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B: "To tell you the truth, I wanted to go to Stanford. I made it on the waiting list, but ninety nine percent of the people accepted to Stanford go there. Like, who wouldn't right? B: "I'm not complaining. I just know that I wanted to come to California. Texas is cool and all, but I wanted to experience different things. B: "I was thinking about political science, but now I'm leaning towards English literature. How about you? B: "Do you know where the Smith building is? I have to pick up the syllabus for my psychology class. I missed the first day.

Can you explain what slow travel is? Dan : Yeah, I mean especially maybe because I'm a blogger, we're always seeking to define things in unique ways. But what I did was always a little bit different, which is I would go and get long term leases or medium term leases at apartments. So I would go and get a house or an apartment in a place for anywhere from one to six months, and enjoy what it feels like to actually live somewhere.

And that to me is so exciting, you know. You might hire people there. You have really good friends there. One of the downsides of being a tourist is that you never really can develop friendships. And so what I found is that I go back to revisit a lot of the places that I once lived because I have lifelong friendships there. So that to me has really been the benefit of slow travel and I have a theory about friendship. I think, you know, really you can't go to place for just one month.

And I think a lot of people would be really hesitant to do that. How would you convince somebody to do this type of lifestyle? Dan : Well, the first thing is to get connected on the blogosphere with a lot of other people who are doing it because I think that once you see other people doing it, the mystery comes away and you realize hey, this is something that I could do. This is achievable for me. So I call that like a precedent case analysis.

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If you can see some other guys doing it and you can relate with them, not such a big deal anymore. The next thing is like I always try to go somewhere where I have a project. My last location in the Philippines, I went there with a project to hire people because I knew it was a great place to hire people. A place before that in Vietnam, I decided that I wanted to do investments in Vietnam. But I find it the idea of having a project gets you engaged. For me as a business person, I've never gone somewhere and not hire somebody there. And that act in and of itself helps me to get engaged.

Save my name, email, and website in this browser for the next time I comment. VOA learning English. ED - Ted. View answers:. The teacher wants the students to …. The teacher suggests eating …. The teacher suggests finding a study place with a lot of …. If students feel stressed they should ….

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The teacher understands that repeating things can be …. Students can do past exam papers …. The teacher recommends a break of five minutes every …. The teacher is sure that the students will …. And, last but not least, good luck! What are these two people doing? Why is he asking a friend for a cigarette? Select the statement that is true from this dialog? Where is this conversation taking place?

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Taking a smoke break. A: "Hey Bobby. What's going on? A: "I forgot my cigarette today. Do you have another one? A: "Really? I've been smoking for over a year now. B: "Oh. You're new to smoking still. I've been smoking for 7 years.

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B: "Many times. I'm really addicted. It's harder to stop than you think.

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B: "I highly recommend you quit soon. The longer you smoke, the harder it becomes to quit. What two states are the guys from? What year are the two students in? What university are they currently at? What are all the majors that were brought up? It acts as a gatekeeper of the genome when cells experience stress conditions such as DNA damage, hypoxia and oncogene activation. Thus, TP53 deficiency may lead to uncontrolled proliferation of damaged cells as the genomic stability is hampered which leads to a faster mutation speed.

It has been shown that p53 mutation adversely affects breast cancer response to tamoxifen These evidences altogether suggest that 'genome instability and mutation' contributes to tumor drug resistance regardless of which subtype it belongs to. Higher level of circulating vitamin D metabolites is shown to be associated with decreased breast cancer risk - , and the statues of vitamin D receptor VRD , AR and ER are known to be correlated with tumor differentiation state Santagata et al.

Tumors classified using these markers have different clinical outcomes, with HR3 tumors being associated with the best survival and HR1 and HR0 tumors the most aggressive An intriguing implication of this novel classification is targeting VDR and AR in conjunction with ER for patients receiving hormone therapy, which is potentially a more efficient therapeutic strategy , These seemingly imply a similar role played by HER2 and AR which, however, differ in that HER2 is a growth factor receptor and AR is a hormonal receptor involved in the control of male characteristics.

Thus, the progressive nature of hormonal receptor ER, PR, or AR positive subtypes may be governed by 'sustaining proliferative signaling'. ER-PR-HER2- tumors are notorious for their poor diagnosis, lack of efficient therapeutic treatments and high heterogeneity. Basal markers, EMT markers, claudins, immune response genes have been revealed to identify basal 85 , 89 , 90 , - , MBC , claudin-low and interferon-rich cancers 93 , from tumors of this kind. CK are the most widely used basal markers, which contribute to cell-cell adhesion, and claudins are a family of proteins that are the most important components of the tight junctions.

These suggest that 'activating invasion and metastasis' drives the differences among basal tumors, MBC, and claudin-low cancers, despite the different markers used for their identification. Also, recall that MBC and claudin-low tumors share many similarities regarding their, e. The interferon-rich subtype, as indicated by its name, may differentiate itself from the other ER-PR-HER2- tumors by 'evading immune destruction'. Novel biomarkers keep emerging, with more and more cancer hallmarks unveiled critical in deciphering breast cancer heterogeneity.

For example, BCL2 is related to 'resisting cell death', TP53 represents the hallmark of 'genome instability and mutation', and VRD is associated with the level of circulating vitamin D metabolites and thus the 'deregulating cellular energetics' hallmark. As a tumor consisting of a collection of different diseases, various biomarkers have been identified to categorize them into different subtypes.

Despite the novel subtypes being kept identified, the dominant cancer hallmarks driving such heterogeneity stay invariant. In tumors lacking hormone receptors, i. Also important for tumors of this kind is the emerging hallmark 'evading immune destruction', according to which a novel subtype, interferon-rich cancer, is identified. Other hallmarks, such as 'resisting cell death', 'genome instability and mutation' and 'deregulating cellular energetics' help to refine tumor classification and contribute, in particular, on predictive value.

With the arrival of the times of precision medicine, precise molecular characterization of the heterogeneity of complex diseases such as breast cancer has become of particular importance. Though the basic receptors ER, PR, HER2 classifying breast tumors stay the same, novel biomarkers and approaches in subtyping of such tumors have been kept reported. This, in turn, has led us to an overwhelming realm of breast tumor subtypes that are not mutually exclusive, complicating our understandings towards breast cancer classification. This, on one hand, is due to the inconsistent criteria used for breast tumor identification and, on the other hand, suggests that we may have lost the global view on unveiling breast tumor heterogeneity.

Here, by reviewing the current biomarkers and their associations with cancer hallmarks, we claim that 'the divergent outcome observed from cancer patients are driven by cancer hallmarks but not biomarkers; thus, biomarkers may vary among studies but cancer hallmarks driving such differences should stay invariant'. Among the 10 cancer hallmarks, 6 have been covered by the current studies on breast tumor classification.

This suggests that further efforts in this area should be inclined to the rest four hallmarks, i. Xiaofeng Dai , Ph. She conducted her postdoctoral researches at the Institute for Molecular Medicine Finland and the department of Obstetrics and Gynecology in Helsinki University, where she started her career in breast cancer. Dai researches focus on breast cancer heterogeneity and subtyping, basal breast cancer stem cell signaling network construction and drug target exploration, as well as bioinformatics studies in biology.

National Center for Biotechnology Information , U. Journal List J Cancer v. J Cancer. Published online Jun Author information Article notes Copyright and License information Disclaimer. E-mail: moc. Competing Interests: The authors have declared that no competing interest exists. Received Jul 5; Accepted May Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.

This article has been cited by other articles in PMC. Abstract Breast cancer is a complex disease encompassing multiple tumor entities, each characterized by distinct morphology, behavior and clinical implications. Keywords: cancer hallmarks, biomarker, breast cancer, subtype. Introduction Breast cancer is the most common neoplasm among women in the majority of the developed countries, accounting for one-third of newly diagnosed malignancies 1.

Hallmark 1: Sustaining proliferative signaling Hormonal and growth receptors define basic breast tumor molecular subtypes IHC markers including ER, progesterone receptor PR and human epidermal growth factor receptor 2 HER2 are classically used for breast tumor subtyping ER ER is the most important and prevalent biomarker for breast cancer classification. KI67 The most widely used proliferation marker in breast cancer is KI67, which is predominantly present in cycling cells Table 1 Different immunohistochemical marker combinations used to define the basal phenotype in various publications.

Open in a separate window. EMT, Stem cell markers deteriorate ER-PR-HER2- tumors Epithelial to mesenchymal transition EMT is a reversible biological process that involves the transition from motile, multipolar or spindle-shaped mesenchymal cells to planar arrays of polarized cells called epithelia. Table 2 Summary of the breast tumor molecular subtypes. Hallmark 4: Resisting cell death BCL2 shows dual roles on tumor outcome prognosis and prediction The protein BCL2 is a suppressor of apoptosis, which has been verified in a variety of in vitro and in vivo experiments - Hallmark 5: Genome instability and mutation TP53 dysfunction increases tumor drug resistance The tumor suppressor TP53 plays a critical role in many cellular signaling controlling cell proliferation, survival, apoptosis and, most importantly, genomic integrity , Hallmark 6: Deregulating cellular energetics VRD provides novel view on breast tumor classification Higher level of circulating vitamin D metabolites is shown to be associated with decreased breast cancer risk - , and the statues of vitamin D receptor VRD , AR and ER are known to be correlated with tumor differentiation state Concluding Remarks As a tumor consisting of a collection of different diseases, various biomarkers have been identified to categorize them into different subtypes.

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Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. Tamoxifen for early breast cancer: an overview of the randomised trials. Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status.

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Time to stop progesterone receptor testing in breast cancer management. Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone receptors in a randomized trial comparing letrozole and tamoxifen adjuvant therapy for postmenopausal early breast cancer: BIG Journal of cancer research and clinical oncology.

Allred DC. Commentary: hormone receptor testing in breast cancer: a distress signal from Canada. The oncologist. Rhodes A, Jasani B. Quantitation of estradiol receptors alpha and beta and progesterone receptors in human breast tumors by real-time reverse transcription-polymerase chain reaction: Correlation with protein assays. Biochemical pharmacology. Biologic and clinical characteristics of breast cancer with single hormone receptor positive phenotype. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.

Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance. Results of two or five years of adjuvant tamoxifen correlated to steroid receptor and S-phase levels. Tumor variants by hormone receptor expression in white patients with node-negative breast cancer from the surveillance, epidemiology, and end results database. Estrogen receptor protein of breast cancer in patients with positive nodes.

High recurrence rates in the postmenopausal estrogen receptor-negative group. Archives of surgery. Prognostic significance of estrogen receptor status in breast cancer in relation to tumor stage, axillary node metastasis, and histopathologic grading. Histological and molecular types of breast cancer: is there a unifying taxonomy? Nature reviews Clinical oncology. The value of estrogen and progesterone receptors in the treatment of breast cancer.

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Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. HER-2 and topoisomerase II as predictors of response to chemotherapy. Role of anthracyclines in the treatment of early breast cancer. Outcome of patients with early-stage breast cancer treated with doxorubicin-based adjuvant chemotherapy as a function of HER2 and TOP2A status. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma.

HER2 and response to paclitaxel in node-positive breast cancer. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG randomised trial. The Lancet Oncology. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. Molecular breast cancer subtypes in premenopausal African-American women, tumor biologic factors and clinical outcome. Annals of surgical oncology.

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Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. The Journal of clinical investigation. Androgen receptor expression and breast cancer survival in postmenopausal women. Androgen receptor expression in breast cancer: relationship with clinicopathological factors and biomarkers.

International journal of clinical oncology. The androgen receptor as a surrogate marker for molecular apocrine breast cancer subtyping. Prognostic value of proliferation in invasive breast cancer: a review. Proliferation index as a prognostic marker in breast cancer. Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now? Annals of Oncology. Proliferation markers predictive of the pathological response and disease outcome of patients with breast carcinomas treated by anthracycline-based preoperative chemotherapy.

Clinical and pathological response to primary chemotherapy in patients with locally advanced breast cancer grouped according to hormonal receptors, Her2 status, grading and Ki proliferation index. Anticancer research. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. Prognostic and predictive value of centrally reviewed Ki labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial comparing adjuvant tamoxifen with letrozole.

Association of GATA3, P53, Ki67 status and vascular peritumoral invasion are strongly prognostic in luminal breast cancer. Novel prognostic immunohistochemical biomarker panel for estrogen receptor-positive breast cancer. Acta oncologica. Amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples. International journal of oncology. Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis.

Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. Explanation of photon correlations in the far-off-resonance optical emission from a quantum-dot-cavity system. Physical review letters. Current directions in psychological science. Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes.