Candidate prognostic biomarkers and prediction models for high-grade serous ovarian cancer from urinary proteomics.

High-grade serous ovarian cancer (HGSOC) is one of the most common histologic types of ovarian cancer. The purpose of this study was to identify potential prognostic biomarkers in urine specimens from patients with HGSOC. First, 56 urine samples with information on relapse-free survival (RFS) months were collected and classified into good prognosis (RFS ≥ 12 months) and poor prognosis (RFS < 12 months) groups. Next, data-independent acquisition (DIA)-based mass spectrometry (MS) analysis was combined with MSFragger-DIA workflow to identify potential prognostic biomarkers in a discovery set (n = 31). With the aid of parallel reaction monitoring (PRM) analysis, four candidate biomarkers (ANXA1, G6PI, SPB3, and SPRR3) were finally validated in both the discovery set and an independent validation set (n = 25). Subsequent RFS and Cox regression analyses confirmed the utility of these candidate biomarkers as independent prognostic factors affecting RFS in patients with HGSOC. Regression models were constructed to predict the 12-month RFS rate, with area under the receiver operating characteristic curve (AUC) values ranging from 0.847 to 0.905. Overall, candidate prognostic biomarkers were identified in urine specimens from patients with HGSOC and prediction models for the 12-month RFS rate constructed. SIGNIFICANCE: OC is one of the leading causes of death due to gynecological malignancies. HGSOC constitutes one of the most common histologic types of OC with aggressive characteristics, accounting for the majority of advanced cases. In cases where patients with advanced HGSOC potentially face high risk of unfavorable prognosis or disease advancement within a 12-month period, intensive medical monitoring is necessary. In the era of precision cancer medicine, accurate prediction of prognosis or 12-month RFS rate is critical for distinguishing patient groups requiring heightened surveillance. Patients could significantly benefit from timely modifications to treatment regimens based on the outcomes of clinical monitoring. Urine is an ideal resource for disease surveillance purposes due to its easy accessibility. Furthermore, molecules excreted in urine are less complex and more stable than those in other liquid samples. In the current study, we identified candidate prognostic biomarkers in urine specimens from patients with HGSOC and constructed prediction models for the 12-month RFS rate.

The preoperative platelet to neutrophil ratio and lymphocyte to monocyte ratio are superior prognostic indicators compared with other inflammatory biomarkers in ovarian cancer.

Background: Previous studies have suggested that the ratios of immune-inflammatory cells could serve as prognostic indicators in ovarian cancer. However, which of these is the superior prognostic indicator in ovarian cancer remains unknown. In addition, studies on the prognostic value of the platelet to neutrophil ratio (PNR) in ovarian cancer are still limited. Methods: A cohort of 991 ovarian cancer patients was analyzed in the present study. Receiver operator characteristic (ROC) curves were utilized to choose the optimal cut-off values of inflammatory biomarkers such as neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and PNR. The correlation of inflammatory biomarkers with overall survival (OS) and relapse-free survival (RFS) was investigated by Kaplan-Meier methods and log-rank test, followed by Cox regression analyses. Results: Kaplan-Meier curves suggested that LMR<3.39, PLR≥181.46, and PNR≥49.20 had obvious associations with worse RFS (P<0.001, P=0.018, P<0.001). Multivariate analysis suggested that LMR (≥3.39 vs. <3.39) (P=0.042, HR=0.810, 95% CI=0.661-0.992) and PNR (≥49.20 vs. <49.20) (P=0.004, HR=1.351, 95% CI=1.103-1.656) were independent prognostic indicators of poor RFS. In addition, Kaplan-Meier curves indicated that PLR≥182.23 was significantly correlated with worse OS (P=0.039). Conclusion: Taken together, PNR and LMR are superior prognostic indicators compared with NLR, PLR, and SII in patients with ovarian cancer.

Clinical and prognostic significance of perioperative change in red cell distribution width in patients with esophageal squamous cell carcinoma.

BACKGROUND: Numerous studies have reported the prognostic significance of the red cell distribution width (RDW) in patients with esophageal squamous cell carcinoma (ESCC), but the relationship between the perioperative change in RDW (delta RDW) and survival in patients with ESCC after surgery has not been evaluated. METHODS: A total of 594 patients with newly diagnosed ESCC after surgery were enrolled in the study. Delta RDW (delta RDW = Postoperative RDW-Preoperative RDW) was counted based on data within one week before surgery and two weeks after surgery. To investigate the relationship between delta RDW and overall survival (OS), the median delta RDW was chosen as the cut-off value. RESULTS: 99 (16.7%) patients had pathological stage 1a-1b, 202 (34.0%) patients had pathological stage 2a-2b, and 293 (49.3%) patients had pathological stage 3a-3c.There were 179 (30.1%) patients who had vessel invasive, and 415 (69.9%) patients without vessel invasive. There were 216 (36.4%) patients with nerve infiltration, and 378 (63.6%) without nerve infiltration. In univariate analysis, five parameters including delta RDW(≥ 0.44 vs.<0.44) (P = 0.039, HR = 1.337, 95% CI = 1.014-1.762) significantly correlated with worse OS. Multivariate analysis revealed that delta RDW(≥ 0.44 vs.<0.44) was an independent prognostic marker for OS (P = 0.033, HR = 1.356, 95% CI = 1.025-1.793). Kaplan-Meier curves showed that delta RDW ≥ 0.44 was significantly associated with worse OS (P = 0.039). Subgroup analysis suggested that delta RDW ≥ 0.44 indicated worse survival in patients with ESCC exclusively in these subtypes such as female patients, age > 60 patients, patients with lymph node metastasis, and patients with vessel invasive. CONCLUSIONS: Perioperative change in red cell distribution width predicts worse survival in patients with ESCC after surgery.

Thiol oxidative stress-dependent degradation of transglutaminase2 via protein S-glutathionylation sensitizes 5-fluorouracil therapy in 5-fluorouracil-resistant colorectal cancer cells.

5-Fluorouracil (5-Fu) is a first-line drug for colorectal cancer (CRC) therapy. However, the development of 5-Fu resistance limits its chemotherapeutic effectiveness and often leads to poor prognoses of CRC. Transglutaminase 2 (TGM2), a member of the transglutaminase family, is considered to be associated with chemoresistance through apoptotic prevention in various cancers including CRC. TGM2 was found to be overexpressed in two 5-Fu-resistant CRC cell lines and down-regulated by increased thiol oxidative stress induced by inhibition of glutathione reductase (GR). The present study aimed to explore the role of TGM2 in 5-Fu-resistant CRC and the mechanism of action by which the elevated thiol oxidative stress down-regulates TGM2 protein level. The results revealed that 5-Fu-resistance induced by overexpression of TGM2 in CRC cells was reversed through up-regulation of thiol oxidative stress. Knockdown of TGM2 increased the chemosensitivity of CRC cells to 5-Fu. Thiol oxidative stress potentially enhanced the therapeutic effect of 5-Fu in the resistant CRC cells by promotion of 5-Fu-induced apoptosis through down-regulation of TGM2. The elevated thiol oxidative stress increased the S-glutathionylation of TGM2 and led to proteasomal degradation of TGM2. Furthermore, Cys193 was identified as the S-glutathionylation site in TGM2, and its mutation resulted in thiol oxidative stress-mediated CRC cell apoptotic resistance. TGM2-induced EMT was also suppressed by the elevated thiol oxidative stress. A xenograft tumor model confirmed the effect of thiol oxidative stress in the reversal of 5-Fu resistance in CRC cells in vivo. TGM2 protein expression level was found to be significantly higher in human CRC specimens than in non-cancerous colorectal tissues. Taken together, the present data suggest an important role of TGM2 in 5-Fu resistance in CRC cells. Up-regulation of thiol oxidative stress could be a potential therapeutic approach for treating 5-Fu-resistant CRC and TGM2 may serve as a potential therapeutic target of thiol oxidative stress.

Multimodal Sonographic Appearance and Survival Outcomes of 69 Cases of Primary Thyroid Lymphoma Over 10 Years.

OBJECTIVES: To investigate ultrasound appearance and the survival outcomes for patients with primary thyroid lymphoma (PTL). METHODS: Ultrasonic images and clinical characteristics from pathologically confirmed 69 PTL patients (2008-2019) were retrospectively analyzed. The clinical characteristics, ultrasonic characters, and prognostic factors were analyzed. Survival curves were plotted using the Kaplan-Meier method. Univariate and multivariate analyses were performed. RESULTS: Of the 69 study patients, 23 were indolent PTL and 46 were aggressive PTL. Age (>70 years old) and elevated lactate dehydrogenase levels were statistically different clinical features between aggressive and indolent PTL. From ultrasonic images, 34 cases were nodular, 11 diffuse, and 24 mixed pattern. Mixed types displayed high invasiveness (45.7%) while diffuse types displayed higher inertness (39.1%), with statistically significant differences (P = .000). Invaded thyroid capsule and increased chaotic vascularity also showed significant differences between aggressive and indolent PTL. We also observed statistical difference in overall survival rates between aggressive and indolent PTL (P = .032). Single factor K-M analyses showed that age >70 years, aggressive pathology, and Ki67 >30% were positively correlated with the risk of poor PTL survival (P < .05). CONCLUSIONS: Multimodal ultrasound provides accurate ultrasonographic information and facilitates PTL invasiveness diagnostics for improved clinical treatment. In addition, PTL patients aged >70 years, with aggressive pathology, and Ki67 >30% were more likely to have a poor survival outcome.

Depletion of METTL3 alters cellular and extracellular levels of miRNAs containing m6A consensus sequences.

Extracellular vesicles (EVs) are capable of transferring cargo from donor to recipient cells, but precisely how cargo content is regulated for export is mostly unknown. For miRNA cargo, we previously showed that when compared to isogenic colorectal cancer (CRC) cells expressing wild-type KRAS, a distinct subset of miRNAs are differentially enriched in EVs from KRAS mutant active CRC cells, with miR-100 being one of the most enriched. The mechanisms that could explain how miR-100 and other miRNAs are differentially exported into EVs have not been fully elucidated. Here, we tested the effect of N6-methyladenosine (m6A) modification on miRNA export into EVs by depletion of METTL3 and ALKBH5, a writer and eraser of m6A modification, respectively. While the effects of ALKBH5 knockdown were quite modest, decreased levels of METTL3 led to reduced cellular and extracellular levels of a subset of miRNAs that contain consensus sequences for m6A modification. Functional testing of EVs prepared from cells expressing shRNAs against METTL3 showed that they were less capable of conferring colony growth in 3D to wild-type KRAS cells and were also largely incapable of conferring the spread of cetuximab resistance. Our data support a role for METTL3 modification on cellular miRNA levels and export of specific miRNAs.

PTP4A3 Is a Prognostic Biomarker Correlated With Immune Infiltrates in Papillary Renal Cell Carcinoma.

PTP4A3 plays an important role in the tumorigenesis and metastasis of multiple tumors, but its prognostic role in renal cancer is not well understood. We utilized the Oncomine and Tumor Immunoassay Resource databases to examine the differential expression of PTP4A3 in tumor tissues and normal tissues in breast, urinary tract, gastrointestinal tract and skin. Using the GEPIA and PrognoScan databases, the independent prognostic role of PTP4A3 was confirmed in clear cell renal cell cancer and papillary renal cell cancer. Expression of PTP4A3 were obviously higher in tumor tissue compare with normal tissues (P=0.028). We haven't found the associations of PTP4A3 and clinicopathological features in our IHC cohort. Ectopic expression of PTP4A3 promotes proliferation, migration and invasion and increased the mRNA level of TGFB1 in RCC cell lines. Immunohistochemical staining indicated that the expression of PTP4A3 associates with CD3+ (P =0.037)/CD8+ (P =0.037) intratumor TILs, not with invasive margins in renal cancer. Comprehensive analysis of immune infiltration in the TIMER database correlated PTP4A3 expression with the infiltration of B cells, CD8+ T cells, CD4+ T cells and neutrophils in both clear cell renal cell carcinoma and papillary renal cell carcinoma. PTP4A3 expression was associated with the infiltration of dendritic cells in papillary renal cell carcinoma. We further confirmed that the infiltration of B cells and CD8+ T cells was associated with poor prognosis in papillary renal cell carcinoma patients, consistent with the prognostic role of PTP4A3 in papillary renal cell carcinoma. PTP4A3 expression correlated genes involved in B cells, monocytes, M1 macrophages, Th2 and Treg cells in papillary renal cell carcinoma. These results suggest PTP4A3 as a prognostic factor with a role in regulating immune cell infiltration in papillary renal cell carcinoma.

Perioperative change in neutrophil count predicts worse survival in esophageal squamous cell carcinoma.

Aims: This study aimed to investigate the relationship between perioperative change in neutrophil count and survival of patients with esophageal squamous cell carcinoma. Method: Neutrophil change (Nc) (where Nc = post-surgery neutrophil count - pre-surgery neutrophil count) was counted according to data within 1 week before surgery and 2 weeks after surgery. Patients were divided into two groups, Nc ≥2.60 and Nc <2.60, according to the median of Nc. Results: Multivariate analysis revealed that Nc ≥2.60 was an independent prognostic marker for overall survival. Subgroup analysis suggested that the overall survival of male patients, patients aged ≤60 years, patients without vessel invasion and patients without nerve infiltration was dramatically worse for those with Nc <2.60. Conclusion: Perioperative change in neutrophil count predicts worse survival in esophageal squamous cell carcinoma after surgery.

Development of a serum miRNA panel for detection of early stage non-small cell lung cancer.

Minimally invasive testing for early detection of lung cancer to improve patient survival is a major unmet clinical need. This study aimed to develop and validate a serum multi-microRNA (multimiR) panel as a minimally invasive test for early detection of nonsmall cell lung cancer (NSCLC) regardless of smoking status, gender, and ethnicity. Our study included 744 NSCLC cases and 944 matched controls, including smokers and nonsmokers, male and female, with Asian and Caucasian subjects. Using RT-qPCR and a tightly controlled workflow, we quantified the absolute expression of 520 circulating microRNAs (miRNAs) in a Chinese cohort of 180 early stage NSCLC cases and 216 healthy controls (male smokers). Candidate biomarkers were verified in two case-control cohorts of 432 Chinese and 218 Caucasians, respectively (including females and nonsmokers). A multimiR panel for NSCLC detection was developed using a twofold cross-validation and validated in three additional Asian cohorts comprising 642 subjects. We discovered 35 candidate miRNA biomarkers, verified 22 of them, and developed a five-miR panel that detected NSCLC with area under curve (AUC) of 0.936-0.984 in the discovery and verification cohorts. The panel was validated in three independent cohorts with AUCs of 0.973, 0.916, and 0.917. The sensitivity of five-miR test was 81.3% for all stages, 82.9% for stages I and II, and 83.0% for stage I NSCLC, when the specificity is at 90.7%. We developed a minimally invasive five-miR serum test for detecting early stage NSCLC and validated its performance in multiple patient cohorts independent of smoking status, gender, and ethnicity.

Next-generation DNA damage sequencing.

Cellular DNA is constantly chemically altered by exogenous and endogenous agents. As all processes of life depend on the transmission of the genetic information, multiple biological processes exist to ensure genome integrity. Chemically damaged DNA has been linked to cancer and aging, therefore it is of great interest to map DNA damage formation and repair to elucidate the distribution of damage on a genome-wide scale. While the low abundance and inability to enzymatically amplify DNA damage are obstacles to genome-wide sequencing, new developments in the last few years have enabled high-resolution mapping of damaged bases. Recently, a number of DNA damage sequencing library construction strategies coupled to new data analysis pipelines allowed the mapping of specific DNA damage formation and repair at high and single nucleotide resolution. Strikingly, these advancements revealed that the distribution of DNA damage is heavily influenced by chromatin states and the binding of transcription factors. In the last seven years, these novel approaches have revealed new genomic maps of DNA damage distribution in a variety of organisms as generated by diverse chemical and physical DNA insults; oxidative stress, chemotherapeutic drugs, environmental pollutants, and sun exposure. Preferred sequences for damage formation and repair have been elucidated, thus making it possible to identify persistent weak spots in the genome as locations predicted to be vulnerable for mutation. As such, sequencing DNA damage will have an immense impact on our ability to elucidate mechanisms of disease initiation, and to evaluate and predict the efficacy of chemotherapeutic drugs.

The Postoperative Lymphocyte to Monocyte Ratio Change Predicts Poor Clinical Outcome in Patients with Esophageal Squamous Cell Carcinoma Undergoing Curative Resection.

BACKGROUND: Postoperative lymphocyte to monocyte ratio (post-LMR) change (LMRc) reflects the dynamic change of balance between inflammatory reaction and immune reaction after curative operation. An elevated preoperative LMR (pre-LMR) has been shown to be a prognostic factor in patients with esophageal squamous cell carcinoma (ESCC), but the clinical value of the LMRc remains unknown. METHODS: 674 patients in ESCC undergoing curative operation were enrolled in this study. LMRc (LMRc = pre-LMR-post-LMR) was counted on the basis of data within one week before and after operation. The median of LMRc was chosen to be the optimal cut-off value to evaluate the prognostic value of LMRc. RESULTS: Kaplan-Meier curves revealed that LMRc ≤ 1.59 was significantly associated with worse overall survival (OS) (P = 0.003) and disease-free survival (DFS) (P = 0.008). Multivariate analysis suggested that LMRc could serve as an independent prognostic predictor for both OS (P = 0.006, HR = 0.687, 95% CI 0.526-0.898) and DFS (P = 0.003, HR = 0.640, 95% CI 0.476-0.859). CONCLUSIONS: LMRc is a promising prognostic predictor for predicting the worse clinical outcome in patients with ESCC undergoing curative operation.

The ABO Blood Group is an Independent Prognostic Factor in Patients with Ovarian Cancer.

Previous studies have suggested a relationship between ABO blood group and clinical outcome of various cancers. Nevertheless, little is known about the association between ABO blood group and survival in patients with ovarian carcinoma. This study aimed to investigate the prognostic significance of ABO blood group in patients with ovarian carcinoma. 941 patients who were newly diagnosed with ovarian carcinoma between February 2007 and February 2016 were enrolled in the present study. The relationship between ABO blood type and clinical features in patients with ovarian cancer was analyzed using chi-square tests. Overall survival (OS) stratified by B antigen was evaluated using log-rank test and Kaplan-Meier method. Presence of the B antigen (B/AB) had a worse OS than those in the absence of the B antigen (A/O) in all patients with ovarian cancer, especially in patients with FIGO stage I, IV, and menopause. Presence of the B antigen (B/AB) was significantly correlated with OS than those with non-B antigen (A/O) (hazard ratios 1.342; 95% confidence interval 1.069-1.685; P=0.011). Multivariate analyses revealed that presence of the B antigen (B/AB) was independently associated with OS (hazard ratios 1.532; 95% confidence interval 1.111-2.112; P=0.009). This study indicated that presence of the B antigen (B/AB) was an unfavorable prognostic factor in ovarian carcinoma, especially in patients with FIGO stage I, IV, and menopause.

Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma.

Previous studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers. However, drug sensitivity biomarkers in esophageal squamous cell carcinoma (ESCC) have not been widely explored. Here, eight patient-derived cell lines (PDCs) are successfully established from 123 patients with ESCC. The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC. Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening. Interestingly, some drug and biomarker relationships are established that were not discovered in the CCLE project. For example, CDKN2A or CDKN2B loss is significantly associated with the sensitivity of CDK4/6 inhibitors. Furthermore, both PDC xenografts and patient-derived xenografts confirm CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity. Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.

Elevated preoperative platelet distribution width predicts poor prognosis in Esophageal Squamous Cell Carcinoma.

Activated platelets play a multifaceted role in tumorigenesis and progression. Platelet distribution width (PDW) is generally applied platelet parameters from routine blood test. Preoperative PDW has been considered a prognostic factor in many cancers. Nevertheless, the prognostic value of PDW in esophageal squamous cell carcinoma (ESCC) remains unknown. The study aimed to investigate whether preoperative PDW could serve as a prognostic factor in patients with ESCC. A total of 495 patients with ESCC undergoing curative surgery were enrolled. The relationship between PDW and clinical features in ESCC was analyzed using chi-square tests. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value. Overall survival (OS) and disease-free survival (DFS) stratified by PDW were evaluated by Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression were used to evaluate the prognostic effect of PDW. Of the 495 patients, elevated PDW was observed in 241(48.7%) of the patients, respectively. An elevated PDW was correlated with depth of tumor (T stage, P = 0.031), nerve infiltration (P = 0.016), hospital time after operation (P = 0.020), platelet (P < 0.001), red cell distribution width (P < 0.001), and aspartate transaminase (P = 0.001). Moreover, elevated PDW (PDW ≥ 13.4 fL) predicted a worse OS and DFS in patients with ESCC (both P < 0.001). Multivariate analyses revealed that PDW was independently associated with OS (hazard ratios 1.194; 95% confidence interval 1.120-1.273; P < 0.001) and DFS (hazard ratios 2.562; 95% confidence interval 1.733-3.786; P < 0.001). Our findings indicated that elevated PDW could serve as an independent worse survival in ESCC.

Postoperative Monocyte Count Change Is a Better Predictor of Survival Than Preoperative Monocyte Count in Esophageal Squamous Cell Carcinoma.

In esophageal squamous cell carcinoma, an elevated preoperative absolute monocyte count (Pre-AMC) is reported to be a predictor of survival, but the clinical application of postoperative absolute monocyte count change (AMCc) remains unknown. The present study was designed to investigate the prognostic value of AMCc in ESCC. 686 patients of ESCC after radical surgery without preoperative adjuvant therapy were enrolled. The Pre-AMC and AMCc were recorded within one week before the operation and one week after surgery. We considered the median of Pre-AMC as the optimal cut-off value to evaluate the relationship between Pre-AMC and patient survival. AMCc was defined as AMCc increased (higher than Pre-AMC) and AMCc decreased (lower than Pre-AMC). Demographic and clinical characteristics, disease-free survival (DFS), and overall survival (OS) were statistically analyzed. Multivariate analysis revealed that AMCc was a better independent prognostic factor for both OS (P = 0.002, HR = 0.614, 95% CI 0.450-0.837) and DFS (P = 0.023, HR = 0.656, 95% CI 0.456-0.943) than Pre-AMC which was only an independent prognostic factor for OS (P = 0.033, HR = 2.031, 95% CI 1.058-3.898). AMCc could be a better prognostic factor than Pre-AMC in patients with ESCC. AMCc decrease predicts worse OS and DFS in ESCC undergoing curative resection.

Perioperative change in lymphocyte count and prognosis in esophageal squamous cell carcinoma.

BACKGROUND: Preoperative lymphocyte count (pre-LC) predicts the relapse and survival in patients with esophageal squamous cell carcinoma (ESCC), the clinical application of postoperative lymphocyte count (post-LC) change (LCc) remains unclear. METHODS: A retrospective analysis of patients with newly diagnosed ESCC who received curative resection from 2008 to 2015 was conducted. Complete blood counts from preoperative within seven days to postoperative within seven days were analyzed. LCc was defined as LCc increased (post-LC higher than pre-LC) and LCc decreased (post-LC lower than pre-LC). LCc was evaluated for an association with disease-free survival (DFS). RESULTS: A total of 677 patients who reach the standard were enrolled into the study. There were 579 (85.5%) male and 98 (14.5%) female patients with ESCC. The median age was 61 years (range, 39-84 years). In univariate analysis, LCc significantly correlated to DFS (P=0.006, HR =0.593, 95% CI: 0.409-0.862). In multivariate analysis (COX model), LCc was an independent prognostic factor for DFS (P=0.011, HR =0.617, 95% CI: 0.424-0.897). CONCLUSIONS: The dynamic change of LC after surgery may serve as a simple and new prognostic factor in patients with newly diagnosed ESCC.

Low Preoperative Lymphocyte to Monocyte Ratio Serves as a Worse Prognostic Marker in Patients with Esophageal Squamous Cell Carcinoma Undergoing Curative Tumor Resection.

Preoperative lymphocyte to monocyte ratio (LMR) has been considered a prognostic factor in various cancers. However, the application of LMR in the assessment of patients with esophageal squamous cell carcinoma (ESCC) remains controversial. This study aimed to investigate whether preoperative LMR could serve as a prognostic marker in patients with ESCC undergoing curative tumor resection. Medical records of 680 patients of ESCC after curative surgery without preoperative adjuvant therapy were obtained. The median of LMR was determined as the optimal cut off value. The association of LMR with clinical features of ESCC was analyzed using chi-square tests. Spearman's correlation coefficient was used to calculate the correlation. Disease-free survival (DFS) and overall survival (OS) stratified by LMR were evaluated using Kaplan-Meier method and log-rank test. The LMR was negatively correlated with sex (r=-0.245, P<0.001). Low LMR (LMR<3.17) predicted a shorter DFS and OS in patients with ESCC. Multivariate analyses revealed that LMR was independently correlated with DFS (hazard ratios 0.854; 95% confidence interval 0.768-0.949; P=0.003) and OS (hazard ratios 0.864; 95% confidence interval 0.779-0.958; P=0.006). Our study indicated that low LMR could serve as an independent worse prognostic marker in patients with ESCC.

Kindlin-2 interacts with and stabilizes DNMT1 to promote breast cancer development.

Integrin-interacting protein Kindlin-2, as a focal adhesion protein, promotes growth and progression of breast cancer. However, the precise mechanism that underlie the role of Kindlin-2 in breast cancer is elusive. Here, we report that the expression of Kindlin-2 positively correlated with DNA methyltransferase 1(DNMT1) in breast cancer patients. Further, we found that DNMT1 was upregulated in mammary gland tissues of mammary specific Kindlin-2 transgenic mice. More importantly, high expression of DNMT1 was observed in mammary tumors formed by Kindlin-2 transgenic mice. On the basis of these observations, DNMT inhibitor 5-aza-CdR was used and found its treatment strongly decreased Kindlin-2-induced breast cancer cell proliferation and migration. Mechanistically, Kindlin-2 increased the stability of DNA methyltransferase DNMT1 through interaction with DNMT1 and methylated CpG islands in the E-cadherin promoter. Kindlin-2 increased the occupancy of DNMT1 at E-cadherin promoter, thereby suppressing E-cadherin expression. Taken together, our data reveal that Kindlin-2 promotes breast cancer development by enhancing the stability of DNMT1.

Glutathione reductase-mediated thiol oxidative stress suppresses metastasis of murine melanoma cells.

Malignant melanoma is a highly metastatic and life-threatening cancer. Reactive oxygen species (ROS) play important roles in cancer initiation and progression including metastasis. It has been reported that the oxidative stress spontaneously generated in circulating melanoma cells was able to suppress distant metastasis in vivo. However, little is known regarding the effects and mechanism of glutathione reductase (GR) inhibition-induced oxidative stress in regulation of melanoma metastasis. Here, we demonstrate that GR inhibition generates oxidative stress and suppresses lung metastasis and subcutaneous growth of melanoma in vivo. In addition, inhibitory effects by GR activity reduction were observed on cell proliferation, colony formation, cell adhesion, migration and invasion in melanoma cells in vitro. GR inhibition-induced oxidative stress was also found to block epithelial-to-mesenchymal transition (EMT) by decreasing the expression of Vimentin, ERK1/2, transcription factor Snail and increasing the expression of E-cadherin. In addition, actin rearrangement, a key element involved in cell motility, was also affected by GR-mediated oxidative stress possibly through protein S-glutathionylation on actin. In conclusion, this study identifies GR as an effective regulator of oxidative stress that affects the multistep processes of metastasis in melanoma cells, and it becomes a potential target for melanoma therapy.

Multifocality is associated with central neck lymph node metastases in papillary thyroid microcarcinoma.

BACKGROUND: This study aimed to assess the predictive factor of multifocality to identify patients at high risk of central lymph node metastasis (CLNM). PATIENTS AND METHODS: Papillary thyroid microcarcinoma patients who underwent total or hemi-thyroidectomy with effective unilateral or bilateral central lymph node dissection were enrolled. RESULTS: Multifocality, age, sex, tumor size, extrathyroidal extension, and nodular goiter were significantly associated with CLNM. Multifocality was an independent predictor for CLNM in multivariate analysis. Compared with unifocal disease, the odds ratio for CLNM was 1.447 for patients with ≥2 tumor foci (P<0.001) and 2.978 for patients with ≥3 tumor foci (P<0.001). The significant association is at ≥3 foci diseases. CONCLUSION: Multifocality with ≥3 tumor foci was an independent predictive factor for CLNM in papillary thyroid microcarcinoma. Multifocality should be assessed when selecting patients for prophylactic central neck lymph node dissection, and we speculate that patients with multifocality should undergo more radical treatment.