represented only 49.03% of cases (97), the re- maining ones being solved by breast conserving surgery. Without thinking strictly of another therapeutic design, the authors consider that the first explanation of this difference lies in the group structure. Thus, starting from the assump- tion that radical surgery is reserved primarily to locally-advanced stages (stage IIB and IIIA), when curative surgery is theoretically possible, it was observed that the percentage of cases as- sessed in these stages was significantly higher in group A, especially in stage IIB (31.75% vs. 24.75%) while, for stage IIIA, the incidence is similar (10.13% group A vs. 13.10% group B); as to stage IIIB, suitable for radical surgery, the in- cidence is still higher for patients from group A (29.05% vs. 22.81%). On the other hand, even for stage IIA, which usually tends to be breast con- serving surgery, and IIB, to which conservatory surgery tends to expand the indications, analy- sis of the semiological characters of tumors be- longing to group A showed that they were within the upper limit of this stage (tumors with a maximum diameter > 3-4 cm), which is rather a contraindication for breast conserving surgery, especially in the case of patients with small breasts, where the large size of the tumor makes nearly impossible to meet and carry out safe re- section margins. Finally, one last argument in favor of radical surgery was the large share of the invasive ductal carcinoma at histopathologi- cal extemporaneous examination.
LncRNAs have key roles in gene regulation and, consequently, affect various aspects of cellular homeostasis, including proliferation, survival, migration or genomic stability. Cancer is primarily caused by genetic alterations that result in the deregulation of the gene networks that are responsible for the maintenance of cellular homeostasis. In addition, tumor suppressor genes and oncogenes may regulate the transcription of lncRNAs. For their application as biomarkers, lncRNAs should present tissue- and cell type-specific expression and, should be stable and easily detectable in body fluids to permit noninvasive diagnosis (43). For example, the lncRNA PCA3 is a specific and sensitive marker of prostate cancer in patient urine samples, which was the first Food and Drug Administration-approved test based on a lncRNA (46). Similarly, the lncRNA HULC is highly expressed in patients with hepatocellular carcinoma and can be detected in the blood by conventional PCR methods. Since lncRNAs regulate specific facets of protein activity, they also represent potential therapeutic targets. Of note, drugs that target lncRNAs can be more refined and less toxic than conventional protein-targeting drugs (43). Some therapeutic strategies utilize oligonucleotides for the knockdown of lncRNAs. siRNAs consist of an antisense (or guide) strand and a sense (or passenger) strand, forming a duplex 19 to 25 bp in length with 3' dinucleotide overhangs, and are mainly located in the cytoplasm. When bound by Argonaut 2 in the RNA-induced silencing complex, the passenger strand is discarded, leaving the guide strand free to bind an RNA target that is subsequently degraded (50,51). Alternatively, LNA TM GapmeRs
The GPC analysis provides important insights into the molecular weight distribution of the PEG-PLA co-polymers synthetized. As the chromatograms in Figure 16 demonstrate the PL4, PL8 and PL30 co-polymers present Gaussian distribution profiles instead of highly broad peaks. This result indicates that the PL polymers have relatively low polidispersity, an important characteristic for therapeutic applications, envisioned since this parameter ultimately influences batch-to-batch reproducibility of polymer-based pharmaceutical formulations . Moreover, it should be emphasized that PL chromatograms present well resolved peaks since the average molecular weight of the different samples is higher than 10%, which is above the resolution limit of GPC . It is also important to mention the experimental conditions of the chromatographic run, since a salt solution (0.2M NaCl) was used as both equilibration and eluent. This fact led to an increase in the mean residence time of larger polymers and a decrease for smaller ones. Generally, in GPC the separation is based on the radius of gyration of the analytes, with larger analytes having a lower mean residence time than smaller ones, with the latter being those that are retained in the gel for longer periods of time . The obtained results demonstrate that after running the three PEG standards, the retention times of the polymers where inverted, i.e., PEG 2000 had a lower retention time than PEG 4000 and 8000. Eluent used (0.2 M NaCl) have high conductivity. After retention of polymer inside the column it passes through the conductance detector, overall eluent conductivity thus decreases, and the signal is registered in a chromatographic detector. In accordance with the previous results, the loading of PL4, Pl8 and PL30 into the column led to the the same pattern of elution, i.e., longer polymers have been retained more than shorter polymers (Figure 16). This can be explained by the establishment of some non- specific interactions between the polymer samples and the Sephacryl S-100 HR column matrix which is composed of allyl dextran and N,N’-methylene bisacrylamide. It is postulated that NaCl salt concentration has a large influence in the radius of gyration of the mPEG polymer or co-polymer chains as recently described by Heeb and co-workers, 2009 and this might contribute for the observed results .
The epithelial-to-mesenchymal transition (EMT) is a highly conserved physiological program involved in development and tissue repair; however, its aberrant activation has been implicated in accelerating the progression of a variety of cancers. In breastcancer, the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) are differentially expressed in the clinically more aggressive basal-like subtype compared to luminal subtype of breastcancer and upregulation of miR-221/222 induces the EMT by targeting the 39 untranslated region (39UTR) of the GATA family transcriptional repressor TRPS1 (tricho-rhino- phalangeal syndrome type 1). The complete mechanism through which miR-221/222 promotes the EMT, however, is not fully understood. We identified adiponectin receptor 1 (ADIPOR1), a receptor for the adipocytokine adiponectin, as a direct target of miR-221/222. ADIPOR1 is expressed at higher levels in the luminal compared to the basal-like subtype of breastcancer cell lines, which can be reduced by miR-221/222 targeting of its 3’UTR. In addition, miR-221/222 were negatively correlated with ADIPOR1 expression across breastcancer cell lines and tumors. ADIPOR1 depletion by siRNA in MCF10A cells induced the EMT and increased cell invasion. Depletion of ADIPOR1 by siRNA induced activation of the canonical nuclear factor-kappaB (NF-kB) and subsequent phosphorylation of signal transducer and activator of transcription 3 (STAT3) in an interleukin 6 (IL6)-dependent manner. Finally, overexpression of ADIPOR1 in the basal-like cell line, MDA-MB-231, attenuated cell invasion and promoted the mesenchymal-to-epithelial transition (MET). We conclude that ADIPOR1 negatively regulates EMT in breastcancer and provides an additional node by which miR-221/222 induces the EMT. These results suggest that ADIPOR1 may play an important role in breastcancer progression and metastasis, and could potentially offer an alternative therapeutic strategy for basal-like breastcancer patients.
Disruption of normal patterns of covalent histone modifications is another hallmark of cancer. One of the most characteristic examples is the global reduction of the trimethylation of H4K20 (H4K20me3) and acetylation of H4K16 (H4K16Ac), along with DNA hypomethylation at repetitive sequences in many primary tumors (Fraga et al. 2005). In cancer, histone modifications can be deregulated by over- expression, mutations and/or chromosomal translocations of any of the histone acetylation/deacetyaltion (HAT/HDAC) and methylation/demethylation (HMT/HDM or sirtuins) enzymes (Seligson et al. 2005). Histone lysine methyltransferases (SETD1 and 2) are found as novel tumor suppressors. Downregulation of SETD2 promotes both initiation and progression in leukemia (Zhu et al. 2014), whereas hSETD1A controls tumor metastasis by activating MMP expression (Salz et al. 2014). An upregulation of EZH2 (Enhancer of Zeste 2, a histone methyltransferase) has been observed in a wide variety of tumors, such as prostate cancer, lymphomas, colorectal and gastric cancer, and bladder and breastcancer. It was suggested that EZH2 could be an oncogene (Liang et al. 2013). Particular gene involved in tumor suppression and cell growth regulation that are known to be silenced through HDAC mediated epigenetic mechanisms include p21, p27, p16, p19, among many others (Atadja 2011).
As células cancerígenas são o resultado de um processo gradual e complexo chamado oncogénese. Durante este processo, as células normais transformam-se progressivamente em células cancerígenas através da acumulação de diversas alterações genéticas, que eventualmente culminam numa ou mais características definidas como ‘’hallmarks of cancer’’. Estas características foram definidas como propriedades essenciais ao desenvolvimento cancerígeno por Hanahan and Weinberg e correspondem a: sustentar sinalização proliferativa, escapar aos supressores tumorais, resistir à morte celular, possibilitar imortalidade replicativa, induzir angiogénese e ativar processos de invasão e metastastização. Este conjunto de características foi mais tarde alargado, considerando igualmente a importância da instabilidade genómica e da inflamação, bem como da reprogramação do metabolismo e do escape à vigilância imunitária no desenvolvimento dos processos tumorais.
Objectives: To construct, validate and apply to clinical reality the CHEUAL BreastCancer (BC) Model, in order to evaluate the cost-utility of new treatment options versus standard systemic therapy protocols (after surgery and radiotherapy, if adequate), in patients with early stage and metastatic breastcancer, from the Portuguese National Health Service (NHS), Hospital and Physician perspectives, supporting and turning easier the work of these professionals in a transparent way. The model application involves a case study for testing a new drug association of Paclitaxel plus Bevacizumab in metastatic breastcancer, through the clinical perspective.
To define therapeutic protocols containing antineoplastic drug combinations used at the organization, we analysed medical prescriptions of adult patients seen at the oncology outpatient clinic. We selected prescriptions given between January and March 2016 that included the combinations of antineoplastic drugs used in breast and colorectal cancer treatment. We excluded prescriptions containing regimens in which the antineoplastic drugs had not been administered on the same day, or those that included only one antineoplastic agent, since the objective of the study was to determine the medication infusion sequence.
p53 is possibly the most important mammalian tumor suppressor and it is mutated or lost in more than half of all human cancers. The stability of p53 is primarily determined by the RING domain E3 ubiquitin ligase Hdm2, which targets p53 for proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. UBE4B has been shown to physically interact with p53 and Hdm2 and to negatively regulate p53 stability and function. However, no one has determined whether UBE4B promotes p53 degradation in breastcancer. In this study, UBE4B promoted the degradation and ubiquitination of p53 to inhibit the apoptosis of cancer cells and promote tumorigenesis. Our results indicate that UBE4B regulates p53 in breastcancer and could be a viable target for developing new therapeutic strategies for breastcancer treatment.
cancer cells. We found that FATP1/SLC27A1 mRNA levels were significantly upregulated within 30 minutes of exposure to C18+estradiol in MDA-MB-231 (Figure 4.1 A) and within 15 minutes of exposure to C18 in MCF7 cells (Figure 4.1 B) comparing to cells grown in control conditions. FATP1/SLC27A1 mRNA levels suffered a boost in expression in the first minutes of exposure but then decreased with time, thus, this gene seems to be able to respond very quickly to exogenous stimulus. It was also found that the highly aggressive and invasive MDA-MB-231 cells exhibit a significant higher expression of FATP1 than the poorly aggressive and non-invasive MCF7 cells (Figure 4.1 C). In such manner, this result suggests that enhanced FATP1/SLC27A1 expression is correlated with more aggressive phenotypes. Most studies have been investigating FATP1 in the context of diet induced obesity, insulin resistance hyperglycemia, hyperinsulinemia and hypertension 116–119 . To our knowledge,
Breastcancer comprises heterogeneous tumors with different clinical characteristics, disease courses, and responses to specific treatments. Moreover, breast carcinomas result mainly from the accumulation of genetic and epigenetic alterations in epithelial cells of mammary gland. The identification of novel genes differentially expressed in breastcancer has important implications in understanding the molecular mechanisms underlying breast tumorigenesis, and developing new diagnostic and therapeutic targets. Therefore, the aim of this work was to identify genes differentially expressed in the breastcancer MCF7 cells, and to confirm its differential regulation in breastcancer. In this study, we used the suppressive subtractive hybridization technique to generate two subtractive libraries with 96 clones each, which were subsequently digested with EcoRI and then, all the plasmids with insert were sequenced. These results were further analyzed by Blast tool and GeneBank. We identify 36 genes as overexpressed and 19 genes as underexpressed in MCF7 cells. Some of these genes were previously identified as over- or underexpressed in breastcancer; however we found several genes that haven’t yet been described as up or down-regulated in MCF7 cell line. In the future, these novel genes may be used as possible biomarkers, diagnostic markers or therapeutic targets in breastcancer.
minimally treated for grade III/IV neutropenia and are not treated prophylactically. We therefore applied neutropenia costs to 50% of the patients on mitoxantrone for their median 4 treatment cycles. For abiraterone, grade III/IV cardiac events costs included electrocardiograms (EKG) and hospitalizations for dysrhythmia (80%) and cardiac arrest/ventricular fibrillation (20%). Bone pain treatment was applied to patients on prednisone alone with grade III/IV bone pain. Treatments included bisphosphonates, opioids, prophylactic stool softener/stimulant combination and acetamin- ophen usage daily, as needed, for 18 months. Other treatment options such as denosumab are also available, and a preferred treatment by some. Our physician experts recommended that bisphosphonates were more commonly used nationally and a more conservative choice for our model. There is likely significant variation in supportive care treatment nationally and more research and a treatment guideline is needed in this area.
In our days, breastcancer represents the most common cause of death from cancer in women all over the world. Because it has a lifetime risk of one in nine and its incidence continues to increase, many efforts in the science field have been taken trying to find out what triggers this type of cancer, in order to develop efficient treatments. Recently, several groups have linked abnormal expression of Notch signalling receptor and ligands to breastcancer. Mittal and his team showed that a crosstalk between Notch and Ras/mitogen activated protein kinase (MAPK) signalling pathways apparently leads to a poor prognostic of the patients (Mittal et al., 2009). Moreover, Notch has been related to the invasive behaviour of cancer cells. Breastcancer metastases in the bones are the most common ones, leading to severe fractures and pain, among other complications (Mundy et al., 2002). The linkage of Jag1 and transforming growth factor beta (TGF- β) pathways is able to create a positive feedback loop between tumour and bone cells promoting osteolytic bone metastasis (Sethi et al., 2011). Another important feature of metastatic behaviour is the Epidermal - to - mesenchymal transition (EMT), phenomena that occurs during development, but can be reactivated by cancer cells. EMT is described as being important for tumour metastasis and progression, in which Notch may play a critical role. It can modulate down regulation of E- cadherin by TGFβ and, consequently interfere with normal cell-cell adhesion (Timmerman et al., 2004; Zavadil et al., 2004).
cal changes, oligonucleosomal DNA fragmentation, cell membrane phospholipid distribution, caspase activation, mitochondrial transmembrane potential and many others. However, there has been a clear need among researchers for methods capable of de- tecting apoptosis in intact tissue specimens (5). Ga- vrieli et al. (6) described a procedure for the detec- tion of DNA fragmentation in situ, by end labeling of DNA strand breaks using terminal deoxyribonu- cleotidyl transferase (TdT). Since double-stranded DNA breaks occur during apoptosis, TdT would be expected to preferentially interact with such cells. The dead end fluorometric TUNEL System is de- signed for the specific detection and quantitation of apoptotic cells within a cell population. The system can be used to assay apoptotic cell death in many systems, including cultured cells and formalin fixed paraffin-embedded tissue sections (6). Azadirachta indica (Neem) is known historically for its miracu- lous healing properties and has been described an ancient cure for a modern world. Neem is the China- berry’s miraculous cousin and known as a tree for solving global problems, an epithet which has been recognized by the US National Acedemy of Sci- ences (7). This plant belongs to the Meliaceae fam- ily and is native to the dry forests of India, Pakistan and Sri Lanka. The Malay name is Semambu. The Neem tree’s reputation as a medicinal herb can be traced as far back as 4500 years ago and Neem has been used traditionally for many centuries. Some impressive therapeutic qualities have been discov- ered; anti-viral, anti-microbial, anti-inflammatory, anti-bacterial, anti-fungal and anti-hyperglycemic. However the anticancer effect of ethanolic Neem leaf extract against breastcancer has not been docu- mented. Previous in vitro studies have proved that Neem leaf extract has the potential to induce apop- tosis in breastcancer cell lines (MDA-MD231 and MCF-10) (8-10). In the present study, the potential therapeutic effect of ethanolic neem leaf extract in breastcancer was evaluated using the 4T1 breastcancer model in BALB/c mice.
Objective: to comprehend the psychosocial and cultural repercussions of breastcancer and its treatment on the sexuality of women. Method: this is a qualitative study grounded in the Sexual Scripts Theory with the participation of 23 women who were interviewed and participated in focus groups discussion. Results: each category was related to a level of the sexual scripts. At the cultural scenario level a discourse on sexuality that includes definitions of sexual attractiveness and sexuality was highlighted. The interpersonal scripts level focused on the communication regarding sexuality established with the partner and with healthcare professionals category; and at the subjectivity scripts level the reports of improvement, deterioration and no change in the sexual life after cancer were analyzed. Conclusion: the experience of cancer involves cultural, relational, and subjective aspects that affect the sexual life, therefore, healthcare professionals should be aware of them to improve integral healthcare.
The performance of the biomechanical tissues can be influenced by many factors, several studies try to discover these factors by quantifying the impact of different factors on the models accuracy  or by comparing different materials . Generally, hyper-elastic constitutive mod- els tend to be superior than the linear models, having the boundary condition a big impact on the model performance. Palomar et al.  affirm that the complexity of the breast can be simplified by giving a average value of mechanical properties to fibroglandular and apipose tissue. While Ruiter et al.  concluded that the results do not vary within a significant range of stiffness ratios of gland and fat regarding the required simulation accuracy. The exponential and Neo–Hookean models can be used as approximations, where the linear elastic approaches performance is not so good. They argued that the simplest tissue model for breast simulation was the Neo–Hookean one, ignoring the differences between the material properties of gland and fat tissues. By comparing different biomechanical breast models Tanner et al.  found that, for a compression of 20%, the effect on accuracy caused by the modification of the material properties was less significant than the application of correct boundary conditions. With regard to the skin, Samami et al.  made the assumption that it can be considered as linear elastic and isotropic for strains lower than 50%. Reishner et al.  examined the two-dimensional mechanical behaviour of human skin, with samples obtained from different anatomical sites, concluding that the skin have varying degrees of anisotropy in different regions of the body.
most of the time that they were taking a hormonal blocker. Few patients had no knowledge about their clinical stage or previous use of any hormonal manipulation, and that may have been the reason for increased refusal among them (78.6% p=0.045 and 100% p= 0.035% log rank; respectively). The absolute refusal among patients who did not know about previous exposure to hormones seems to reflect the un- certainty about a possible connection between them and their tumors’ devel- opment. Hence it is understandable that they would not accept the risks of relapse by using HRT. These findings probably reflect the importance that correct information about disease, and the exposure to potential risk factors has on decision-making among breastcancer patients.
There are multiple barriers to identifying and diagnosing mental health disorders among cancer patients. These include patient-level barriers such as fear of the stigma of a psychiatric di- agnosis, and concerns that a focus on a psychiatric disorder may distract from oncological treat- ment . At the provider level, barriers may include lack of time to make a mental health assessment, reluctance to shift focus of treatment from cancer, and limited availability of mental health specialists collaborating with oncologists on treatment plans [15,16]. At the institutional level, low priority, fragmented or poorly coordinated psychosocial services, and ineffective com- munication across clinical settings may contribute to low levels of mental health diagnoses among cancer patients . Despite those considerations, to the best of our knowledge very few studies have examined the prevalence of mental health diagnoses among women with breastcancer who have been admitted to the hospital [17–19], an indication of more severe disease. Hospitalized breastcancer patients are likely at greater risk for psychological distress compared with their outpatient counterparts as a result of being admitted, while also potentially experienc- ing the personal and provider level barriers that may limit diagnosis of mental illness .
general female population. This finding is rather unexpected, in contrast to the well-established high risk of yet another breastcancer for breastcancer patients, and thereby potentially puts into question the validity of the results. Kurian et al  assessed hormone receptor status rather than ER and progesterone receptor (PR) separately; hormone receptor-positive was defined as ER- and/or PR-positive. They showed, in consistency with our results, that patients with hormone receptor-positive first breastcancer have approximately twice the risk of CBC compared to the risk of breastcancer in the general female population, and the relative risk increase was independent of ER-status of the second cancer. However, Kurian et al. also showed a more than three-fold risk of CBC if the first cancer was ER-negative, which was driven by the almost 10 times increased relative risk of ER-negative CBC for patients with ER-negative first cancer. Kurian et al found that women who were young at diagnosis and women belonging to ethnic groups other than non-Hispanic whites had the highest relative risks of ER-negative CBC following an ER-negative first cancer, this could potentially explain the discrepancy between that study and ours, since both these groups are significantly more frequent in the study by Kurian et al.