ABSTRACT
Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors. Yet, prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking. A phase II clinical trial was initiated to evaluate the efficacy of toripalimab, a humanized IgG4K monoclonal antibody to human PD-1, in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high. A total of 15 patients were enrolled, 14 of whom were assessed for treatment efficacy. There was a 21.4% overall response rate, with a disease control rate of 57.1%. The median overall survival and median progression-free survival were 17.9 (95% CI 13.5-not reach) months and 2.5 (95% CI 1.4-not reach) months, respectively. For patients with exonuclease domain mutations, the objective response rate was 66.7% (2/3), with a disease control rate of 66.7% (2/3). For those with non-exonuclease domain mutations, the rates were 9.1% (1/11) and 54.5% (6/11), respectively. Notably, patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0% (3/4). This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy, urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.
Subject(s)
Antibodies, Monoclonal, Humanized , DNA Polymerase II , Mutation , Neoplasms , Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Female , Male , Middle Aged , Aged , Neoplasms/genetics , Neoplasms/drug therapy , DNA Polymerase II/genetics , DNA Polymerase III/genetics , Poly-ADP-Ribose Binding Proteins/genetics , Adult , Aged, 80 and overABSTRACT
Lead (Pb) is a major source of heavy metal contamination, and poses a threat to biodiversity and human health. Elevated levels of Pb can hinder insect growth and development, leading to apoptosis via mechanisms like oxidative damage. The midgut of silkworms is the main organ exposed to heavy metals. As an economically important lepidopteran model insect in China, heavy metal-induced stress on silkworms causes considerable losses in sericulture, thereby causing substantial economic damage. This study aimed to investigate Pb-induced detoxification-related genes in the midgut of silkworms using high-throughput sequencing methods to achieve a deeper comprehension of the genes' reactions to lead exposure. This study identified 11,567 unigenes and 14,978 transcripts. A total of 1265 differentially expressed genes (DEGs) were screened, comprising 907 upregulated and 358 downregulated genes. Subsequently, Gene Ontology (GO) classification analysis revealed that the 1265 DEGs were distributed across biological processes, cellular components, and molecular functions. This suggests that the silkworm midgut may affect various organelle functions and biological processes, providing crucial clues for further exploration of DEG function. Additionally, the expression levels of 12 selected detoxification-related DEGs were validated using qRT-PCR, which confirmed the reliability of the RNA-seq results. This study not only provides new insights into the detoxification defense mechanisms of silkworms after Pb exposure, but also establishes a valuable foundation for further investigation into the molecular detoxification mechanisms in silkworms.
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Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.
ABSTRACT
PIK3CA mutations are highly prevalent in solid tumors. Targeting phosphatidylinositol 3-kinase α is therefore an attractive strategy for treating cancers harboring PIK3CA mutations. Here, we report the results from a phase Ia, open label, dose-escalation and -expansion study (NCT03544905) of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors. The primary outcomes were the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of CYH33. The secondary outcomes included evaluation of pharmacokinetics, preliminary efficacy and changes in pharmacodynamic biomarkers in response to CYH33 treatment. The exploratory outcome was the relationship between the efficacy of CYH33 treatment and tumor biomarker status, including PIK3CA mutations. A total of 51 patients (19 in the dose escalation stage and 32 in the dose expansion stage) including 36 (70.6%) patients (4 in the dose escalation stage and 32 in the dose expansion stage) with PIK3CA mutations received CYH33 1-60 mg. The MTD of CYH33 was 40 mg once daily, which was also selected as the RP2D. The most common grade 3/4 treatment-related adverse events were hyperglycemia, rash, platelet count decreased, peripheral edema, and fatigue. Forty-two out of 51 patients were evaluable for response, the confirmed objective response rate was 11.9% (5/42). Among 36 patients harboring PIK3CA mutations, 28 patients were evaluable for response, the confirmed objective response rate was 14.3% (4/28). In conclusion, CYH33 exhibits a manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations.
Subject(s)
Neoplasms , Pyrroles , Humans , Class I Phosphatidylinositol 3-Kinases/genetics , Pyrroles/therapeutic use , Piperazines/therapeutic use , Neoplasms/drug therapy , Neoplasms/geneticsABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive carcinoma with genome instability. Long non-coding RNAs (LncRNAs) have been functionally associated with genomic instability in cancers. However, the identification and prognostic value of lncRNAs related to genome instability have not been explored in hepatocellular carcinoma. In this study, we aim to identify a genomic instability-related lncRNA signature for predicting prognosis and the efficacy of immunotherapy in HCC patients. METHODS: According to the somatic mutation and transcript data of 364 patients with HCC, we determined differentially expressed genome instability-related lncRNAs (GInLncRNAs). Gene ontology (GO) enrichment analyses and Kyoto Encyclopedia of genes and genomes enrichment analyses revealed the potential functions of genes co-expressed with those lncRNAs involved in cancer development and immune function. We further determined a genome instability-related lncRNA signature (GInLncSig) through Cox regression analysis and LASSO regression analysis. Thereafter, we performed correlation analyses with mutations, clinical stratification analyses, and survival analyses to evaluate GInLncSig predictive function. Subsequently, we construct a nomogram model for prognostic assessments of patients with HCC. Finally, we performed Immunocytes infiltration analysis, gene set enrichment analysis (ssGSEA) of immunity circle-associated pathways, and T cell-inflamed score to explore GInLncSig's potential value in guiding immunotherapy. RESULTS: We identified 11 independent prognosis-associated GInLncRNAs (AC002511.2, LINC00501, LINC02055, LINC02714, LINC01508, LOC105371967, RP11_96A15.1, RP11_305F18.1, RP11_342M1.3, RP11_432J24.3, U95743.1) to construct a GInLncSig. According to the risk score calculated by GInLncSig, the high-risk group was characterized by a higher somatic mutation count, significantly poorer clinical prognosis, higher T cell-inflamed score, and specific tumor immune infiltration status compared to the low-risk group. Furthermore, we constructed a nomogram model to improve the reliability and clinical utility of predicting the prognosis of patients with HCC. CONCLUSION: Our study established a reliable prognostic prediction signature that could be a tool for prognosis prediction and a promising predictive biomarker of immunotherapy in hepatocellular carcinoma.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , RNA, Long Noncoding , Carcinoma, Hepatocellular/pathology , Gene Expression Regulation, Neoplastic , Genomic Instability , Humans , Kaplan-Meier Estimate , Liver Neoplasms/pathology , Mutation , Prognosis , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Reproducibility of Results , Tumor Microenvironment/geneticsABSTRACT
Background: Patients who achieve a tumor pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have better outcomes than patients with residual tumor. However, tumors still recur in the pCR patients. Therefore, we aim to explore factors associated with tumor recurrence in this patient population. Methods: A total of 1,913 patients diagnosed with breast cancer between 1995 and 2020 and received NAC were included in this analysis. Clinicopathological data of the patients were retrospectively collected. We used Cox regression analysis to assess the associations of clinicopathological factors with patients' outcome. Proteomic study of tumors was applied to identify differentially expressed proteins (DEPs) between tumors from the pCR patients with tumor recurrence and tumors from those without tumor recurrence. PPI network analysis of the corresponding genes of DEPs was used to identify the hub genes. The prognostic value of the corresponding genes of DEPs was evaluated using two online databases, Kaplan-Meier Plotter and bc-GenExMiner. The genes that were significantly associated with patients' survival in both databases, as well as being identified as hub genes, were considered as potential prognostic markers for pCR patients. Publicly available data from Gene Expression Omnibus (GEO) was used to verify the prognostic value of the identified marker. Results: Among the 1,913 included patients, 420 had tumor pCR. The median follow-up for the pCR patients was 32.6 months (IQR, 16.3-55.5). Overall estimated 5-year risk of tumor recurrence for the pCR patients was 11%. Multivariable analysis showed that a higher pre-NAC clinical T stage and N stage were independent predictors for increased risk of tumor recurrence (hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.01-6.51, P=0.047 for clinical T stage and HR 3.48, 95%CI 1.37-8.83, P=0.009 for clinical N stage). NAC regimens, the type of breast and axillary surgery, and adjuvant chemotherapy were not associated with tumor recurrence. Finally, aldehyde dehydrogenase (ALDH) 3A2 was identified by the proteomic study and was verified as a potential predictor for tumor recurrence in the pCR patients (with a median follow up of 3.78 years for dataset GSE32603 and 2.74 years for dataset GSE25066 from GEO, tumor recurrence rate: low versus high expression, 20.7% versus 4.5% [data from GSE32603]; 10.9% versus 0% [data from GSE25066]). Conclusions: Clinical T stage, clinical N stage and tumor expression of ALDH3A2 were potential markers for predicting tumor recurrence in the pCR patients after NAC.
ABSTRACT
There are varying definitions of women at high risk of breast cancer across different institutions, and there are reports suggesting that the breast cancer risk assessment tools have not been well integrated into clinical practice. In this study, we tried to investigate the perceived importance of different breast cancer risk factors by physicians in China. A cross-sectional survey involving 386 anonymous physicians was conducted using a 20-item, 5-point Likert scale questionnaire. The Kruskal-Wallis test and post-hoc pairwise comparisons were used to compare the differences in response. Most of the respondents were either breast surgeons/specialists (n=161; 41.7%) or medical oncologists (n=151; 39.1%), and the results showed that the breast cancer risk factors were not perceived as equally important. The weighting of each risk factor also varied depending on the physician's medical specialty, location of practice, and the number of years of clinical experience. This study provides a more updated insight into the perceptions of physicians in China toward the breast cancer risk factors, as well as underlines the potential improvements in breast cancer risk assessment strategies that can be done.
Subject(s)
Breast Neoplasms , Early Detection of Cancer/psychology , Oncologists/psychology , Physicians/psychology , Surgeons/psychology , Adult , Attitude of Health Personnel , China , Cross-Sectional Studies , Female , Humans , Middle Aged , Practice Patterns, Physicians'/statistics & numerical data , Surveys and QuestionnairesABSTRACT
PURPOSE: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy. PATIENTS AND METHODS: We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses. RESULTS: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n = 196) or trastuzumab plus chemotherapy (CT group, n = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0-44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7-21.7)] in the ET group and 14.8 months (12.8-16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71-1.09; Pnoninferiority < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group. CONCLUSIONS: Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.
Subject(s)
Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aromatase Inhibitors , Breast Neoplasms/pathology , Disease-Free Survival , Female , Humans , Receptor, ErbB-2 , Trastuzumab , Treatment OutcomeABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and its prognosis remains dismal. Hence, it is important to identify the diagnostic and prognostic biomarkers for HCC. Urokinase plasminogen activator (uPA), an extracellular matrix (ECM)-degrading protease, plays a pivotal role in the invasion and metastasis of HCC. METHODS: To confirm the clinical significance of uPA in HCC, we explored uPA expression in HCC in The Cancer Genome Atlas (TCGA) database. The expression level of uPA was further verified by quantitative reverse transcription polymerized chain reaction (qRT-PCR) in 133 pairs of primary HCC samples. A survival analysis was conducted with the Kaplan-Meier method in the HCC samples and TCGA database. RESULTS: Our results showed that uPA was overexpressed in HCC and was significantly associated with HCC tumor size (P=0.015), differentiation grade (P=0.028), and absence of tumor encapsulation (P=0.010). Patients with high uPA expression levels had a poor outcome (P=0.026). TCGA database analysis was also consistent with our experimental results. CONCLUSIONS: In conclusion, our findings revealed that uPA was overexpressed in HCC and was related to HCC malignant features including tumor size, differentiation grade and absence of tumor encapsulation. High uPA expression had a shorter survival time. It is a potential prognostic biomarker of HCC.
ABSTRACT
BACKGROUND: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphate-4 (PFKFB4) is a key factor that plays an important role in tumorigenesis. However, its role in triple-negative breast cancer (TNBC) progression needs to be further validated. We investigated whether PFKFB4 is directly involved in the oncogenic signaling networks of TNBC. METHODS: First, we assessed the expression level of PFKFB4 in tumor tissue specimens by immunohistochemistry and evaluated its prognostic value. Next, the effect of PFKFB4 on TNBC cell growth and associated mechanisms were investigated. Finally, the results were further verified in vivo. RESULTS: We found that PFKFB4 overexpression was associated with an unfavorable prognosis in TNBC patients. PFKFB4 was overexpressed in TNBC cell lines in hypoxic environments, and its overexpression promoted tumor progression in vitro and in vivo. Further analyses demonstrated that the possible mechanism might be that PFKFB4 overexpression facilitates TNBC progression by enhancing the G1/S phase transition by increasing the protein level of CDK6 and phosphorylation of Rb. CONCLUSIONS: These data suggest that PFKFB4 plays significant roles in the tumorigenesis and development of TNBC.
Subject(s)
Phosphofructokinase-2/genetics , Phosphofructokinase-2/metabolism , Triple Negative Breast Neoplasms/pathology , Up-Regulation , Adolescent , Adult , Aged , Cell Cycle , Cell Line, Tumor , Cell Proliferation , Cyclin-Dependent Kinase 6/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , Hypoxia , Middle Aged , Neoplasm Staging , Prognosis , Retinoblastoma Binding Proteins/metabolism , Survival Analysis , Tissue Array Analysis , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , Ubiquitin-Protein Ligases/metabolism , Young AdultABSTRACT
BACKGROUND: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. FINDINGS: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group. INTERPRETATION: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. FUNDING: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Subject(s)
Capecitabine/administration & dosage , Chemotherapy, Adjuvant/methods , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Neoplasms/drug therapy , Administration, Metronomic , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
Importance: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01112826.
Subject(s)
Capecitabine/administration & dosage , Triple Negative Breast Neoplasms/drug therapy , Adult , Capecitabine/adverse effects , Chemotherapy, Adjuvant , Disease-Free Survival , Drug Administration Schedule , Female , Follow-Up Studies , Hand-Foot Syndrome/etiology , Humans , Maintenance Chemotherapy , Mastectomy , Middle Aged , Neoplasm Grading , Neoplasm Staging , Neoplasm, Residual , Observation , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/surgeryABSTRACT
BACKGROUND: Triple-negative breast cancer (TNBC) patients have relatively poor clinical outcomes. A marker predicting the prognosis of patients with TNBC could help guide treatment. Extensive evidence demonstrates that angiopoietin-like 4 (ANGPTL4) is involved in the regulation of cancer growth, metastasis and angiogenesis. Therefore, its role in TNBC is of interest. METHODS: We tested the ANGPTL4 expression level in tumor tissues by immunohistochemistry (IHC) and detected its association with the clinical features of TNBC patients. Next, the effects and mechanisms of ANGPTL4 on TNBC cell migration and adhesion were investigated. RESULTS: We found that ANGPTL4 overexpression was associated with favorable outcomes in TNBC patients. ANGPTL4 upregulation inhibited cell adhesion, migration and invasion in vitro. Further analyses demonstrated that the possible mechanism might involve suppression of TNBC progression by interacting with extracellular matrix-related genes. CONCLUSIONS: The present findings demonstrated that enhancement of ANGPTL4 expression might inversely correlate with TNBC progression. ANGPTL4 is a promising marker of TNBC and should be evaluated in further studies. TRIAL REGISTRATION: Retrospectively registered.
Subject(s)
Angiopoietin-Like Protein 4/genetics , Prognosis , Triple Negative Breast Neoplasms/genetics , Cell Adhesion/genetics , Cell Line, Tumor , Cell Movement/genetics , Disease Progression , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic/genetics , Humans , Middle Aged , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Treatment Outcome , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/therapyABSTRACT
Pseudomonas syringae pv. tomato is a seedborne pathogen that causes bacterial speck disease in tomato. P. syringae pv. tomato is typically detected in tomato seed using quantitative real-time PCR (qPCR) but the inability of qPCR to distinguish between viable and nonviable cells might lead to an overestimation of viable P. syringae pv. tomato cells. In the present study, a strategy involving a propidium monoazide (PMA) pretreatment followed by a qPCR (PMA-qPCR) assay was developed for quantifying viable P. syringae pv. tomato cells in contaminated tomato seed. PMA could selectively bind to the chromosomal DNA of dead bacterial cells and, therefore, block DNA amplification of qPCR. The primer pair Pst3F/Pst3R was designed based on gene hrpZ to specifically amplify and quantify P. syringae pv. tomato by qPCR. The PMA pretreatment protocol was optimized for selectively detecting viable P. syringae pv. tomato cells, and the optimal PMA concentration and light exposure time were 10 µmol liter-1 and 10 min, respectively. In the sensitivity test, the detection limit of PMA-qPCR for detecting viable cells in bacterial suspension and artificially contaminated tomato seed was 102 CFU ml-1 and 11.86 CFU g-1, respectively. For naturally contaminated tomato seed, viable P. syringae pv. tomato cells were quantified in 6 of the 19 samples, with infestation levels of approximately 102 to 104 CFU g-1. The results indicated that the PMA-qPCR assay is a suitable tool for quantifying viable P. syringae pv. tomato cells in tomato seed, which could be useful for avoiding the potential risks of primary inoculum sources from contaminated seed.
Subject(s)
Solanum lycopersicum , Azides , Propidium/analogs & derivatives , Pseudomonas syringae , Real-Time Polymerase Chain Reaction , SeedsABSTRACT
Cripto-1 may act as an independent predictor for prognosis in hepatocellular carcinoma (HCC). However, the function of Cripto-1 in HCC cells and its response to postoperative transarterial chemoembolization (TACE) in HCC patients remains unclearly. Up-regulated Cripto-1 expression boosted the ability of cell proliferation, migration and invasion in HCC cells in vitro. While opposite results were observed in HCC cells with down-regulated Cripto-1 expression. Cripto-1 expression was correlated with epithelial-mesenchymal transition (EMT) relevant biomarkers. Furthermore, in high Cripto-1 expression patients, those with adjuvant TACE had favorable TTR and OS times. On contrary, adjuvant TACE may promote tumor recurrence but had no influence on OS time in patients with low Cripto-1 expression. In different subgroups of vascular invasion, larger tumor size or liver cirrhosis, patients with adjuvant TACE had longer TTR and OS times than those without TACE in patients with high Cripto-1 expression, while they could not obtain benefits from adjuvant TACE in patients with low-expressed Cripto-1 expression. In conclusion, Cripto-1 may be a potential prognostic factor in predicting outcome of HCC patients with TACE therapy, and combined with Cripto-1 and tumor features may be helpful to stratify patients with respect to prognosis and response to adjuvant TACE.
Subject(s)
Carcinoma, Hepatocellular/therapy , Chemoembolization, Therapeutic , GPI-Linked Proteins/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Liver Neoplasms/therapy , Neoplasm Proteins/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/mortality , Cell Line, Tumor , Epithelial-Mesenchymal Transition , Female , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/mortality , Male , Middle Aged , Young AdultABSTRACT
Cyclin-dependent kinase inhibitor 2A (p16INK4a) protein is a surrogate immunohistochemical marker of human papillomavirus infection in oropharynx squamous cell carcinoma (OPSCC). However, the effects of p16INK4a in non-OPSCC require additional analysis. In addition, major gaps remain in the literature, including small volumes of data for China. Therefore, the present study evaluated the frequency of p16INK4a positivity in patients with non-OPSCC in Southern China, and assessed its prognostic value. p16INK4a expression status in patients with non-OPSCC was determined by immunohistochemistry. p16INK4a-positive expression was defined as a strong and diffuse staining in ≥70% of the tumor cells. Then, the diagnostic value of p16INK4a in predicting overall survival (OS) and disease-free survival (DFS) rate was determined. The positive rate of p16INK4a was 26.3% in larynx cancer and 24.8% in oral cavity cancer. Multivariate analysis revealed that the protein status independently predicted improved OS rate, but not DFS rate (P=0.096). Comparing different disease stages, patients at an early stage with p16INK4a-positive non-OPSCC exhibited improved DFS and OS rates compared with those exhibited by patients who were negative. The p16INK4a-positive rate in patients with non-OPSCC was 25.1% [26.3% in Laryngeal squamous cell carcinoma (LSCC) and 24.8% in Oropharyngeal squamous cell carcinomas (OSCC)] in the present cohort from South China. The present study suggested that p16INK4a expression in non-OPSCC predicts favorable clinical outcomes, particularly in early stage non-OPSCC and oral cancer.
ABSTRACT
Okra (Abelmoschus esculentus (L.) Moench) has gained more popularity as an economically significant plant for its nutritional and medicinal value, especially in China. During 2014-2016, the root disease of okra was discovered in four okra commercial fields surveyed in China. A fungul was isolated from the infected tissues, and was identified by Verticillium dahliae based on morphological characteristics. Pathogenicity test demonstrated that the fungus was pathogenic on okra, and fulfilled Koch's postulates. The analysis of three sequences revealed 99-100% identity with the reported V. dahliae strain in GenBank. Neighbor-joining analysis of the gene sequences revealed that the representative isolates were clustered with V. dahliae. To the best of our knowledge, this is the first report of Verticillium wilt of okra in China.
ABSTRACT
BACKGROUND: The clinical implication of plasma ESR1 mutations in the estrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who had progressed after prior aromatase inhibitor (AI)-based therapy remains controversial. We conducted the first meta-analysis to investigate the prognostic significance and predictive role of plasma ESR1 mutations in MBC patients with prior exposure to AI therapy. MATERIALS AND METHODS: We searched PubMed, Embase, and Cochrane Library databases for eligible studies. Meta-analysis was conducted to calculate combined hazard ratios (HRs) with 95% CIs for progression-free survival (PFS) and overall survival (OS). Subgroup and sensitivity analyses were also performed. RESULTS: This study enrolled a total of 1,530 patients with ER-positive MBC cases from six articles, including 429 ESR1 mutation carriers (28.04%). Meta-analysis demonstrated that plasma ESR1 mutation carriers had significantly worse PFS (HR: 1.40, 95% CI: 1.17-1.66; P<0.0001) and OS (HR: 1.65, 95% CI: 1.36-2.01; P<0.0001) compared to wild-type ESR1. Subgroup analysis showed that plasma ESR1 mutations were associated with shorter PFS after AI-based treatment, but were not significantly predictive of outcome on fulvestrant-containing therapy (HR: 1.26, 95% CI: 0.98-1.62; P=0.077). As for different ESR1 mutations, D538G mutation implied significantly worse PFS (HR: 1.50, 95% CI: 1.18-1.91; P=0.01), while Y537S mutation was not correlated with PFS (HR: 1.65, 95% CI: 0.87-1.73; P=0.134). CONCLUSION: The meta-analysis indicated that plasma ESR1 mutation assessment may have prognostic significance and clinical value in guiding further endocrine therapy choice in ER+ MBC patients who received prior AI therapy.
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Severe root rot was observed in fields of cabbages (Brassica oleracea L.) in 2015 in China. Cardinal symptoms of this disease included root rot and wilting leaves. A fungus was isolated from diseased tissues consistently. Based on the morphological features and molecular analysis of the ITS-5.8S rDNA and D1/D2 domain of the 28S rRNA gene, it was identified as Plectosphaerella cucumerina. This is the first report of P. cucumerina causing cabbage root rot in China and the world.
ABSTRACT
PURPOSE: The renal safety of cisplatin-based chemotherapy has not been investigated in patients with urothelial carcinoma of the upper urinary tract (UUT-UC) who retain a solitary kidney after nephroureterectomy. This study aimed to assess and compare the renal safety and efficacy of gemcitabine-cisplatin (GP) and gemcitabine-carboplatin (GC) in these patients. METHODS: The medical records of patients diagnosed with urothelial carcinoma at the Sun Yat-Sen University Cancer Center between January 2005 and December 2015 were retrospectively reviewed. The creatinine clearance (CrCl) and estimated glomerular filtration rate (eGFR) were used to assess renal function and were calculated using different formulas. RESULTS: A total of 71 patients were enrolled in this study; 48 patients were on GP, and 23 were on GC. The renal function indicators (CrCl and eGFR) were all significantly lower after GP chemotherapy than at baseline, a phenomenon that was not observed in the GC group. Severe nephrotoxicities (SNTs) were reported in 12 patients on GP (25%) and zero on GC. SNT risk factors included a more than 20% decrease in eGFR after one GP cycle and the presence of diabetes (all p < 0.05). Among patients treated with first-line palliative chemotherapy (n = 32), GC (n = 13) patients had an ORR of 46.2%, which was not significantly different from GP patients (36.8%, n = 19), whereas GC patients tended to have a shorter OS than GP patients (9.2 vs. 29 months, p = 0.200). CONCLUSIONS: Our results confirm that GP has an adverse impact on the renal function of patients with UUT-UC who retain a solitary kidney, but it can be safely administered to the majority of these patients without inducing SNT. In specific patients, GC is an alternative to GP that has comparable efficacy and favourable renal toxicity.