA PRKCQ-AS1 could weaken autophagy and drug resistance level and could promote cell apoptosis. Overexpression of lncRNA PRKCQ-AS1 reversed the pro-apoptotic effect and down-regulation of autophagy and resistance levels was induced by miR-361-5p. In vivo experiments were performed to verify the role of lncRNA PRKCQ-AS1. We demonstrate that down-regulation of lncRNA PRKCQ-AS1 weakened PTX resistance and promoted cell apoptosis by miR-361-5p/PIK3C3 mediated autophagy.

Real-world outcomes for Chinese breast cancer patients with tumor location of central and nipple portion.

Background: The association between tumor location and breast cancer prognosis has been controversial. We sought to explore the relationship between tumors located in central and nipple portion (TCNP) and Chinese breast cancer. Patients and methods: A total of 1,427 breast cancer patients were recruited. There were 328 cases of TCNP and 1,099 cases of tumors in the breast peripheral quadrant (TBPQ). The chi-square test was used to compare different variables between TCNP and TBPQ groups. A one-to-one propensity score matching (PSM) was applied to construct a matched sample consisting of pairs of TCNP and TBPQ groups. Kaplan-Meier curves were used for survival analysis of disease-free survival (DFS), breast cancer-specific survival (BCSS) and overall survival (OS). The Cox proportional hazards regression model was applied to identify prognostic risk factors. Results: The median follow-up time was 58 months. Compared to TBPQ, TCNP patients had significantly larger tumor size, more frequent metastasis to lymph nodes (LN) and more proportions of TNM stage II-III. DFS, OS and BCSS rates were markedly lower in the TCNP group as compared to the TBPQ group before and after PSM (all p < 0.05). Multivariate Cox analysis showed that TCNP was an independent prognostic factor for breast cancer. Subgroup analysis indicated that for breast molecular subtypes and TNM stage II-III breast cancer, TCNP were related to worse prognosis. Multivariate logistic regression revealed that TCNP was an independent contributing factor for LN metastasis. Conclusion: In Chinese breast cancer, compared to TBPQ, TCNP is associated with more LN metastasis and poorer prognosis.

Male Breast Carcinoma Metastatic to the Choroid: A Case Report and Opinions of Management.

Male breast carcinoma metastatic to the choroid is very rare and often related to poor prognosis. Herein, we report the findings in a Chinese male breast cancer patient who developed choroidal metastasis, and give opinions on systemic treatments. A 45-year-old Chinese male represented with difficulty breathing and visual impairment in the left eye 6 years after his breast cancer surgery and postoperative adjuvant treatment. PET/CT revealed multi-organs metastasis of the patient. The IHC indicated the lung lesion to be originated from the breast (ER+/PR+/HER2-). Eye examination provided evidence for breast cancer choroidal metastasis. Two cycles of TX (docetaxel + capecitabine) followed by two courses of GP (gemcitabine + cis-platinum) were applied as salvage chemotherapy. Metastases in his lung and bone remained stable. As for choroidal metastasis, a regimen of CDK4/6 inhibitor (Palbociclib) plus fulvestrant was recommended to the patient, which led to a good response. Notably, CDK4/6 inhibitor combined with endocrine therapy may be considered as an effective treatment for hormonal receptor-positive breast cancer patients with choroidal metastasis. We recommend that eye examination should not be neglected in breast cancer patients.

Development of prognostic nomograms using institutional data for patients with triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is an aggressive disease. Nomograms can predict prognosis of patients with TNBC. Methods: A total of 745 eligible TNBC patients were recruited and randomly divided into training and validation groups. Endpoints were disease-free survival and overall survival. Concordance index, area under the curve and calibration curves were used to analyze the predictive accuracy and discriminative ability of nomograms. Results: Based on the training cohort, neutrophil-to-lymphocyte ratio, positive lymph nodes, tumor size and tumor-infiltrating lymphocytes were used to construct a nomogram for disease-free survival. In addition, age was added to the overall survival nomogram. Conclusion: The current study developed and validated well-calibrated nomograms for predicting disease-free survival and overall survival in patients with TNBC.

Serum TSH levels are associated with postoperative recurrence and lymph node metastasis of papillary thyroid carcinoma.

OBJECTIVE: To explore the relationship between thyroid-stimulating hormone (TSH) levels in the serum and postoperative recurrence and lymph node metastasis (LNM) in papillary thyroid cancer (PTC) patients after surgery. METHODS: We selected 272 patients diagnosed with PTC from June 2011 to July 2014. The clinical and pathological data of 272 PTC patients were collected at the First Affiliated Hospital of Wenzhou Medical University and analysed retrospectively. All PTC patients were tested for the BRAFV600E gene mutation before surgery by fine-needle aspiration (FNA) cytology, and TSH levels in the serum were determined one month after surgery. The optimal cut-off value of thyroid-stimulating hormone (TSH) for predicting the recurrence or metastasis of PTC after surgery was determined by the establishment of a receiver operating characteristic (ROC) curve. Kaplan-Meier and Cox regression analyses were used to evaluate the correlation between the optimal cut-off value of TSH and disease-free survival rate and prognosis. RESULTS: Of 272 patients, only 182 (73 BRAFV600E+, 109 BRAFV600E-) met the final study criteria. Among them, 60 cases had recurrence or metastasis, and 122 cases were controls. The optimal cut-off value of TSH for the prediction of recurrence or metastasis of PTC after surgery was 2.615 mlU/L. In our study, a high TSH level (> 2.615 mlU/L) was correlated with the BRAFV600E mutation, multifocality, lymph node metastasis, recurrence, and metastasis. In all 182 patients, those with high TSH levels had worse disease-free survival. This result was more obvious in the 73 BRAFV600E+ patients. The univariate analysis showed that lymph node metastasis, multifocality, lymph node dissection, tumour size, sex, BRAFV600E mutation, and a high postoperative TSH level were all significantly correlated with recurrence or metastasis in PTC patients (all P < 0.05). In addition, the Cox multivariate analysis showed that lymph node metastasis, BRAFV600E mutation, and high postoperative TSH levels were independent risk factors for PTC recurrence or metastasis (all P < 0.05). CONCLUSION: PTC patients with high TSH levels (> 2.615 mlU/L) have worse disease-free survival, which is more obvious in the BRAFV600E+ population.

circGFRA1 affects the sensitivity of triple-negative breast cancer cells to paclitaxel via the miR-361-5p/TLR4 pathway.

In recent years, the role of circular RNAs (circRNAs) in tumours has attracted widespread attention. Some circRNAs have been reported to play a role in triple-negative breast cancer (TNBC). However, circRNAs have rarely been reported in terms of TNBC resistance. This study aimed to clarify that circGFRA1 affects the sensitivity of TNBC cells to paclitaxel (PTX) by the miR-361-5p/TLR4 pathway. Compared with the non-PTX-resistant TNBC cell line MDA-MB-231, the expression of circGFRA1 in the PTX-resistant TNBC cell line MDA-MB-231.PR was significantly increased. The small hairpin RNA-mediated circGFRA1 knockdown inhibited the resistance of TNBC cells to PTX. RNA pull-down assay and luciferase reporter gene assay confirmed the binding between circGFRA1 and miR-361-5p and between miR-361-5p and TLR4. It has been proven that circGFRA1 knockdown can inhibit the resistance of TNBC cells to PTX by promoting the expression of miR-361-5p, and subsequently reduce the expression of TLR4.

Indole-2-Carboxamide Derivative LG25 Inhibits Triple-Negative Breast Cancer Growth By Suppressing Akt/mTOR/NF-κB Signalling Pathway.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer which is associated with poor patient outcome and lack of targeted therapy. Our laboratory has synthesized a series of indole-2-carboxamide derivatives. Among this series, compound LG25 showed a favorable pharmacological profile against sepsis and inflammatory diseases. In the present study, we investigated the chemotherapeutic potential of LG25 against TNBC utilizing in vitro and in vivo models. METHODS: Changes in cell viability, cell cycle phases and apoptosis were analyzed using MTT, clonogenic assay, FACS and Western blotting assays. The anti-cancer effects of LG25 were further determined in a xenograft mouse model. RESULTS: Our findings reveal that LG25 reduced TNBC viability in a dose-dependent manner. Flow cytometric and Western blot analyses showed that LG25 enhances G2/M cell cycle arrest and induced cell apoptosis. In addition, LG25 treatment significantly inhibited Akt/mTOR phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB). These inhibitory activities of LG25 were confirmed in mice implanted MDA-MB-231 TNBC cells. CONCLUSION: Our studies provide experimental evidence that indole-2-carboxamide derivative LG25 effectively targeted TNBC in preclinical models by inducing cell cycle arrest and apoptosis, through suppressing Akt/mTOR/NF-κB signaling pathway.

Schisandrin A inhibits triple negative breast cancer cells by regulating Wnt/ER stress signaling pathway.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking prognostic and effective therapeutic targets currently. In this study, we evaluated the toxic potential of schisandrin A (SchA), a bioactive phytochemical found in Schisandra chinensis in TNBC. The anti-cancer effect and underlying mechanism of SchA on MDA-MB-231 and BT-549 cells were determined in vitro and in xenograft mouse model. Our data show that SchA markedly inhibited the growth of TNBC cells via induction of cell cycle arrest and cell apoptosis. Moreover, over activation of Wnt signaling was observed in TNBC cells, which was significantly suppressed by the treatment of SchA. Also, SchA treatment activated ER stress in TNBC cells. Finally, we verified these inhibitory effects of SchA in the MDA-MB-231 xenograft mouse model. In conclusion, SchA effectively inhibited TNBC in preclinical models by inducing cell cycle arrest and apoptosis via regulating Wnt/ER stress signaling pathway. All of these data indicate that SchA could be a potential candidate for the treatment of TNBC.

Development and Validation of Nomograms for Predicting the Prognosis of Triple-Negative Breast Cancer Patients Based on 379 Chinese Patients.

PURPOSE: We aimed to construct universally applicable nomograms incorporating prognostic factors to predict the prognosis of patients with triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Clinicopathological data of 379 patients with TNBC from March 2008 to June 2014 were retrospectively collected and analyzed. The endpoints were disease-free survival (DFS) and overall survival (OS). Patients were randomly divided into a training group and an independent validation group. In the training group, the prognostic factors were screened to develop nomograms. C-index and calibration curves were used to evaluate the predictive accuracy and discriminative ability of nomograms in both groups. The accuracy of the nomograms was also compared with the traditional American Joint Committee on Cancer Tumor-Node-Metastasis anatomical stage (8th edition). RESULTS: Four prognostic factors (albumin-to-globulin ratio, neutrophil-to-lymphocyte ratio, positive lymph nodes, and tumor size) were used to construct the nomogram of DFS. In addition to the aforementioned factors, age was taken into account in the construction of the OS nomogram. The C-index of the DFS nomogram in the training and validation groups was 0.71 (95% confidence interval [CI]: 0.64-0.77) and 0.69 (95% CI: 0.58-0.79), respectively; the C-index of the OS nomogram was 0.77 (95% CI: 0.70-0.84) and 0.74 (95% CI: 0.62-0.86), respectively. This suggests that the nomograms had high accuracy. Moreover, calibration curves showed good consistencies in both groups. Our models showed superiority in predicting accuracy compared with the AJCC TNM staging system. Furthermore, two web pages of the nomograms were produced: DFS: https://sh-skipper.shinyapps.io/TNBC1/; OS: https://sh-skipper.shinyapps.io/TNBC2/. CONCLUSION: These predictive models are simple and easy to use, particularly the web versions. They have certain clinical value in predicting the prognosis of patients with TNBC. They can assist doctors in identifying patients at different prognostic risks and strengthen the treatment or follow-up accordingly.

Osthole inhibits triple negative breast cancer cells by suppressing STAT3.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subgroup of human breast cancer. Patients with TNBC have poor clinical outcome as they are non-responsive to current targeted therapies. There is an urgent need to identify new therapeutic targets and develop more effective treatment options for TNBC patients. Osthole, a natural product from C. monnieri, has been shown to inhibit certain cancer cells. However, the mechanisms of action as well as its effect on TNBC cells are not currently known. METHODS: We investigated the effect of osthole in cultured TNBC cells as well as in a xenograft model of TNBC growth. We also used a high-throughput proteomics platform to identify the direct binding protein of osthole. RESULTS: We found that osthole inhibited the growth of a panel of TNBC cells and induced apoptosis in both cultured cells and TNBC xenografts. We used a high-throughput proteomics platform and identified signal transducer and activator of transcription 3 (STAT3) as a potential binding protein of osthole. We further show that osthole suppressed STAT3 in TNBC cells to inhibit growth and induce apoptosis. Overexpressing STAT3 in TNBC reduced the effectiveness of osthole treatment. CONCLUSIONS: These results provide support for osthole as a potential new therapeutic agent for the management of TNBC. Moreover, our results indicate that STAT3 may be targeted for the development of novel anti-TNBC drugs.

A mono-carbonyl analog of curcumin induces apoptosis in drug-resistant EGFR-mutant lung cancer through the generation of oxidative stress and mitochondrial dysfunction.

INTRODUCTION: Targeted therapies using epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR mutations, leading to the approval of gefitinib and erlotinib as standard first-line clinical treatment. Inevitably, a considerable proportion of patients develop resistance to EGFR-TKIs due to the acquisition of secondary mutations within EGFR. Therefore, alternative strategies to target NSCLC are desperately needed. MATERIALS AND METHODS: In this study, we have evaluated the effect of a reactive oxygen species (ROS)-inducing agent WZ35, a mono-carbonyl analog of curcumin, to target an inherent biological property of cancer cells, increased oxidative stress. To study whether WZ35 can inhibit NSCLC tumorigenesis, we used gefitinib- and erlotinib-resistant cell line H1975. RESULTS: In this study, we show that WZ35 treatment dramatically decreases cell viability and induces apoptosis in H1975 cells through the generation of ROS. We also found that the antitumor activity of WZ35 involved ROS-mediated activation of the endoplasmic reticulum stress pathway and mitochondrial dysfunction. Furthermore, WZ35 significantly inhibited H1975 xenograft tumor growth through the inhibition of cell proliferation and induction of apoptosis. DISCUSSION: These findings show that WZ35 may be a promising candidate for the treatment of EGFR-TKI-resistant NSCLC.

Schisandrin B exhibits potent anticancer activity in triple negative breast cancer by inhibiting STAT3.

Triple negative breast cancer (TNBC) is an aggressive subgroup of human breast cancer. In this study, we have examined the potential of Schisandrin B (Sch B), a bioactive chemical compound found in Schisandra chinensis, against TNBC. We used MDA-MB-231, BT-549, and MDA-MB-468 TNBC cells and immunodeficient mice to study the effect of Sch B. Our results show that Sch B inhibits TNBC growth by inducing cell cycle arrest and by triggering apoptotic death. Sch B also inhibited the migration and colony formation of tumor cells, and prevented the growth of TNBC cells in mice. We found that these inhibitory activities were mediated through suppression of signal transducer and activator of transcription-3 (STAT3) phosphorylation and nuclear translocation. Taken together, our studies show that Sch B has potent anti-tumor activity against TNBC via a novel mechanism involving STAT3 inactivation.

LncRNA PROX1-AS1 promotes proliferation, invasion, and migration in papillary thyroid carcinoma.

Evidence has been provided that long noncoding RNAs (LncRNAs) play major roles in affecting essential physiological processes, and many of which seem to have functional roles in tumorigenesis and progression. However, the intrinsic molecular mechanism of LncRNAs acting on papillary thyroid carcinoma is not well understood. In the present study, we found that PROX1-AS1 levels were obviously increased in thyroid cancer cells compared with the normal thyroid epithelial cells. Knockdown of PROX1-AS1 gene expression by siRNA could inhibit cell proliferation. Subsequently, we also observed that silencing PROX1-AS1 might inhibit invasion and migration of thyroid cancer cell lines via modulating the expression of epithelial-mesenchymal transition related proteins. In conclusion, our study indicated that LncRNA PROX1-AS1 could promote papillary thyroid carcinoma development and might serve as a potential targeting marker for papillary thyroid carcinoma.

Novel allylated monocarbonyl analogs of curcumin induce mitotic arrest and apoptosis by reactive oxygen species-mediated endoplasmic reticulum stress and inhibition of STAT3.

Curcumin is a promising active compound from a natural source and is extensively being tested in clinical trials because of its bio-functional properties. However, poor bioavailability has hampered its clinical application. Numerous attempts have been made in our laboratory to discover analogs of curcumin with enhanced bioavailability and superior pharmacological activity. In this study, we have investigated a new series of allylated monocarbonyl analogs of curcumin (MAC) and tested their effect on gastric cancer cells. Our results show six MAC that selectively targeted cancer cell lines to inhibit growth and induce apoptosis. This activity was achieved by generation of reactive oxygen species (ROS) by MAC. We selected one effective MAC (CA10) for further investigation and show that CA10 inhibits cell growth by causing G2/M cell cycle arrest and induction of apoptotic death. CA10 induced ROS generation and subsequent activation of endoplasmic reticulum (ER) stress and inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation, inhibits cancer cell proliferation. These anti-tumor activities of CA10 were confirmed in gastric cancer xenografts. CA10 induced ROS, activated the ER stress pathway and inhibited STAT3 phosphorylation and gastric xenografts tumor growth in mice. Our studies provide experimental evidence that MAC CA10 effectively targets gastric cancer in preclinical models by enhancing ROS and ROS-mediated signaling.

(S)-crizotinib induces apoptosis in human non-small cell lung cancer cells by activating ROS independent of MTH1.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancers and is usually diagnosed at an advanced stage with poor prognosis. Targeted therapy has produced unprecedented outcomes in patients with NSCLC as a number of oncogenic drivers have been found. Crizotinib, a selective small-molecule inhibitor, has been widely used for the treatment of NSCLC patients with ALK gene rearrangements. A recent study has also shown that (S)-enantiomer of crizotinib exhibits anticancer activity by targeting the protein mutT homologue (MTH1). Since this discovery, contradictory studies have cast a doubt on MTH1 as a therapeutic target of (S)-crizotinib. METHODS: NCI-H460, H1975, and A549 cells and immunodeficient mice were chosen as a model to study the (S)-crizotinib treatment. The changes induced by (S)-crizotinib treatment in cell viability, apoptosis as well as ROS, and endoplasmic reticulum stress pathway in the cells were analyzed by MTT assay, FACSCalibur, Western blotting, ROS imaging and electron microscopy. RESULTS: Here, we report that MTH1 does not affect survival of NSCLC cells. We found that (S)-crizotinib induces lethal endoplasmic reticulum stress (ER) response in cultured NSCLC cells by increasing intracellular levels of reactive oxygen species (ROS). Blockage of ROS production markedly reversed (S)-crizotinib-induced ER stress and cell apoptosis, independent of MTH1. We confirmed these findings in NSCLC xenograft studies and showed that (S)-crizotinib-induced ER stress and cell apoptosis. CONCLUSIONS: Our results reveal a novel antitumor mechanism of (S)-crizotinib in NSCLC which involves activation of ROS-dependent ER stress apoptotic pathway and is independent of MTH1 inhibition.

Impact of platelet to lymphocyte ratio and metabolic syndrome on the prognosis of colorectal cancer patients.

OBJECTIVE: The aim of this study was to evaluate the prognostic value of both platelet to lymphocyte ratio (PLR) and metabolic syndrome (MetS) in colorectal cancer (CRC) patients. PATIENTS AND METHODS: We retrospectively enrolled 1,163 CRC patients. Preoperative values of PLR were stratified into three groups according to cut-off values of 120 and 220. The Kaplan-Meier analysis was used to calculate cumulative survival rate related to PLR and MetS. Cox proportional hazard regression models were used to analyze potential risk factors and the prognosis associated with PLR and MetS in CRC patients. RESULTS: PLR was significantly higher in the MetS(+) group as compared to MetS(-) group (P=0.039). An elevated PLR was significantly associated with mortality (P=0.014), but not the existence of MetS (P=0.235). In multivariate regression analysis, PLR was an independent risk factor for overall survival (OS) (P=0.046). For the subgroup with a PLR >220, MetS was an independent predictor for both OS and disease-free survival (P=0.039 and P=0.047, respectively) by multivariate analysis adjusting for confounding covariates. In addition, the presence of MetS was associated with a 2-fold increased risk of mortality and tumor recurrences (hazard ratio [HR] =2.0 and HR =1.9, P<0.05, respectively). CONCLUSION: Preoperative PLR was associated with MetS in CRC patients. Testing for the combined presence of PLR and MetS could potentially improve the predictive accuracy of CRC prognosis.

Primary ectopic substernal thyroid cancer with trachea relapse: a case report and opinions of management.

BACKGROUND: Ectopic substernal thyroid is a rare symptom of thyroid disease that entirely results from the developmental defects at early stages of thyroid embryogenesis and during its descent. Cases were seldom reported as primary ectopic substernal thyroid cancer, especially those with severe local invasion and tracheal relapse. CASE PRESENTATION: In this report, the patient presented odynophagia and a sense of progressing swallowing obstruction. She underwent total thyroidectomy and lump resection. However, she refused to use postoperative radioactive iodine or take adjuvant external-beam radiotherapy, except for thyroid hormone replacement therapy. Tracheal relapse was observed after 6 months. Tracheal stent was used to reconstruct the airway twice. CONCLUSIONS: Trachea invasion might be a worse independent predictor of prognosis than any others and should be given particular attention. Furthermore, tracheal stent might be a palliative option for patients with tracheal relapse.