Homogeneous Bridging Induces Compact and Scalable Perovskite Thick Films for X-Ray Flat-Panel Detectors.

Solution-processed organic-inorganic hybrid perovskite polycrystalline thick films have shown great potential in X-ray detection. However, the preparation of compact perovskite thick films with large area is still challenging due to the limitation of feasible ink formulation and pinholes caused by solvent volatilization. Post-treatment and hot-pressing are usually involved to improve the film quality, which is however unsuitable for subsequent integration. In this work, a homogeneous bridging strategy is developed to prepare compact perovskite films directly. A stable perovskite slurry with suitable viscosity consisting of undissolved grains and supersaturated solution is formed by adding a weak coordination solvent to the pre-synthesized microcrystalline powders. Small perovskite grains in situ grow from the saturated solution during the annealing, filling the pinholes and connecting the surrounding original grains. As a result, large-area perovskite thick film with tight grain arrangement and ultralow current drift is blade-coated to achieve X-ray imaging. The optimal device displays an impressive mobility-lifetime product of 2.2 × 10-3  cm2  V-1 and a champion ratio of sensitivity to the dark current density of 2.23 × 1011  µC Gyair -1  A-1 . This work provides a simple and effective route to prepare high-quality perovskite thick films, which is instructive for the development of perovskite-based X-ray flat-panel detectors.

A protein with broad functions: damage-specific DNA-binding protein 2.

Damage-specific DNA-binding protein 2 (DDB2) was initially identified as a component of the damage-specific DNA-binding heterodimeric complex, which cooperates with other proteins to repair UV-induced DNA damage. DDB2 is involved in the occurrence and development of cancer by affecting nucleotide excision repair (NER), cell apoptosis, and premature senescence. DDB2 also affects the sensitivity of cancer cells to radiotherapy and chemotherapy. In addition, a recent study found that DDB2 is a pathogenic gene for hepatitis and encephalitis. In recent years, there have been few relevant literature reports on DDB2, so there is still room for further research about it. In this paper, the molecular mechanisms of different biological processes involving DDB2 are reviewed in detail to provide theoretical support for research on drugs that can target DDB2.

Long-term oncologic safety of immediate reconstructive surgery in patients with invasive breast cancer: a retrospective matched-cohort study.

OBJECTIVE: Immediate reconstruction (IR) is a safe and effective surgical treatment for patients with breast cancer. We aimed to assess the prognosis, aesthetic outcomes, and patient satisfaction of IR compared with breast conservation surgery (BCS) and total mastectomy (TM). METHODS: This retrospective matched-cohort study was conducted between May 2005 and December 2014. We established two cohorts according to the tumor (T) size of breast cancer. In the T≤3cm group, cases (IR) and controls (BCS or TM) were matched for age, pathological tumor size, and pathologic nodal status in a 1:1:1 ratio. In the T>3cm group, cases (IR) and controls (TM) were matched with the same factors and ratio. The primary outcome was the 5-year disease-free survival (DFS). The secondary outcome was patient satisfaction and quality of life. RESULTS: A total of 12,678 breast cancer patients were assessed for eligibility, of which 587 were included (T≤3 cm group: 155 IR vs 155 BCS vs 155 TM; T>3cm group: 61 IR vs 61 TM). In the T≤3 cm cohort, patients who underwent IR had no difference compared with those who underwent BCS or TM regarding the 5-year DFS (P=0.539); however, an improved aesthetic satisfaction, psychosocial, and sexual well-being were achieved in the IR group (P<0.001). In the T>3 cm cohort, the IR group had a worse median 5-year DFS (P=0.044), especially for Her2+ or triple-negative breast carcinoma (TNBC) subtypes compared with the TM group. CONCLUSIONS: IR improves aesthetic satisfaction, psychosocial, and sexual well-being for breast cancer patients with T≤3 cm. For patients with T > 3 cm invasive breast cancer, TM is superior to IR as it predicts a better 5-year DFS.

Application of conventional ultrasonography combined with contrast-enhanced ultrasonography in the axillary lymph nodes and evaluation of the efficacy of neoadjuvant chemotherapy in breast cancer patients.

OBJECTIVE: Axillary lymph node status assessment has always been an important issue in clinical treatment of breast cancer. However, there has been no effective method to accurately predict the pathological complete response (pCR) of axillary lymph node after neoadjuvant chemotherapy (NAC). The objective of our study was to investigate whether conventional ultrasonography combined with contrast-enhanced ultrasonography (CEUS) can be used to evaluate axillary lymph node status of breast cancer patients after NAC. METHODS: A total of 74 patients who underwent NAC were recruited for the present study. Prior to and after NAC, examinations of conventional ultrasonography and CEUS were performed. After evaluating the images of conventional ultrasonography, four characteristics were recorded: lymph node medulla boundary, cortex of lymph node, lymph node hilus, and lymph node aspect ratio. Two additional imaging characteristics of CEUS were analyzed: CEUS way and CEUS pattern. Receiver operating characteristiccurve analysis was applied to evaluate their diagnostic performance. RESULTS: After 6~8 cycles of NAC, 46 (71.9%) patients had negative axillary lymph node, and 18 (28.1%) patients turned out non-pCR. According to statistical analysis, lymph node medulla, lymph node aspect ratio and CEUS way were independently associated with pCR of axillary lymph node after NAC. The area under the curve of the prediction model with three imaging characteristics was 0.882 (95% confidence interval: 0.608-0.958), and the accuracy to predict the patients' lymph node status was 78.1% (p < 0.01). CONCLUSIONS: Conventional ultrasonography combined with CEUS technology can accurately predict axillary lymph nodes status of breast cancer patients after NAC. ADVANCES IN KNOWLEDGE: The usefulness of CEUS technology in predicting pCR after neoadjuvant chemotherapy is highlighted.

DCTPP1, an Oncogene Regulated by miR-378a-3p, Promotes Proliferation of Breast Cancer via DNA Repair Signaling Pathway.

Breast cancer (BRCA) is one of the most deadly cancers worldwide, with poor survival rates that could be due to its high proliferation. Human all-alpha dCTP pyrophosphatase 1 (DCTPP1) is implicated in numerous diseases, including cancers. However, its role in BRCA is unclear. In this study, we used bioinformatic analyses of the ONCOMINE, UALCAN, and GEPIA databases to determine the expression pattern of DCTPP1 in BRCA. We found that elevated DCTPP1 levels correlate with poor BRCA prognosis. DCTPP1 silencing inhibited BRCA cell proliferation and induced apoptosis in vitro, as well as in vivo. Our data show that this tumorigenic effect depends on DNA repair signaling. Moreover, we found that DCTPP1 is directly modulated by miR-378a-3p, whose downregulation is linked to BRCA progression. Our results showed down-regulation of miR-378a-3p in BRCA. Upregulation of miR-378a-3p, on the other hand, can inhibit BRCA cell growth and proliferation. This study shows that reduced miR-378a-3p level enhances DCTPP1 expression in BRCA, which promotes proliferation by activating DNA repair signaling in BRCA.

Clinical Significance of Oncoplastic Breast-Conserving Surgery and Application of Volume-Displacement Technique.

ABSTRACT: Oncoplastic breast-conserving surgery for breast cancer has been continuously developing in recent years, and it has become an important part of breast cancer surgery. Its safety and aesthetics have been widely recognized by domestic and foreign experts. However, due to the complexity and diversity of individuals and diseases, and the need for integrating the thinking of breast surgery and plastic surgery, it is still a challenge for breast surgeons. This review summarizes the pros and cons of its clinical application through a comprehensive discussion of hot issues in oncoplastic breast-conserving surgery and introduces common volume-displacement techniques in the clinic for reference by doctors in daily work.

Hypoxia-Induced Intracellular and Extracellular Heat Shock Protein gp96 Increases Paclitaxel-Resistance and Facilitates Immune Evasion in Breast Cancer.

BACKGROUNDS: Hypoxia contributes to cancer progression, drug resistance and immune evasion in various cancers, including breast cancer (BC), but the molecular mechanisms have not been fully studied. Thus, the present study aimed to investigate this issue. METHODS: The paclitaxel-sensitive BC (PS-BC) cells were administered with continuous low-dose paclitaxel treatment to establish paclitaxel-resistant BC (PR-BC) cells. Exosomes were isolated/purified by using the commercial kit, which were observed by Transmission electron microscopy (TEM). Cell viability was measured by MTT assay, cell apoptosis was determined by flow cytometer (FCM). Gene expressions were respectively measured by Real-Time qPCR, Western Blot and immunofluorescence staining assay. The peripheral mononuclear cells (PBMCs) derived CD8+ T cells were obtained and co-cultured with gp96-containing exosomes, and cell proliferation was evaluated by EdU assay. ELISA was employed to measure cytokine secretion in CD8+ T cells' supernatants. RESULTS: HSP gp96 was significantly upregulated in the cancer tissues and plasma exosomes collected from BC patients with paclitaxel-resistant properties. Also, continuous low-dose paclitaxel treatment increased gp96 levels in the descendent PR-BC cells and their exosomes, in contrast with the parental PS-BC cells. Upregulation of gp96 increased paclitaxel-resistance in PS-BC cells via degrading p53, while gp96 silence sensitized PR-BC cells to paclitaxel treatments. Moreover, PR-BC derived gp96 exosomes promoted paclitaxel-resistance in PS-BC cells and induced pyroptotic cell death in the CD8+ T cells isolated from human peripheral blood mononuclear cells (pPBMCs). Furthermore, we noticed that hypoxia promoted gp96 generation and secretion through upregulating hypoxia-inducible factor 1 (HIF-1), and hypoxia increased paclitaxel-resistance and accelerated epithelial-mesenchymal transition (EMT) in PS-BC cells. CONCLUSIONS: Hypoxia induced upregulation of intracellular and extracellular gp96, which further degraded p53 to increase paclitaxel-sensitivity in BC cells and activated cell pyroptosis in CD8+ T cells to impair immune surveillance.

Overexpression of Arginase-1 is an indicator of poor prognosis in patients with colorectal cancer.

AIM: Arginase-1 (Arg-1) metabolizes l-arginine to l-ornithine and urea. It has been documented to have a role in various malignancies. However, the relationship between Arg-1 expression and clinicopathological characteristics of colorectal cancer (CRC) patients remains to be elucidated. The present study aimed to analyze the expression and prognostic value of Arg-1 in patients with CRC. MATERIAL AND METHODS: The mRNA and protein expressions of Arg-1 in fresh colorectal cancer tissue specimens and the corresponding noncancerous tissue specimens were examined by RT-qPCR (n = 24) and western blot analysis (n = 17). Arg-1 expression levels were determined in paraffin-embedded CRC tissue specimens (n = 236) by immunohistochemistry. The associations of Arg-1 expression and clinicopathological features and clinical prognosis in 236 CRC patients were analyzed. RESULTS: The expression levels of Arg-1 were significantly higher in the CRC tissues compared with the matched noncancerous tissues, and elevated Arg-1 expression was remarkably associated with stage III-IV tumors (P = 0.007), lymph node metastasis (P = 0.019) and a plasma albumin concentration <35 g/l (P = 0.022). Kaplan-Meier analysis indicated that Arg-1 overexpression was associated with adverse prognoses for overall survival (OS) (P < 0.001) and disease-free survival (DFS) (P < 0.001) in all cases. Further analysis revealed that the patients with high Arg-1 expression had significantly shorter OS and DFS at the advanced stages (III + IV) (P = 0.032 for OS, and P = 0.012 for DFS) but not at the early stages (I + II) (P = 0.194 for OS, and P = 0.065 for DFS). Multivariate analysis revealed that Arg-1 overexpression was an independent prognostic factor for OS (P = 0.002) and DFS (P < 0.001) in patients with CRC. CONCLUSION: The data indicated that Arg-1 overexpression in CRC may be a marker that can discriminate subgroups of patients with a poor prognosis.

Gankyrin drives metabolic reprogramming to promote tumorigenesis, metastasis and drug resistance through activating ß-catenin/c-Myc signaling in human hepatocellular carcinoma.

Gankyrin plays important roles in tumorigenicity and metastasis of hepatocellular carcinoma (HCC). We have for the first time investigated the effects of Gankyrin on glycolysis and glutaminolysis both in vitro and in vivo, including in patient-derived xenografts. We reported Gankyrin increases glucose consumption, lactate production, glutamine consumption and glutamate production in HCC through upregulating the expression of the transporters and enzymes involved in glycolysis and glutaminolysis, including HK2, GLUT1, LDHA, PKM2, ASCT2 and GLS1. We further demonstrated that Gankyrin drives glycolysis and glutaminolysis through upregulating c-Myc via activating ß-catenin signaling. Importantly, we found c-Myc mediated metabolic reprogramming might contribute to the tumorigenicity, metastasis and drug resistance induced by Gankyrin. c-Myc inhibitor synergizes with Sorafenib or Regorafenib to suppress HCC PDX tumors with high Gankyrin levels. We detected a significant correlation between Gankyrin and ß-catenin expression levels in a cohort of HCC biopsies, and combination of these two parameters is a more powerful predictor of poor prognosis. Collectively, our results uncovered that Gankyrin functions as an essential regulator in glycolysis and glutaminolysis via activation of ß-catenin/c-Myc to promotes tumorigenesis, metastasis and drug resistance in human HCC.

Knockdown of lncRNA H19 restores chemo-sensitivity in paclitaxel-resistant triple-negative breast cancer through triggering apoptosis and regulating Akt signaling pathway.

Triple negative breast cancer (TNBC) is associated with poor prognosis and systemic chemotherapy is the only treatment for TNBC. However, development of chemo-resistance remains a major obstacle for TNBC treatment. Paclitaxel-resistance is mainly related to the activation of the Akt signaling pathway and deregulation of apoptotic regulatory proteins. LncRNAs are frequently dysregulated in various malignancies, including breast cancer, facilitating cell proliferation, metastasis and drug resistance. LncRNA H19 is overexpressed in approximately 70% of breast cancer patients, and has been reported to confer chemo-resistance in breast cancer. In the present study, we investigated the expression level of lncRNA H19 in paclitaxel-resistant and paclitaxel-sensitive cell lines. The results showed that the level of lncRNA H19 expression in paclitaxel-resistant cells was significantly higher than that in paclitaxel-sensitive cells, and knockdown of lncRNA H19 might restore chemo-sensitivity in paclitaxel-resistant TNBC by mediating the AKT signaling pathway. Thus, lncRNA H19 might be an efficient therapeutic target in paclitaxel-resistant TNBC treatment.

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit ß-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer.

BACKGROUND/AIMS: Little is known about the potential mechanism of action for androgen receptor (AR) targeting treatment in estrogen receptor (ER)-negative breast cancer. This study aimed to evaluate AR status and its prognosis in four breast cancer subtypes. Bicalutamide has been identified as an AR antagonist and used for treating AR+/ER- breast cancer in a phase II trial. Our studies will clarify its mechanism in breast cancer treatment. METHODS: A total of 510 consecutive cases of invasive ductal cancer (IDC) were evaluated in this study. The expression of AR was analyzed by immunohistochemistry and compared with patient survival, and its implications were evaluated in four subtypes of IDC. We examined bicalutamide as an AR antagonist to inhibit proliferation and increased apoptosis in AR+/ER- breast cancer cell lines. We explored the tumor suppressive functions of bicalutamide in vitro and vivo and its related mechanisms in AR+/ER- breast cancer. RESULTS: AR expression was related to that of ER (P<0.001), PR (P<0.001), Her2 (P=0.017), Ki-67(P=0.020) and to four subtypes (P<0.001). AR retained independent prognostic signifcance (P=0.007, ER- cases; P=0.001, ER+ cases; P=0.001, total cases). We found that bicalutamide significantly decreased viability and increased apoptosis in vitro and vivo. The mechanistic analysis revealed that bicalutamide blocked androgen-stimulated oncogenic AR and Wnt/ß-catenin signaling and inhibited the growth of AR+/ER- breast cancer. CONCLUSION: Our studies provide novel insights into bicalutamide as an antagonist of AR function in AR+/ER- breast cancer and reveal the mechanistic basis for targeting AR as a therapeutic opportunity for patients with AR+/ER- breast cancer.

A novel panel of serum miR-21/miR-155/miR-365 as a potential diagnostic biomarker for breast cancer.

PURPOSE: Insufficient sensitivity and specificity prevent the use of most existing biomarkers for early detection of breast cancer. Recently, it was reported that serum microRNAs (miRNAs) may be potential biomarkers in many cancer diseases. In this study, we investigated whether serum levels of 5 miRNAs including miR-21, miR-125b, miR-145, miR-155, and miR-365 could discriminate breast cancer patients and healthy controls. METHODS: Serum levels of miRNAs were measured by using quantitative real-time polymerase chain reaction in 99 breast cancer patients and 21 healthy controls. The abundance change of serum miRNAs were also evaluated following surgical resection in 20 breast cancer patients. Receiver operating characteristic (ROC) curve analysis was performed to assess the sensitivity and specificity of miRNAs as diagnostic biomarkers. RESULTS: Serum levels of miR-21 and miR-155 was significantly higher, while miR-365 was significantly lower in breast cancer as compared with healthy controls. The serum levels of miR-21 and miR-155 significantly decreased following surgical resection. Additionally, the serum level of miR-155 at stages I and II was significantly higher compared to stage III. The serum miR-145 level was remarkably higher in progesterone receptor (PR)-positive patients than PR-negative. The positivity of miR-21, miR-155, and miR-365 was high compared to CA 153 and CEA in breast cancer. ROC curve analyses of a combination of miR-21, miR-155, and miR-365 yielded much higher area under curve and enhanced sensitivity and specificity in comparison to each miRNA alone. CONCLUSION: The combination of serum miR-21/miR-155/miR-365 may potentially serve as a sensitive and specific biomarker that enables differentiation of breast cancer from healthy controls.

MicroRNA-224 inhibits proliferation and migration of breast cancer cells by down-regulating Fizzled 5 expression.

The Wnt/ß-catenin signaling is crucial for the proliferation and migration of breast cancer cells. However, the expression of microRNA-224 (miR-224) in the different types of breast cancers and its role in the Wnt/ß-catenin signaling and the proliferation and migration of breast cancer cells are poorly understood. In this study, the levels of miR-224 in different types of breast cancer tissues and cell lines were examined by quantitative RT-PCR and the potential targets of miR-224 in the Wnt/ß-catenin signaling were investigated. The effects of altered miR-224 expression on the frequency of CD44+CD24- cancer stem-like cells (CSC), proliferation and migration of MCF-7 and MDA-MB-231 cells were examined by flow cytometry, MTT and transwell migration. We found that the levels of miR-224 expression in different types of breast cancer tissues and cell lines were associated inversely with aggressiveness of breast cancers. Enhanced miR-224 expression significantly reduced the fizzled 5-regulated luciferase activity in 293T cells, fizzled 5 expression in MCF-7 and MDA-MB-231 cells, the ß-dependent luciferase activity in MCF-7 cells, and the nuclear translocation of ß-catenin in MDA-MB-231 cells. miR-224 inhibition significantly increased the percentages of CSC in MCF-7 cells and enhanced proliferation and migration of MCF-7 cells. Enhanced miR-224 expression inhibited proliferation and migration of MDA-MB-231 cells, and the growth of implanted breast cancers in vivo. Induction of Frizzled 5 over-expression mitigated the miR-224-mediated inhibition of breast cancer cell proliferation. Collectively, these data indicated that miR-224 down-regulated the Wnt/ß-catenin signaling possibly by binding to Frizzled 5 and inhibited proliferation and migration of breast cancer cells.

Expression of tissue levels of matrix metalloproteinases and their inhibitors in breast cancer.

BACKGROUND: We examined mRNA expression for MMP-2, MMP-7, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 in human breast cancer tissues, and the association between their expression and clinicopathological variables. PATIENTS AND METHODS: Breast tissue samples from 120 patients with breast cancer were available for this study. To determine mRNA expression for MMP-2, MMP-7, MMP-9, MT1-MMP, TIMP-1, and TIMP-2, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out on tumor and normal tissues, respectively. RESULTS: Mean MMP-2, MMP-7, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 mRNA expression in the breast cancer was significantly higher than in the normal tissue. In terms of tumor size and lymph node metastasis of breast cancer, the differences in MMP-2, MMP-7, MMP-9, and MT1-MMP mRNA expression levels were significant. CONCLUSION: The association between the increased expression of MMP-2, MMP-7, MMP-9, and MTI-MMP and clinicopathological parameters reflects a role in predicting the aggressive behavior of breast cancer.

Clinicopathologic characteristics and prognosis of young patients with breast cancer.

BACKGROUND: The aim was to describe the clinicopathological features and prognosis of young patients with breast cancer. PATIENTS AND METHODS: We reviewed the records of 1478 consecutive patients aged ≤50 years with first diagnosis of invasive breast cancer referred to surgery from January 1999 to March 2005. A total of 174 patients were aged <35 years (group I) and 1304 were aged 35-50 years (group II). RESULTS: Compared with patients of group II, patients of group I had a higher percentage of tumors classified as estrogen receptors (ER) negative, progesterone receptors (PR) negative, with a Ki-67 labeling index ≥20% of the cells. The 5-year survival of group I was 78.3% as compared with 84.2% for group II (P = 0.006). CONCLUSION: Compared with patients aged between 35 and 50 years, patients aged <35 years have a greater chance of having an endocrine-unresponsive tumor and a significantly poor prognosis.

Risk of genome-wide association study newly identified genetic variants for breast cancer in Chinese women of Heilongjiang Province.

Recent genome-wide association studies have identified seven single nucleotide polymorphisms (SNPs) associated with breast cancer, but mainly in Europeans. In this study, the authors evaluated the effect of these loci on breast cancer and its disease characteristics in women from northeast of China, Heilongjiang Province. Seven SNPs were successfully genotyped in 492 breast cancer patients and 510 healthy controls using the SNaPshot method. The associations between SNPs and breast cancer were examined by logistic regression. The associations between SNPs and disease characteristics were examined by the chi-square test or one-way ANOVA as needed. The authors confirmed the effects of the allele A for rs2046210 at 6q25 on increased breast cancer risk in the population, with odds ratio 1.417 (P = 2×10⁻4). However, no significant association was detected between SNPs from TNCR9, LSP1, MAP3K1, 2q35, and 8q24 and breast cancer. Analyses of the disease characteristics showed that SNP rs2046210 was associated with age at menopause (P = 0.001). MAP3K1 SNP rs889312 and LSP1 SNP rs3817198 were associated with HER2 status in the patient cohort (P = 0.036 and P = 0.005, respectively). And SNP rs3817198 was also associated with the combined status of estrogen receptor, progesterone receptor, and HER2 (P = 0.012). SNP rs13281615 was associated with age at menarche (P = 0.023), and SNP rs3803662 was associated with average duration of breastfeeding (P = 0.036). All other disease characteristics, including tumor grade, clinical stage, and the status of estrogen receptor or P53, were not significantly associated with any of these variants. These results suggested that the rs2046210 was associated with breast cancer in a Northern Chinese population, and some SNPs were also associated with breast cancer characteristics.

[Reversal effect and mechanism of arsenic trioxide on multidrug resistance of gastric carcinoma cells SGC7901].

The purpose of this study is to investigate the reversal effect and its mechanism of arsenic trioxide (As2O3) on multidrug resistance of gastric carcinoma cells. The concentration of vincristine (VCR) increased gradually to induce the drug resistance of gastric carcinoma cell SGC7901. MTT assay was used to determine the lethal effect of anticarcinogens on tumor cells and Western blotting assay was applied to determine the expression of P-glucoprotein (P-gp) and glutathione S-transferase (GST-s) in tumor cells. As a result, the resistance of SGC7901/VCR cells to VCR, fluorouracil and epirubicin was 16.56, 2.69 and 13.05 times, respectively, more than that of SGC7901 cells. After 24 h precondition with As2O3, RI of vincristine, fluorouracil and epirubicin decreased significantly (P < 0.05). Expression of P-gp and GST-s in resting SGC7901/VCR cells was significantly higher than that in carcinogen-sensitive SGC7901 cells. As2O3 decreased the expression of P-gp and GST-s in SGC7901/VCR cells significantly, while it showed no significant effect on carcinogen-sensitive SGC7901 cells. The result suggested that As2O3 could partly reverse drug resistance of SGC7901/VCR cells by probably the mechanism of decreasing the expression of P-gp and GST-s.