Interaction of base excision repair gene polymorphism and estrogen-DNA adducts in breast cancer risk among East Asian women.

PURPOSE: In East Asia, the incidence of breast cancer has been increasing rapidly, particularly among premenopausal women. An elevated ratio of estrogen-DNA adducts was linked to a higher risk of breast cancer. The present study explored the influence of the interaction between base excision repair (BER) gene polymorphisms and estrogen-DNA adducts on breast cancer risk. METHODS: We conducted a case-control study comprising healthy volunteers and individuals with benign breast disease (control arm, n = 176) and patients with invasive carcinoma or carcinoma in situ (case arm, n = 177). Genotyping for BER-related genes, including SMUG1, OGG1, ERCC5, and APEX1, was performed. A logistic regression model, incorporating interactions between gene polymorphisms, estrogen-DNA adduct ratio, and clinical variables, was used to identify the risk factors for breast cancer. RESULTS: Univariate analysis indicated marginal associations between breast cancer risk and APEX1 rs1130409 T > G (P = 0.057) and APEX1 rs1760944 T > G (P = 0.065). Multivariate regression analysis revealed significant associations with increased breast cancer risk for APEX1_rs1130409 (GT/GG versus TT) combined with a natural logarithmic value of the estrogen-DNA adduct ratio (estimated OR 1.164, P = 0.023) and premenopausal status with an estrogen-DNA adduct ratio > 2.93 (estimated OR 2.433, P = 0.001). CONCLUSION: APEX1_rs1130409 (GT/GG versus TT) polymorphisms, which are related to decreased BER activity, combined with an increased ratio of estrogen-DNA adducts, increase the risk of breast cancer in East Asian women.

In situ HER2 RNA expression as a predictor of pathologic complete response of HER2-positive breast cancer patients receiving neoadjuvant chemotherapy and anti-HER2 targeted treatment.

BACKGROUND: Immunohistochemistry (IHC) and in situ hybridization (ISH) remain standard biomarkers for therapeutic decisions in human epidermal growth factor 2 (HER2)-positive breast cancers (BCs); however, they are insufficient to explain the heterogeneous anti-HER2 response. METHODS: We aimed to investigate the correlation of in situ HER2 RNA expression (isHRE), using RNAscope, with HER2 biomarkers and the impact of isHRE on the pathological complete response (pCR) rates of 278 patients with HER2 IHC/fluorescence ISH (FISH)-positive BC receiving neoadjuvant chemotherapy and anti-HER2 targeted treatment (NCTT). RESULTS: We validated HER2 RNAscope scoring as a semiquantitative method to determine isHRE and showed a positive correlation between RNAscope scores and pCR rates, with particularly different rates between patients with a score of 5 versus 1-4 BCs (66.7% vs. 15.9%, p < 0.0001). There were higher RNAscope scores and pCR rates in patients with HER2 IHC 3 + versus IHC 2+/FISH + BCs and HER2 RNAscope scores and pCR rates showed similar non-linear positive correlations with HER2 copy numbers and HER2/centromere 17 ratios. Moreover, in each HER2-positive IHC/FISH category, higher pCR rates were observed in patients with RNAscope scores of 5 versus 1-4 BC. Patients achieving pCR had BCs with notably higher HER2 RNAscope scores. Multivariate analysis identified HER2 RNAscope 5 as a strong pCR predictor [odds ratio = 10.865, p < 0.001]. The combined impact of multivariate analysis-defined pCR predictors demonstrated that a higher pCR rate was observed in patients with a score of 5 versus a score of 1-4 BCs regardless of the status of hormone receptor and mono-or dual anti-HER2 blockade. CONCUSIONS: Our results demonstrated that high isHRE (RNAscope score 5) is a strong pCR predictor in patients with HER2-positive BCs receiving NCTT, highlighting the complementary role of isHRE in stratifying HER2 status in tissue. Such stratification is relevant to anti-HER2 therapeutic efficacy, particularly using the cutoff of score 1-4 versus 5.

Ago2/CAV1 interaction potentiates metastasis via controlling Ago2 localization and miRNA action.

Ago2 differentially regulates oncogenic and tumor-suppressive miRNAs in cancer cells. This discrepancy suggests a secondary event regulating Ago2/miRNA action in a context-dependent manner. We show here that a positive charge of Ago2 K212, that is preserved by SIR2-mediated Ago2 deacetylation in cancer cells, is responsible for the direct interaction between Ago2 and Caveolin-1 (CAV1). Through this interaction, CAV1 sequesters Ago2 on the plasma membranes and regulates miRNA-mediated translational repression in a compartment-dependent manner. Ago2/CAV1 interaction plays a role in miRNA-mediated mRNA suppression and in miRNA release via extracellular vesicles (EVs) from tumors into the circulation, which can be used as a biomarker of tumor progression. Increased Ago2/CAV1 interaction with tumor progression promotes aggressive cancer behaviors, including metastasis. Ago2/CAV1 interaction acts as a secondary event in miRNA-mediated suppression and increases the complexity of miRNA actions in cancer.

A novel computer-assisted tool for 3D imaging of programmed death-ligand 1 expression in immunofluorescence-stained and optically cleared breast cancer specimens.

BACKGROUND: Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are the two most common immune checkpoints targeted in triple-negative breast cancer (BC). Refining patient selection for immunotherapy is non-trivial and finding an appropriate digital pathology framework for spatial analysis of theranostic biomarkers for PD-1/PD-L1 inhibitors remains an unmet clinical need. METHODS: We describe a novel computer-assisted tool for three-dimensional (3D) imaging of PD-L1 expression in immunofluorescence-stained and optically cleared BC specimens (n = 20). The proposed 3D framework appeared to be feasible and showed a high overall agreement with traditional, clinical-grade two-dimensional (2D) staining techniques. Additionally, the results obtained for automated immune cell detection and analysis of PD-L1 expression were satisfactory. RESULTS: The spatial distribution of PD-L1 expression was heterogeneous across various BC tissue layers in the 3D space. Notably, there were six cases (30%) wherein PD-L1 expression levels along different layers crossed the 1% threshold for admitting patients to PD-1/PD-L1 inhibitors. The average PD-L1 expression in 3D space was different from that of traditional immunohistochemistry (IHC) in eight cases (40%). Pending further standardization and optimization, we expect that our technology will become a valuable addition for assessing PD-L1 expression in patients with BC. CONCLUSION: Via a single round of immunofluorescence imaging, our approach may provide a considerable improvement in patient stratification for cancer immunotherapy as compared with standard techniques.

SCEL regulates switches between pro-survival and apoptosis of the TNF-α/TNFR1/NF-κB/c-FLIP axis to control lung colonization of triple negative breast cancer.

BACKGROUND: Patients with metastatic triple-negative breast cancer (mTNBC) have a higher probability of developing visceral metastasis within 5 years after the initial diagnosis. Therefore, a deeper understanding of the progression and spread of mTNBC is urgently needed. METHODS: The isobaric tag for relative and absolute quantitation (iTRAQ)-based LC-MS/MS proteomic approach was applied to identify novel membrane-associated proteins in the lung-tropic metastatic cells. Public domain datasets were used to assess the clinical relevance of the candidate proteins. Cell-based and mouse models were used for biochemical and functional characterization of the protein molecule Sciellin (SCEL) identified by iTRAQ to elucidate its role and underlying mechanism in promoting lung colonization of TNBC cells. RESULTS: The iTRAQ-based LC-MS/MS proteomic approach identified a membrane-associated protein SCEL that was overexpressed in the lung-tropic metastatic cells, and its high expression was significantly correlated with the late-stage TNBC and the shorter survival of the patients. Downregulation of SCEL expression significantly impaired the 3D colony-forming ability but not the migration and invasion ability of the lung colonization (LC) cells. Knockdown of SCEL reduced TNF-α-induced activation of the NF-κB/c-FLIP pro-survival and Akt/Erk1/2 growth signaling pathways in the LC cells. Specifically, knockdown of SCEL expression switched TNF-α-mediated cell survival to the caspase 3-dependent apoptosis. Conversely, ectopic expression of SCEL promoted TNF-α-induced activation of NF-κB/c-FLIP pro-survival and Akt/Erk1/2 pro-growth signaling pathway. The result of co-immunoprecipitation (Co-IP) and GST pull-down assay showed that SCEL could interact with TNFR1 to promote its protein stability. The xenograft mouse model experiments revealed that knockdown of SCEL resulted in increase of caspase-3 activity, and decrease of ki67 and TNFR1 expression as well as increase of tumor-associated macrophages in the metastatic lung lesions. Clinically, SCEL expression was found to be positively correlated with TNFR1 in TNBC tissues. Lastly, we showed that blocking TNF-α-mediated cell survival signaling by adalimumab effectively suppressed the lung colonization of the SCEL-positive, but not the SCEL-downregulated LC cells in the tail-vein injection model. CONCLUSIONS: Our findings indicate that SCEL plays an essential role in the metastatic lung colonization of TNBC by promoting the TNF-α/TNFR1/NF-κB/c-FLIP survival and Akt/Erk1/2 proliferation signaling. Thus, SCEL may serve as a biomarker for adalimumab treatment of TNBC patients.

Lifestyle Factors and Energy Intakes with Risks of Breast Cancer among Pre- and Post- Menopausal Women in Taiwan.

Although the incidence of invasive breast cancer (BC) among women in Asian is generally lower than that in Western countries, the incidence of BC has been on the rise in the past three decades in Asian countries. This hospital-based case-control study aimed to explore the relationship between dietary and metabolic factors and BC risk in pre- and post-menopausal women. We enrolled 285 patients with newly diagnosed BC at the National Taiwan University Hospital and 297 controls from the local community and hospital staff. Before receiving anticancer therapy, all patients with BC and control participants completed a 57-question semi-quantitative Food Frequency Questionnaire. For pre-menopausal women, plant-based factor scores rich in seeds and nuts, soy, fruits, and seaweeds correlated significantly with reduced BC risks, whereas menarche occurring at <12 years of age, reduced physical activity, and high-density lipoprotein <40 mg/dL were associated with increased BC risks. For post-menopausal women, plant-based dietary factor scores were also associated with reduced risks, whereas increased body mass index and energy intake levels correlated with increased BC risks. Diets rich in plant-based dietary patterns are protective against BC risk, regardless of menopausal status. Habitual physical activity is protective against BC risk among pre-menopausal Taiwanese women. Maintaining optimal weight and caloric intake is beneficial for reducing post-menopausal BC risk.

MAP7D3, a novel prognostic marker for triple-negative breast cancer, drives cell invasiveness and cancer-initiating cell properties to promote metastatic progression.

BACKGROUND: Patients with triple-negative breast cancer (TNBC) tend to develop visceral metastasis within five years, making them the most challenging BC patients to treat. The MAP7 protein family is a group of microtubule-binding proteins with a well-known role in microtubule-related cell migration, but its role in metastasis-related properties of TNBC remains unclear. METHODS: qRT-PCR and western blot were used to validate mRNA and protein expression of the MAP7 family in the isogenic pairs of TNBC cell lines with low and high metastasis potential. Functional characterization of MAP7D3 was carried out using cell-based and mouse models. The clinical association between MAP7D3 and TNBC was established using datasets in the public domain. RESULTS: MAP7D3 expression was consistently upregulated in the metastatic subline IV2 and 468-LN at both mRNA and protein levels. Knockdown of MAP7D3 inhibited the 3D colony-forming ability, cell migration, and invasion ability of IV2 and 468-LN, indicating its significant contribution to the metastasis phenotypes. Mechanistically, inhibition of MAP7D3 could significantly increase the sensitivity of metastatic TNBC cells to docetaxel and gemcitabine treatment by reducing the expression of proteins related to breast cancer-initiating cells (BCICs) and drug resistance, as well as suppressing the activity of Rac1. The animal study showed that the depletion of MAP7D3 drastically reduced TNBC tumor growth and impaired the metastatic capability of TNBC cells. Elevated expression of MAP7D3 was found in the metastatic lymph nodes and was significantly associated with advanced stage and higher grade TNBC. Moreover, MAP7D3 expression was significantly correlated with the TNBC population, and its high expression was significantly associated with lymph node metastasis and poor survival outcomes of patients with TNBC. CONCLUSION: Our study indicates that targeting MAP7D3 could be a promising therapeutic strategy for addressing the progression of TNBC, and MAP7D3 may serve as a novel predictive biomarker for the survival outcomes of triple-negative breast cancer.

Combating breast cancer progression through combination therapy with hypomethylating agent and glucocorticoid.

Breast cancer is the leading cause of cancer-related death in women. Among breast cancer types, triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers with aggressive tumor behavior. By using bioinformatic approaches, we observed that the microRNA-708 promoter is highly methylated in breast carcinomas, and this methylation is linked to a poor prognosis. Moreover, microRNA-708 expression correlates with better clinical outcomes in TNBC patients. Combination treatment with the hypomethylating agent decitabine and synthetic glucocorticoid significantly increased the expression of microRNA-708, reactivated DNMT-suppressed pathways, and decreased the expression of multiple metastasis-promoting genes such as matrix metalloproteinases (MMPs) and IL-1ß, leading to the suppression of breast cancer cell proliferation, migration, and invasion, as well as reduced tumor growth and distant metastasis in the TNBC xenograft mouse model. Overall, our study reveals a therapeutic opportunity in which a combined regimen of decitabine with glucocorticoid may have therapeutic potential in treating TNBC patients.

Assessment of Brown and Beige Adipose Tissue Activation in Mice Using PET/CT Imaging.

In response to cold induction, brown adipose tissues (BAT) and emerged brown-like adipocytes (beige adipocytes) in subcutaneous white adipose tissues (WAT browning/beiging) are activated. Thermogenesis is increased during glucose and fatty acid uptake and metabolism in adult humans and mice. This activation of BAT or WAT beiging to generate heat helps to counteract diet-induced obesity. This protocol applies the glucose analog radiotracer 18F-fluorodeoxyglucose (FDG), coupled with positron emission tomography and computed tomography (PET/CT) scanning to evaluate cold-induced thermogenesis in the active BAT (interscapular region) and browned/beiged WAT (subcutaneous adipose region) in mice. The PET/CT scanning technique not only can quantify cold-induced glucose uptake in well-known BAT and beige-fat depots but also helps to visualize the anatomical location of novel uncharacterized mouse BAT and beige fat where cold-induced glucose uptake is high. Histological analysis is further employed to validate signals of delineated anatomical regions in PET/CT images as bona fide mouse BAT or beiged WAT fat depots.

High rate of postoperative upstaging of ductal carcinoma in situ when prioritizing ultrasound evaluation of mammography-detected lesions: a single-center retrospective cohort study.

BACKGROUND: The initial diagnosis of ductal carcinoma in situ (DCIS) can be upstaged to invasive cancer after definitive surgery. This study aimed to identify risk factors for DCIS upstaging using routine breast ultrasonography and mammography (MG) and to propose a prediction model. METHODS: In this single-center retrospective study, patients initially diagnosed with DCIS (January 2016-December 2017) were enrolled (final sample size = 272 lesions). Diagnostic modalities included ultrasound-guided core needle biopsy (US-CNB), MG-guided vacuum-assisted breast biopsy, and wire-localized surgical biopsy. Breast ultrasonography was routinely performed for all patients. US-CNB was prioritized for lesions visible on ultrasound. Lesions initially diagnosed as DCIS on biopsy with a final diagnosis of invasive cancer at definitive surgery were defined as "upstaged." RESULTS: The postoperative upstaging rates were 70.5%, 9.7%, and 4.8% in the US-CNB, MG-guided vacuum-assisted breast biopsy, and wire-localized surgical biopsy groups, respectively. US-CNB, ultrasonographic lesion size, and high-grade DCIS were independent predictive factors for postoperative upstaging, which were used to construct a logistic regression model. Receiver operating characteristic analysis showed good internal validation (area under the curve = 0.88). CONCLUSIONS: Supplemental screening breast ultrasonography possibly contributes to lesion stratification. The low upstaging rate for ultrasound-invisible DCIS diagnosed by MG-guided procedures suggests that it is unnecessary to perform sentinel lymph node biopsy for lesions invisible on ultrasound. Case-by-case evaluation of DCIS detected by US-CNB can help surgeons determine if repeating biopsy with vacuum-assisted breast biopsy is necessary or if sentinel lymph node biopsy should accompany breast-preserving surgery. TRIAL REGISTRATION: This single-center retrospective cohort study was conducted with the approval of the institutional review board of our hospital (approval number 201610005RIND). As this was a retrospective review of clinical data, it was not registered prospectively.

Estrogen-DNA Adducts and Breast Cancer Risk in Premenopausal Asian Women.

The incidence of breast cancer among premenopausal women has been increasing rapidly in recent decades in East Asia. This case-control study investigated whether estrogen-DNA adducts were associated with breast cancer risk in Taiwan. The control group (n = 146) comprised healthy female volunteers and women with non-proliferative breast disease. The case group (n = 221) comprised women either with proliferative benign breast disease or breast cancer. The ratios of estrogen-DNA adducts to their respective metabolites and conjugates in plasma were analyzed using ultraperformance LC/MS-MS. The SNPs of CYP1A1, CYP1B1, and COMT were genotyped. Logistic regression model was used to compare the estrogen-DNA adduct ratios between the two groups. The estrogen-DNA adduct ratio in the case group was significantly higher than that in the control group (median ratio: 58.52 vs. 29.36, P = 0.004). A multiple logistic regression model demonstrated that a unit increase in the natural log of the estrogen-DNA adduct ratio in premenopausal women was a significant predictor of breast cancer risk, with an estimated hazard ratio of 1.718 (1.444-2.046, P < 0.001). However, the CYP1A1, CYP1B1, and COMT SNPs were not associated with the estrogen-DNA adduct ratios. In conclusion, plasma estrogen-DNA adduct ratio was associated with the presence of breast cancer or proliferating benign breast disease in premenopausal women in Taiwan. PREVENTION RELEVANCE: This study provides evidence that endogenous estrogen-induced genotoxicity may contribute to the carcinogenesis of breast cancer in premenopausal Asian women. This work could have important preventive implication for the emerging disease in East Asia.

A longitudinal study on the changes in the self-efficacy of breast cancer patients during adjuvant chemotherapy.

AIM: We aimed to investigate the changes in the self-efficacy of patients with breast cancer (BC) during adjuvant chemotherapy. DESIGN: A longitudinal study was conducted. METHODS: One hundred thirty patients with BC who underwent postoperative adjuvant chemotherapy at a medical centre in northern Taiwan were evaluated using self-efficacy survey tools before the first (T1), second (T2) and last (T3) cycles of adjuvant chemotherapy. The independent t-test, Kruskal-Wallis test, one-way analysis of variance, Pearson's correlation coefficient and generalized estimating equation were used for data analysis. RESULTS: The self-efficacy measures of patients with BC were significantly higher at both T2 and T3 than at T1 (p < 0.001). Religious beliefs and changes in self-efficacy showed a significant correlation (p = 0.04). These findings will facilitate timely interventional measures to improve self-efficacy in patients with maladaptive behaviours, alleviate psychological distress and reduce the risk of future disease recurrence.

Impact of BRCA mutation on the survival and risk of contralateral breast cancer in Asian breast cancer patients.

PURPOSE: Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with BRCA mutations. METHODS: A total of 128 breast cancer patients with germline BRCA mutations and 4,754 control breast cancer patients were enrolled. Data on clinical-pathologic characteristics, survival, and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan-Meier method. RESULTS: The mean age of onset in BRCA mutation carriers was significantly younger than control patients (BRCA vs. Non-BRCA: 43.9 vs. 53.2 years old). BRCA mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%, p < 0.001). The risk of CBC was significantly higher in BRCA mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71-5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00-7.82) for BRCA1 and 3.13 (1.78-5.49) for BRCA2 carriers, respectively. Moreover, BRCA1 mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29-9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients. CONCLUSION: Our study suggest that BRCA patients had a significantly higher risk of developing CBC, particularly for BRCA1 mutation carriers with TNBC as the first breast cancer.

The effect of the preoperational psychoeducation program for Taiwanese breast cancer patients: A three-month follow-up study.

Objective: Studies suggest that psychosocial interventions might be more effective during highly stressful periods, such as before surgery. This study aimed to explore the effectiveness of the Preoperational Health Psychology Education program among Taiwanese breast cancer patients. Methods: A total of 137 adult women (1) diagnosed with breast cancer; and (2) admitted to the ward for surgery were recruited to join the program one day before surgery. Emotional distress, worries, and cancer self-efficacy were evaluated at admission, post-program, and 3-month post-surgery. Patients were grouped into high/low distress groups, and mixed-design ANOVA was used to examine the program's effectiveness. Results: The results showed significant interactions of Group × Time in emotional distress (F = 16.15, p = .000) and worry (F = 5.81, p = .005), but not in self-efficacy (F = 2.97, p = .068). The post-hoc tests revealed significant decreases in emotional distress and worry in the high distress group. Conclusion: The program was found helpful in reducing emotional distress and worries. The effect lasting for three-month for those with higher preoperational emotional distresses. Innovation: This psycho-education program with a relatively rare one-session design, targeted at a less-studied pre-surgery period, is helpful to a less-studied population, Asian cancer patients.

Monocytes secrete CXCL7 to promote breast cancer progression.

Certain immune cells and inflammatory cytokines are essential components in the tumor microenvironment to promote breast cancer progression. To identify key immune players in the tumor microenvironment, we applied highly invasive MDA-MB-231 breast cancer cell lines to co-culture with human monocyte THP-1 cells and identified CXCL7 by cytokine array as one of the increasingly secreted cytokines by THP-1 cells. Further investigations indicated that upon co-culturing, breast cancer cells secreted CSF1 to induce expression and release of CXCL7 from monocytes, which in turn acted on cancer cells to promote FAK activation, MMP13 expression, migration, and invasion. In a xenograft mouse model, administration of CXCL7 antibodies significantly reduced abundance of M2 macrophages in tumor microenvironment, as well as decreased tumor growth and distant metastasis. Clinical investigation further suggested that high CXCL7 expression is correlated with breast cancer progression and poor overall survival of patients. Overall, our study unveils an important immune cytokine, CXCL7, which is secreted by tumor infiltrating monocytes, to stimulate cancer cell migration, invasion, and metastasis, contributing to the promotion of breast cancer progression.

Overexpression of Adiponectin Receptor 1 Inhibits Brown and Beige Adipose Tissue Activity in Mice.

Adult humans and mice possess significant classical brown adipose tissues (BAT) and, upon cold-induction, acquire brown-like adipocytes in certain depots of white adipose tissues (WAT), known as beige adipose tissues or WAT browning/beiging. Activating thermogenic classical BAT or WAT beiging to generate heat limits diet-induced obesity or type-2 diabetes in mice. Adiponectin is a beneficial adipokine resisting diabetes, and causing "healthy obese" by increasing WAT expansion to limit lipotoxicity in other metabolic tissues during high-fat feeding. However, the role of its receptors, especially adiponectin receptor 1 (AdipoR1), on cold-induced thermogenesis in vivo in BAT and in WAT beiging is still elusive. Here, we established a cold-induction procedure in transgenic mice over-expressing AdipoR1 and applied a live 3-D [18F] fluorodeoxyglucose-PET/CT (18F-FDG PET/CT) scanning to measure BAT activity by determining glucose uptake in cold-acclimated transgenic mice. Results showed that cold-acclimated mice over-expressing AdipoR1 had diminished cold-induced glucose uptake, enlarged adipocyte size in BAT and in browned WAT, and reduced surface BAT/body temperature in vivo. Furthermore, decreased gene expression, related to thermogenic Ucp1, BAT-specific markers, BAT-enriched mitochondrial markers, lipolysis and fatty acid oxidation, and increased expression of whitening genes in BAT or in browned subcutaneous inguinal WAT of AdipoR1 mice are congruent with results of PET/CT scanning and surface body temperature in vivo. Moreover, differentiated brown-like beige adipocytes isolated from pre-adipocytes in subcutaneous WAT of transgenic AdipoR1 mice also had similar effects of lowered expression of thermogenic Ucp1, BAT selective markers, and BAT mitochondrial markers. Therefore, this study combines in vitro and in vivo results with live 3-D scanning and reveals one of the many facets of the adiponectin receptors in regulating energy homeostasis, especially in the involvement of cold-induced thermogenesis.

Biomarker discovery in highly invasive lung cancer cell through proteomics approaches.

Lung cancer is one of the leading causes of cancer-related death worldwide. The most common type of lung cancer is non-small cell lung cancer (NSCLC). When NSCLC is detected, patients are typically already in a metastatic stage. Metastasized cancer is a major obstacle of effective treatment and understanding the mechanisms underlying metastasis is critical to treat cancer. Herein, we selected an invasive subpopulation from the human lung cancer cell line A549 using the transwell system and named it as A549-I5. Invasive and migratory activities of this cell line were analysed using wound healing, invasion, and migration assays. In addition, epithelial-mesenchymal transition (EMT) markers, such as Snail 1, Twist, Vimentin, N-cadherin and E-cadherin, were assessed through immunoblotting. In comparison to A549 cells, the invasive A549-I5 lung cancer cells had enhanced invasiveness, motility and EMT marker expression. Proteomic analysis identified 83 significantly differentially expressed proteins in A549-I5 cells. These identified proteins were classified according to their cellular functions and most were involved in cytoskeleton, redox regulation, protein degradation and protein folding. In summary, our results provide potential diagnostic markers and therapeutic candidates for the treatment of NSCLC metastasis. SIGNIFICANCE OF THE STUDY: When NSCLC is detected, most patients are already in a metastatic stage. Herein, we selected an invasive subpopulation from a human lung cancer cell line which had increased EMT markers as well as high wound healing, invasion and migration abilities. Proteomic analysis identified numerous proteins associated with functions in cytoskeleton, redox regulation, protein degradation and protein folding that were differentially expressed in these cells. These results may provide potential diagnostic markers and therapeutic candidates for the treatment of NSCLC metastasis.

Diffusion of innovation in radiation oncology in the United States.

OBJECTIVE: To develop an instrument for quantifying innovation and assess the diffusion of innovation in radiation oncology (RO) in the United States. METHODS: Primary data were collected for using total population convenience sampling. Innovation Score and Innovation Utilization Score were determined using 20 indicators. 240 medical physicists (MPs) practicing in RO in the United States completed a custom Internet-based survey. RESULTS: Centers with no academic affiliation are trailing behind in innovation in total (MD = 1.65, 95% C I[0.38,2.917], p = 0.011, d = 0.351), in patient treatment (MD = 0.39, 95% CI [0.021,0.76], p = 0.038, d = 0.282), and workflow innovation (MD = 7.09, 95% CI [0.78,13.39], p = 0.028, d = 0.330). Centers with no academic affiliation are trailing behind in innovation utilization in total (MD = 0.46, 95% CI [0.05,0.86], p = 0.028, d = 0.188). Rural center are trailing behind in patient positioning in innovation (MD = 0.31, 95% CI [0.011,0.612], p = 0.042, d = 0.293) and innovation utilization (MD = 16.22, 95% CI [0.73,31.72], p = 0.04, d = 0.608). Rural centers are trailing behind in innovative treatments (MD = 0.62, 95% CI [0.23,1.00], p = 0.002, d = 0.457). Motivation (rs = 0.224, p = 0.002) and appreciation (rs = 0.215, p = 0.003) were statistically significant personal factors influencing innovation utilization. CONCLUSIONS: There is a wide range of innovation across RO centers in the United States. RO centers in the United States are not practicing as innovative as reasonably achievable. ADVANCES IN KNOWLEDGE: This work quantified how innovative RO in the United States is and results provide guidance on how to improve it in the future.

Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer Stem Cells.

The enlarged distinct bulky-ball-like nucleolus matrix assembly is observed in most cancer stem cells (CSCs); however, the underlying mechanism is largely unknown. We show that matrix metalloproteinase-7 (MMP-7) shedding MUC-1 SEA domain releases MUC-1 C-ter, facilitating the nucleolus trafficking of p53 in gefitinib-resistant lung CSCs. The nucleolus colocalizations of p53, MUC-1 C-ter, MMP-7 and nucleolin were observed in the CD34+ CXADR+ CD44v3 + gefitinib-resistant EGFRL858R/T790M CSC colonies. MUC-1 C-ter induced a unique porous bulky-ball-shaped, cagelike nucleolus that functions as a nucleus molecular "garage" for potent tumor suppressor, p53. Nucleolus could also facilitate the novel sub-nucleus compartment for proteolytic processing p53 by MMP-7 to generate a 35 kDa fragment. Moreover, we show that salinomycin, an anti-CSC agent, disrupts nucleolus by inducing nucleoplasm translocation of p53 and sensitizing CSC to chemotherapy drugs. Thus, this study highlights the MMP-7-MUC-1-p53 axis in nucleolus as a potential therapeutic target for anti-CSCs to resolve the chemotherapy-resistance dilemma.