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OBJECTIVES Oesophagectomy was always recommended after noncurative endoscopic resection (ER). And the optimal time interval from ER to oesophagectomy remains unclear. This study was to explore the effect of interval on pathologic stage and prognosis. METHODS We included 155 patients who underwent ER for cT1N0M0 oesophageal cancer and then received subsequent oesophagectomy from 2009 to 2019. Overall survival and disease-free survival (DFS) were analysed to find an optimal cut-off of interval from ER to oesophagectomy. In addition, pathologic stage after ER was compared to that of oesophagectomy. Logistic regression model was built to identify risk factors for pathological upstage. RESULTS The greatest difference of DFS was found in the groups who underwent oesophagectomy before and after 30 days (P = 0.016). Among total 155 patients, 106 (68.39%) received oesophagectomy within 30 days, while 49 (31.61%) had interval over 30 days. Comparing the pathologic stage between ER and oesophagectomy, 26 patients had upstage and thus had worse DFS (hazard ratio = 3.780, P = 0.042). T1b invasion, lymphovascular invasion and interval >30-day group had a higher upstage rate (P = 0.014, P CONCLUSIONS It was the first study exploring the relationship between time interval and prognosis in oesophageal cancer. The longer interval between noncurative ER and additional oesophagectomy was associated with a worse DFS, so oesophagectomy was recommended performed within 1 month after ER. Older age, T1b stage, lymphovascular invasion and interval >30 days were significantly associated with pathologic upstage, which is related to the worse outcome too.

Background PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients with BRCA mutations, and their efficacy is even more limited in triple-negative breast cancer (TNBC) due to clinical primary and acquired resistance. Here, we found that the efficacy of the PARPi olaparib in TNBC can be improved by combination with the CDK4/6 inhibitor (CDK4/6i) palbociclib. Methods We screened primary olaparib-sensitive and olaparib-resistant cell lines from existing BRCAmut/TNBC cell lines and generated cells with acquired olaparib resistance by gradually increasing the concentration. The effects of the PARPi olaparib and the CDK4/6i palbociclib on BRCAmut/TNBC cell lines were examined in both sensitive and resistant cells in vitro and in vivo. Pathway and gene alterations were assessed mechanistically and pharmacologically. Results We demonstrated for the first time that the combination of olaparib and palbociclib has synergistic effects against BRCAmut/TNBC both in vitro and in vivo. In olaparib-sensitive MDA-MB-436 cells, the single agent olaparib significantly inhibited cell viability and affected cell growth due to severe DNA damage. In olaparib-resistant HCC1937 and SUM149 cells, single-agent olaparib was ineffective due to potential homologous recombination (HR) repair, and the combination of olaparib and palbociclib greatly inhibited HR during the G2 phase, increased DNA damage and inhibited tumour growth. Inadequate DNA damage caused by olaparib activated the Wnt signalling pathway and upregulated MYC. Further experiments indicated that the overexpression of β-catenin, especially its hyperphosphorylation at the Ser675 site, activated the Wnt signalling pathway and mediated olaparib resistance, which could be strongly inhibited by combined treatment with palbociclib. Conclusions Our data provide a rationale for clinical evaluation of the therapeutic synergy of the PARPi olaparib and CDK4/6i palbociclib in BRCAmut/TNBCs with high Wnt signalling activation and high MYC expression that do not respond to PARPi monotherapy.

Background: MicroRNAs (miRNAs) can influence many biological processes and also show promise as biomarkers for cancer. Few researches have focused on the expression of microRNA-223 (miR-223) and its precise role in breast cancer (BC). We aimed to examine the expression level of miR-223 and further explored the prognostic value in BC.Methods: Tissue microarray-based miRNA detection in situ hybridization with LNA probe was used to detect miR-223 expression in 450 BC tissue. Overall survival (OS) and disease-free survival (DFS) were compared between two groups using the Kaplan-Meier method and Cox regression model.Results: Better OS and DFS were observed in the high-miR-223 expression patients compared to those of low expression patients (P < 0.0001 and P = 0.017, respectively), especially in the triple-negative breast cancer (TNBC) subtype (P = 0.046and P < 0.001, respectively). Combined with the univariate and multivariate Cox regression analysis, TNM stage (p = 0.008), molecular subtype (p =0.049) and miR-223 (p < 0.001) were independently linked to OS and DFS. External validation was performed in METABRIC and TCGA database via online webtool and consistent with the data above.Conclusions: This study provided evidence that high-miR-223 expression at diagnosis was associated with better DFS and OS for BC, especially for the TNBC subtype. miR-223 is a valid and independent prognostic biomarker in BC. Table Univariate and multivariate survival analysis for disease-free survivalUnivariate MultivariateVariableHR95% CIP valueHR95% CIP valueAge0.594≤40 vs >601.3510.626-2.9140.44440-60 vs >600.9940.548-1.8030.984Menopausal statuspre vs post0.7370.487-1.1130.147DifferentiationII vs III0.7300.457-1.1640.186TNM stage0.0080.008II vs I1.4210.860-2.3460.1701.4850.887-2.4850.132III vs I2.7581.446-5.2590.0022.8581.469-5.5630.002Molecular subtype0.1940.049Luminal B vs Luminal A1.1060.580-2.1070.7600.8130.415-1.5930.546HER2+ vs Luminal A0.9860.497-1.9560.9670.7010.337-1.4580.342Triple-negative vs Luminal A1.6260.930-2.8430.0881.4930.849-2.6260.164MicroRNA-223low vs high3.9602.201-7.126 Citation Format: Li Chen, Xiuzhi Zhu, Ling Yao, Zonghua Wang. High expression of MicroRNA-223 indicates better prognosis in triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-21.

Background: PARP inhibitors (PARPi) benefit only a fraction of breast cancer with BRCA mutation, and are even more limited in triple negative breast cancer (TNBC), due to clinical primary and acquired resistance. Here we found that the efficacy of PARPi in TNBC can be expanded with CDK4/6 inhibitors (CDK4/6i). Methods: We screened sensitive and resistant PARPi cell lines from existing TNBC cell lines and cultured PARPi-resistant strains by gradient concentration increase method. The effects of PARP inhibitor Olaparib and CDK4/6 inhibitor Palbociclib on TNBC cells lines were examined in vitro and in vivo. Combination index (CI) was used to evaluate the synergistic effects of drug combination. Results: We screened out the cell line MDA-MB-436, which was the most sensitive to PARPi, and the cell lines HCC1937 and SUM149, which were relatively resistant to PARPi, all of which were BRCA1 mutants. We demonstrated for the first time that the combination of PARPi and CDK4/6i has synergistic effects against some TNBCs both in vitro and in vivo, and was verified by CI The combination index index of HCC1937 at different drug concentrations (uM)The combination index index of HCC1937 at different drug concentrations (uM)OlaparibPalbociclib25.0016.6711.117.414.943.292.191.460.980.65P-25.000.459110.668320.866540.869640.993450.989890.97841.003221.073741.00809P-20.000.537090.851131.022651.149561.231561.270271.189071.145021.14811.25795P-15.000.594121.018141.134481.056960.928140.955670.889760.842040.81060.81348P-10.000.475540.860580.77190.717480.62330.615880.561390.52960.510250.49752P-5.000.509450.762230.746560.683340.56030.499410.467390.41490.390670.37502P-2.500.573130.706410.714750.661230.519270.455960.350980.29340.319310.2756 Citation Format: Xiuzhi Zhu, Li Chen, Zhonghua Wang. Efficacy of combined CDK4/6 inhibitor and PARP inhibitor in the treatment of BRCA1 mutant triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-39.

The fleshy fruits of Camellia oleifera Abel are the immature fruits of C. oleifera, which are infected by Exobasidium vexans Massee and then turn to be intumescent and hollowed. They contain rich t...

As a cell proliferation biomarker, Ki-67 is principally used in ER+/HER2− breast cancer. However, the importance and the best cutoff point of Ki-67 in triple-negative breast cancer (TNBC) remains unclear and was evaluated in this study.A total of 1800 patients with early invasive TNBC between 2011 and 2016 at Fudan University Shanghai Cancer Center were consecutively recruited for this study. The optimal cutoff for Ki-67 was assessed by Cutoff Finder. Propensity score matching (PSM, ratio = 1:2) was performed to match the Ki-67low group with the Ki-67high group. Overall survival (OS) and disease-free survival (DFS) were compared between the two groups using the Kaplan-Meier method and Cox regression model. The most relevant cutoff value for Ki-67 for prognosis was 30% (p = 0.008). At the cutoff point of 30%, worse DFS and OS were observed in the Ki-67high group. In multivariate analyses, N-stage (p p = 0.038), and Ki-67 at the 30% threshold (p = 0.020) were independently linked to OS. In subgroup analysis, Ki-67 cutoff at 30% had prognostic and predictive potential for DFS with either tumor size ≤2 cm (p = 0.008) or lymph node-negative (N−) (p = 0.038) and especially with T1N0M0 (stage I) TNBCs. For 945 N− TNBC patients, adjuvant chemotherapy (CT) was associated with better OS in the Ki-67high group (p = 0.017) than in the Ki-67low group (p = 0.875). For stage I/Ki-67low patients, adjuvant CT did not affect DFS (p = 0.248). Thus, Ki-67 cutoff at 30% had early independent prognostic and predictive potential for OS and DFS in TNBCs, and Ki-67 > 30% was significantly associated with worse prognosis, especially for stage I patients. For stage I/Ki-67low TNBC patients, the advantage of CT is unclear, providing the basis for future de-escalation therapy.

Abdominal aortic aneurysms (AAA) are pathological dilations in local aortic wall. The inflammatory infiltrates of the perivascular adipose tissue (PAT) surrounding AAAs were associated with AAAs and have been shown to contribute vascular pathology. However, the mechanism by which PAT inflammation contributes to vascular pathology in AAA remains to be clarified. This study aimed to explore the association between immune cell infiltration and key gene expression profile in PAT of AAA. For that, a gene expression dataset of human dilated perivascular adipose tissue (dPAT), non-dilated perivascular adipose tissue (ndPAT), subcutaneous abdominal fat (SAF) and omental-visceral fat (OVF) samples, as well as another microarray dataset of the abdominal perivascular adipose tissue in peripheral artery disease patients were downloaded from GEO database for analysis in this study. The CIBERSORT algorithm, weighted gene co-expression network analysis (WGCNA) and LASSO algorithm were used for the identification of immune infiltration, immune-related genes and the development of diagnostic signature. Our data discovered a significant higher proportion of activated mast cells and follicular helper T (Tfh) cells in dPAT than ndPAT, OVT and SAF samples. Moreover, AP-1 family members (FOS, FOSB, ATF3, JUN and JUNB) were found to compose the hub genes of purple module in WGCNA. Among them, FOS gene acts as a higher efficient marker to discriminate dPAT from ndPAT, OVT and SAF in AAA. Meanwhile, the expression profiles of the AP-1 family members are all significantly positive correlated with activated mast cell, plasma cell and Tfh cell infiltration in dPAT of AAA. Therefore, in the PAT surrounding AAA, the signature of inflammatory infiltration might be represented by a FOS-dominated cell network consist of activated mast cell, plasma cell and Tfh cell. Given the complicated etiology of AAA, our results are likely to shed new light on the pathophysiologic mechanism of AAA influenced by the local dPAT.

Metformin (MET) can effectively treat endometrial hyperplasia (EH), and the expression of glucose transporter type 4 insulin‑responsive (GLUT4) is closely associated with the development of EH. The present study aimed to verify the effect of MET in functional EH and polycystic ovary syndrome (PCOS). HE staining was performed to analyze the severity of EH, and immunohistochemistry was performed to evaluate the expression of GLUT4 in the endometrium of PCOS rats. Reverse transcription‑quantitative PCR was used to calculate the expression of long non‑coding (lnc)RNA‑maternally expressed gene 3 (MEG3), lncRNA‑small nucleolar RNA host gene 20 (SNHG20), GLUT4 mRNA, microRNA (miR)‑223 and miR‑4486. Sequence analysis and luciferase assays were performed to explore the regulatory relationship among certain lncRNAs, miRNAs and target genes. EH in PCOS rats was efficiently inhibited by MET administration. The increased expression of GLUT4 in PCOS rats was attenuated by MET treatment. Moreover, the expression levels of lncRNA‑MEG3 and lncRNA‑SNHG20 were significantly inhibited in the endometrium of PCOS rats. MET treatment also showed remarkable efficiency in restoring the expression of lncRNA‑MEG3 and lncRNA‑SNHG20. Meanwhile, the expression levels of miR‑223 and miR‑4486 were notably elevated in the endometrium of PCOS rats, while MET treatment reduced the expression of miR‑223 and miR‑4486 in PCOS rats. Furthermore, a luciferase assay confirmed the inhibitory relationship between miR‑223 and lncRNA‑MEG3/GLUT4 expression, as well as between miR‑4486 and lncRNA‑SNHG20/GLUT4 expression. GLUT4 knockdown restored the decreased viability of HCC‑94 cells induced by overexpression of lncRNA‑MEG3. To conclude, MET exhibited a therapeutic effect in the treatment of EH by modulating the lncRNA‑MEG3/miR‑223/GLUT4 and lncRNA‑SNHG20/miR‑4486/GLUT4 signaling pathways. This work provides mechanistic insight into the development of EH.

Additional file 2: Figure S1. Synergistic response to combined PARPi and CDK4/6i treatment in BRCAmut/TNBCs. Figure S2. Severe DNA damage caused by the combination of olaparib and palbociclib. Figure S3. Colony formation assays of SUM149 cells treated with PARPi and/or CDK4/6i. Figure S4. The combined use of olaparib and palbociclib can inhibit the WNT pathway, which is not downregulated by single-agent olaparib treatment. Figure S5. Ser675 phosphorylation of β-catenin in the Wnt pathway mediates resistance to olaparib but can be inhibited by palbociclib. Figure S6. Growth curves of parental and acquired-resistant HCC1937 cells at different concentrations of olaparib. Figure S7. Weights of (A) MDA-MB-436 and (B) HCC1937 xenografted NOD-SCID mice.

The aim of the present work was to investigate the risk factors for gastric cancer- (GC-) associated thrombotic diseases in a Han Chinese population. A total of 333 patients diagnosed with GC, 68 with thrombotic diseases included in the case group and the remaining 265 in the control group, were enrolled. The relevant data for the participants, including general information (gender, age, smoking, and drinking), comorbidities (diabetes, hypertension, and anemia), tumor-related data (tumor site, histology, degree of differentiation, and clinical stage), and treatment-related data (surgery, chemotherapy, hormones, transfusion, and peripherally inserted central venous catheter (PICC)), were collected. Statistically significant factors derived from univariate analyses were then subjected to multivariate logistic regression analyses. The results demonstrate a statistically significant difference in age, diabetes, hypertension, histology, surgery, chemotherapy, and PICC ( P < 0.05 ), compared with control. Age, diabetes, surgery, and PICC serve as independent risk factors for GC-associated thrombotic diseases ( P < 0.05 ). The present work demonstrates that GC-associated thrombotic diseases are significantly associated with age, diabetes, surgery, and PICC, suggesting a potential target for early detection and preventive strategy for GC patients with thrombophilia.

Background: PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients with BRCA mutations and their efficacy is even more limited in triple-negative breast cancer (TNBC) due to clinical primary and acquired resistance. Here, we found that the efficacy of PARPi in TNBC can be improved with CDK4/6 inhibitors (CDK4/6i).Methods: We screened primary PARPi-sensitive and resistant cell lines from existing BRCAmut/TNBC cell lines and generated cells with acquired PARPi resistance by gradually increasing the concentration. The effects of the PARPi olaparib and the CDK4/6i palbociclib on BRCAmut/TNBC cell lines were examined in both sensitive and resistant cells in vitro and in vivo. Pathway and gene alterations were assessed mechanistically and pharmacologically.Results: We demonstrated for the first time that the combination of PARPi and CDK4/6i has synergistic effects against BRCAmut/TNBC both in vitro and in vivo. In the PARPi-sensitive MB436 cells, the single agent olaparib significantly inhibited cell viability and affected cell growth due to severe DNA damage. In the PARPi-resistant HCC1937 and SUM149 cells, single-agent olaparib was ineffective due to potential homologous recombination (HR) repair, and the combination of PARPi and CDK4/6i greatly inhibited HR during the G2 phase, increased DNA damage and inhibited tumor growth. Inadequate DNA damage caused by PARPi activated the Wnt signaling pathway and upregulated MYC. Further experiments indicated that the overexpression of β-catenin, especially its hyperphosphorylation at the Ser675 site activated the Wnt signaling pathway and mediated PARPi resistance, which could be strongly inhibited by the combined treatment with CDK4/6i.Conclusions: Our data provide a rationale for the clinical evaluation of the therapeutic synergy of PARPi and CDK4/6i in BRCAmut/TNBCs with high Wnt signaling activation, high MYC expression and do not respond to PARPi monotherapy.

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Background Liver metastasis is a significant adverse predictor of overall survival (OS) among breast cancer patients. The purpose of this study was to determine the risk and prognostic factors of breast cancer with liver metastases (BCLM). Methods Data on 311,573 breast cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database and 1728 BCLM patients from Fudan University Shanghai Cancer Center (FUSCC) were included. Logistic regression was used to identify risk factors for liver metastasis. Cox proportional hazards regression model was adopted to determine independent prognostic factors in BCLM patients. Results Young age, invasive ductal carcinoma, higher pathological grade, and subtype of triple-negative and human epidermal growth factor receptor 2 positive (HER2+) were risk factors for developing liver metastasis. The median OS after liver metastasis was 20.0 months in the SEER database and 27.3 months in the FUSCC dataset. Molecular subtypes also played a critical role in the survival of BCLM patients. We observed that hormone receptor-positive (HR+)/HER2+ patients had the longest median OS (38.0 for SEER vs. 34.0 months for FUSCC), whereas triple-negative breast cancer had the shortest OS (9.0 vs. 15.6 months) in both SEER and FUSCC. According to the results from the FUSCC, the subtype of HR+/HER2+ (hazard ratio (HR) = 2.62; 95% confidence interval (CI) = 1.88–3.66; P P P Conclusions Breast cancer patients at a high risk for developing liver metastasis deserve more attention during the follow-up. BCLM patients with HR+/HER2+ subtype displayed the longest median survival than HR+/HER2- and triple-negative patients due to the introduction of HER2-targeted therapy and therefore it should be recommended for HER2+ BCLM patients.

Background Breast cancer patients generally have a worse prognosis in presence of liver metastasis. The purpose of this study was to evaluate the risk factors and prognosis of breast cancer patients with liver metastases (BCLM). Methods Data on 311,573 breast cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database diagnosed 2010 to 2016 and 1728 BCLM patients from Fudan University Shanghai Cancer Center (FUSCC) were analyzed for further exploration. We extracted the clinicopathological characteristics for analysis by two independent authors. Logistic regression was used to identify factors associated with the risk of liver metastases. Survival analysis was completed using Cox proportional hazards regression model and Kaplan-Meier analysis. Results Young age, invasive ductal carcinoma, higher pathological grade, and subtype of triple-negative and human epidermal growth factor receptor 2 positive (HER2+), were associated with increased risk of the liver metastases. The median overall survival (OS) after BCLM diagnosis was 20.0 months in the SEER database and 27.3 months in the FUSCC dataset. We observed that hormone receptor-positive (HR+)/HER2+ patients had the longest median OS 38.0 for SEER vs. 34.0months for FUSCC), whereas triple-negative breast cancer had the poorest OS (9.0 vs. 15.6 months) in both SEER and FUSCC. According to the results from the FUSCC, the subtype of HR+/HER2+ (hazard ratio (HR)=2.62; 95% confidence interval (CI)= 1.88-3.66; P

Increasing evidence has suggested that depression is a neuropsychiatric condition associated with neuroplasticity within specific brain regions. However, the mechanisms by which neuroplasticity exerts its effects in depression remain largely uncharacterized. In the present study we show that chronic stress effectively induces depression-like behaviors in rats, an effect which was associated with structural changes in dendritic spines and synapse abnormalities within neurons of the ventromedial prefrontal cortex (vmPFC). Moreover, unpredictable chronic mild stress (UCMS) exposure significantly increased the expression of miR-134 within the vmPFC, an effect which was paralleled with a decrease in the levels of expression and phosphorylation of the synapse-associated proteins, LIM-domain kinase 1 (Limk1) and cofilin. An intracerebral infusion of the adenovirus associated virus (AAV)-miR-134-sponge into the vmPFC of stressed rats, which blocks mir-134 function, significantly ameliorated neuronal structural abnormalities, biochemical changes and depression-like behaviors. Chronic administration of ginsenoside Rg1 (40 mg/kg, 5 weeks), a potential neuroprotective agent extracted from ginseng, significantly ameliorated the behavioral and biochemical changes induced by UCMS exposure. These results suggest that miR-134-mediated dysregulation of structural plasticity may be related to the display of depression-like behaviors in stressed rats. The neuroprotective effects of ginsenoside Rg1, which produces an antidepressant like effect in this model of depression, appears to result from modulation of the miR-134 signaling pathway within the vmPFC.

Depression is a common neuropsychiatric disorder which has been associated with a wide range of structural and functional changes within specific brain regions. Ginsenoside Rg1 has been shown to exert a number of neuroprotective effects as demonstrated in various in vivo and in vitro studies. However, little information is available regarding the site and mechanisms of ginsenoside Rg1 in promoting antidepressant effects. The present study aimed to investigate the neuroprotective and ameliorating effects of ginsenoside Rg1 on depression-like behavior as induced by chronic unpredictable mild stress (CUMS). The results showed that CUMS was effective in producing depression-like behaviors in rats as indicated by decreased responses in sucrose preference and forced swim tests which were associated with ultrastructural changes in neurons within the amygdala. Moreover, levels of PKA and CREB phosphorylation and the expression of brain-derived neurotrophic factor (BDNF) were decreased in the amygdala of CUMS rats. Remarkably, chronic ginsenoside Rg1 (40 mg/kg, i.p., 5 weeks) treatment significantly ameliorated these behavioral and biochemical alterations associated with CUMS-induced depression. Taken together, the results of the present study demonstrate that ginsenoside Rg1 exhibits antidepressant-like effects against CUMS-induced depression. This amelioration of depression-like behaviors by ginsenoside Rg1 appears to be mediated, at least in part, by a CREB-regulated increase of BDNF expression in the amygdala of rats. Therefore, these findings reveal the therapeutic potential of ginsenoside Rg1 for use in clinical trials in the treatment of depression.

Depression is a major neuropsychiatric disorder that exerts deleterious effects upon public health. However, the neuronal mechanisms of depression remain largely uncharacterized, which has retarded the identification and development of effective therapeutic tools for the treatment of this disorder. The aim of this study was to explore the neuronal mechanisms underlying the protective effects of ginsenoside Rg1, a natural steroidal saponin found in ginseng, against chronic stress-induced depression.The results showed that chronic administration of ginsenoside Rg1 (40 mg/kg, i.p., 5 weeks) significantly ameliorated depression-like behaviours in rats as assessed in the sucrose preference and forced swim tests. Furthermore, chronic stress decreased the phosphorylation levels of the extracellular signal-regulated kinase and cAMP-response element-binding protein in the prefrontal cortex as well as producing a reduction of brain-derived neurotrophic factor expression. Of particular importance, all reductions in these parameters were significantly reversed by pre-treatment with ginsenoside Rg1. Taken together, the results of the present study suggest that the antidepressant-like effect of ginsenoside Rg1 might be mediated, at least in part, by activating the cAMP-response element-binding protein-brain-derived neurotrophic factor system within the prefrontal cortex. These findings not only reveal some of the underlying neuronal mechanisms of depression, but also the therapeutic potential of ginsenoside Rg1 as a preventive agent in the treatment of depression.