Abstract—Cancer can be described as the uncontrolled growth of abnormal cells. Breastcancer is the second most common type of cancer after lung cancer. Normal breast cells and most breastcancer cells have receptors that attach to circulating estrogen and progesterone. Estrogen and progesterone bind to the receptors and may work with growth factors (e.g., oncogenes and mutated tumor suppressor genes) to cause cancer cell growth and proliferation. Some of the most commonly used breastcancerdrugs are Tamoxifen, Raloxifene, Toremifene etc, breastcancer cells need estrogen to grow. These drugs mainly work against the effects of estrogen on these cells. The Protein- Ligand interaction plays a significant role in structural based drug designing. In our research work we have taken the Human estrogen receptor and the commercially available drugs against breastcancer. The receptor was docked to the above said drugs and the energy value obtained as follows Tamoxifen (-49.0), Raloxifene (-158.0), Toremifene (-108.0) using the HEXdocking software. Depending on the energy values we have chosen the best two drugs they are Raloxifene and Toremifene. We tried to improve the binding efficiency and steric compatibility of the two drugs namely Raloxifene and Toremifene. Several modifications were made to the probable functional groups which were interacting with the receptor molecule. Analogs of this drug molecule were prepared using ACD ChemSketch and docked usingHeXdocking software. Raloxifene Analog 7 and Toremifene analog 6 were detected with significant energy values and probable lead molecules. The Modified drugs was sketched using Chemsketch were found to be better than the conventional drugs available. Further from this work we can improve the steric compatibility and then ADME/T properties of the Analogs can be analyzed using Inslico ADME/T tools available.
It is important that a micelle can retain the drug in its inner core during relatively long periods of time, in order to provide its controlled release. In addition, increasing the period among which drug is released it is important to reduce de number of administrations, whilst always assuring that the drug concentrations are within the therapeutic window. After an intravenous injection it is highly important to ensure that the greatest possible amount of drug reaches its final destination, i.e., tumor cells. This characteristic is ensured by a slow release profile . The release profile of nanoparticles was quantified as described above using UPLC technology. Regarding the release profile obtained, several aspects have contribute for the behavior of drugs encapsulated in micellar carriers . Drug solubility, desorption of surface bound drugs, DDS degradation, drug diffusion, or the combination of all of these characteristics determines the release profile of an encapsulated drug . PEG- PLA micelles are described to hold encapsulated hydrophobic drugs with high efficacy . Based on the better encapsulation efficiency of PL8 formulation, as well as greater negative zeta potential, the following studies were performed with PL8 formulation only. The micelles produced herein were able to sustain 80% of its payload of Crizotinib, resulting on a release of only 20% during 8 days of study (Figure 26). On the contrary, sildenafil appears to have a burst release profile, which is slightly explained by its increased water solubility in comparison with than of Crizotinib. As Sildenafil is more soluble in water (medium used for micelle self-assembly), its interaction with the hydrophobic chains of the polymer will be lower. Due to poor hydrophobic interaction with PLA hydrophobic chain, encapsulated sildenafil might be weakly interacting with PEG chains, which in turn promotes its faster release .
used in pharmaceutical studies to test compounds and their toxicity towards cells, but we preferred to use a milder level of toxicity, IC20, so as to trigger a response from the cells without inducing excessive cell death. The 7 cell lines and the 5 treatments were clustered according to log10(IC20) using the Euclidian dissimilarity measure. In the first dimension, the cell lines were clustered by similarity of their log10(IC20) profile across the 5 treatments. In the second dimension, the treatments were clustered by similarity of their log10(IC20) profile across the 7 cell lines. In the colour-coded grid, cell lines and treatments have been listed in the two dimensions, and each grid block shows the log10(IC20) value for each cell line and treatment. Brightness of colour is correlated with log10(IC20), with red for higher IC20 and green for lower IC20 (Fig. 1A). Cell lines were separated into two clusters represented by the two major dendrogram branches: MCF7 and OVCAR-8/ADR on one side with a very low IC20 for 5-FU and very high for the other treatments (except BCNU for OVCAR-8/ ADR and ADR for MCF7). On the other side, the other cell lines were grouped together, with a higher IC20 for BCNU than for the other treatments, all of which had an intermediate IC20. Inside this cluster, HCT-116 was significantly closer to HCT-15, showing a similar sensitivity of the two colon cancer cell lines for the different treatments (Fig. 1B). The treatments could be divided into 3 different groups: on the one hand, CDDP, ADR and OHP were grouped together, with IC20 for MCF7 and OVCAR-8/ ADR higher than for the other cell lines. 5-FU was opposed to this group, with IC20 for MCF7 and OVCAR-8/ADR much lower than for the other cell lines. Finally, BCNU was classed separately, with a much higher IC20 for every cell line except OVCAR-8/ ADR (Fig. 1C).
3.5. Allium sativum L. Allium sativum, commonly known as garlic, presents different biologically useful secondary metabolites with high sulphur content, such as S-allyl- cysteine, diallyl disulphide, diallyl trisulfide, and methyl allyl trisulfide . Garlic also contains other beneficial compounds such as arginine, oligosaccharides, flavonoids, and selenium (i.e., cellular antioxidants) . The main active ingredients of garlic, organic sulphur compounds, have attracted great attention as cancer prevention and treatment agents in breastcancer [260–263]. Among these constituents derived from garlic, the oil-soluble compounds are more effective than water-soluble compounds in suppressing breastcancer . The mechanisms involved in the anticancer effect of garlic-containing compounds include activation of metabolizing enzymes that detoxify chemical carcinogens, inhibition of DNA adduct formation, suppression of reac- tive oxygen species production, induction of apoptosis, and regulation of cell cycle progression and signal transduction modification . All referred to studies used experimen- tal breastcancer cell lines, other studies extended their anticancer evidences to in vivo models [265, 266], and no clinical trials are available in literature. For example, Liu et al.  demonstrated that diallyl trisulfide, a natural organosulphuric compound with most sulphur atoms found in garlic, suppressed the migration and invasion of breastcancer cell lines (MDA-MB-231 cells and HS 578t cells) and suggested that the inhibitory effects are associated with downregulation of the transcriptional activities of nuclear factor-kappa (NF-𝜅B, a transcription factor that regulates the expression of antiapoptotic proteins) and ERK/MAPK (i.e., major kinases involved in cell survival) signalling path- ways. In many malignant tumours, constitutive NF-activation occurs and consequently inflammation, proliferation, resis- tant to apoptosis, invasion, and so forth . These authors reported that a concentration of diallyl trisulfide equal to 10 𝜇M should be achieved in vivo for preventing or treating breastcancer. Chandra-Kuntal and collaborators established the critical role for reactive oxygen species in the anticancer effects of diallyl trisulfide compound using human breastcancer cells (MCF-7 and MDA-MB-231). Using an oestrogen receptor-negative human breastcancer cell line (MDA-MB- 231), Nakagawa et al.  reported that diallyl disulphide synergizes the effect of eicosapentaenoic acid, a breastcancer suppressor, and antagonizes the effect of linoleic acid, a
Patient sample for weighted prevalence analysis To determine the weighted prevalence of a hereditary breastcancer phenotype in the population being studied, two groups of patients were evaluated: (a) 885 unrelated women with a family history of cancer and (b) 910 unre- lated women of the same cohort with no family history of cancer upon recruitment at the primary health care unit and who were invited to participate in this study during their an- nual mammographic screening examinations. Recruitment was done consecutively during a period of 12 months. The evaluation included an interview, an estimation of the risk of breastcancer, and registration of the family history in pedigrees of at least three generations. The presence of cri- teria for breastcancer predisposition syndromes was as- sessed by three clinical geneticists (PAP, FLR and CBON) who independently reviewed each pedigree. The group of patients referred for genetic risk evaluation was also the group used for the validation of the seven question instru- ment for identification of hereditary breastcancer families (Ashton-Prolla P, Giacomazzi J, Schmidt AV, Roth FL, Palmero EI, Kalakun L, Aguiar E, Moreira SM, Batassini E, Belo-Reyes V, Caleffi M, Camey S; unpublished data).
A rapid sensitive and versatile method for the individual and simultaneous determination of the anticancerdrugs emodin (Em) and irinotecan (Irino) in biological fluids based on the square wave voltammetry (SWV) using a renewable pencil graphite electrode (PGE) was investigated. Controlled adsorptive accumulation of both Em and Irino on the PGE surface was exploited for trace determination of the anticancerdrugs in biological fluids. Under the optimized experimental conditions such as supporting electrolyte pH, accumulation potential and time and electrochemical parameters, calibration curves for trace assay of Em and Irino individually and simultaneously showed an excellent linear response. Limits of detection of 5.17 × 10 −10 and 1.68 × 10 −9 mol L −1
Machine learning is the process of learning a set of rules from instance from a training set, or more generalizing, creating a classifier that can be used to generalize from new instances. The procedures or learning is as follow; the first step is to collect the dataset, if a dataset collected by any of the arbitrary method is not directly suitable for induction. It may contain noisy and missing data values, and therefore requires significant pre-processing . The second step is the data preparation and data pre-processing and the feature subset selection is the process of identifying and removing as many irrelevant and redundant features as possible . This reduces the dimension of the data and allowing algorithms to perform faster and more efficiently. But many features depend on one another and may influence the accuracy of supervised Machine Learning classification models.
that induces sensitisation of cancer cells to treatment with the anticancer compound gemcita- bine . G12 is characterized by three mutations with respect to the wild type dCK enzyme. However, it has remained undetermined whether the sensitisation activity observed in G12 depends on the presence of all three mutations and, if so, what the relative contribution of each of these mutations to the G12 phenotype is. To address these issues, we constructed six mutants, three containing either the E171K, the E247K, or the L249M mutation alone, and three containing two mutations each, covering all the possible combinations of double mutants (E171K/E247K, E171K/L249M, and E247K/L249M). The mutants were inserted in the previ- ously described pSDY plasmid , and used for transfection with transcomplementation plas- mids as described in the Materials and Methods, in order to generate lentiviral vectors. With respect to the pSDY plasmids we previously described , the plasmids we used (pSDY-SIN) contained a partially deleted and therefore non-functional version of the 3' U3 sequence (Fig 1A). The resulting lentiviral vectors will generate, after reverse transcription, non-functional LTR sequences and are therefore called self-inactivating (SIN) vectors (SDY-SIN in our case). These lentivectors were chosen for this test for their pertinence for biomedical applications. As controls, the G12 and the wt dCK sequences were also inserted in pSDY-SIN plasmid. For each variant of dCK, the lentivectors were used to establish a polyclonal population of Messa 10K cells. These polyclonal populations (SINvec-G12 population for G12, SINvec-wt dCK for wt dCK, SINvec-E171K for the E171K mutants, and so on) were generated by transducing 10 6 HEK 293T cells with different amounts of lentiviral vector in order to obtain, after puromycin selection, 50 to 200 individual clones. This way, each clone was almost certainly derived from a cell containing a single integrated copy of proviral DNA. The clones were then pooled ensuring that the resulting population was constituted by cells carrying the same transgene, but with the gene integrated at different locations in the genome, thereby averaging over possible effects that might be attributable to the integration site. The fact that the cells contained a single copy of the transgene allowed the exclusion, when comparing populations one with the other, of possible dose effects due to the number of transgene integrated. Sensitisation to gemcitabine treatment was then evaluated by MTT tests. To this end, the different Messa 10K polyclonal populations were μded into 96-well plates, exposed to varying concentrations of gemcitabine, and cell survival was measured for each condition as previously described .
Abstract Delays in treating breastcancer have been associated with a more advanced stage of the disease and a decrease in patient survival rates. The scope of this integrative review was to ana- lyze the main causal factors and types of patient and system delays. The underlying causal factors of delays were compared among studies conducted in developing and developed countries. Of the 53 studies selected, 24 were carried out in developing countries and 29 in developed countries, respec- tively. Non-attribution of symptoms to cancer, fear of the disease and treatment and low educa- tional level were the most frequent causes of pa- tient delay. Less comprehensive health insurance coverage, older/younger age and false negative diagnosis tests were the three most common caus- al factors of system delay. The effects of factors such as age were not decisive per se and depended mainly on the social and cultural context. Some factors caused both patient delay and system de- lay. Studies conducted in developing countries identified more causal factors of patient delay and had a stronger focus on patient delay or the com- bination of both. Studies conducted in developed countries had a stronger focus on aspects of system delay during treatment and guidance of breastcancer patients in the health care system.
Based on the consulted articles and literature aiming to obtain a characterization of the work produced in the area of health involving this theme. It was decided to do an analysis of the evidence in order to understand if it is relevant to the association between the use of HRT in menopause be considered as a risk factor for the development of breastcancer. Moreover, from the data obtained in this study it becomes easier for health professionals to better clarify the patients at possible risk, developing ways and alternatives to minimize the effects of menopause. Thus contributing to a more conscious use of HRT on the part of both professionals and patients.
A schematic diagram of the system is shown in Fig. 6 [17-20]. Under operator guided computer control, a very short frequency-modulated pulse is applied from an ultra wideband (UWB) antenna beside the breast of a patient in the face-down (prone) position via a switching unit. At the same time, an acoustic signal is applied from a transducer below the breast. The proposed hybrid system utilizes the combined benefits of microwaves, with UWB spectrum, and acoustic excitations to produce a three-dimensional image. In this method, microwaves are employed to give a full view of the dielectric contrasts, while acoustics give the elasticity distributions within the breast. The two distributions are then used to produce a final image with high contrast and resolution.
Candida albicans is an important opportunistic fun- gal pathogen of the humans. Systemic candidiasis is a seri- ous situation in patients undergoing treatment for cancer (Safdar and Armstrong, 2002). Candida species now rank among the ten most prominent pathogens in leukemia pa- tients, accounting for 75% of fungal infections in general and these infections result in 25-60% mortality (Winston et al., 2000). In the last two decades, use of azole antifungals has rapidly led to the development of drug resistance in pa- tients with advance cancers, AIDS, organ transplantations, and surgeries etc. C. albicans cells exist in different mor- phological forms, including yeast, pseudohyphal and true hyphal forms (Pauw, 2004). Yeast to hyphal form morpho- genesis in C. albicans is believed to be related to its viru- lence, since mutants defective in hyphal growth are less virulent in mouse models than their wild-type (Lo et al., 1997). There are various reports ondrugs inhibiting yeast to hyphal form switching. For example, 6-Amino-2n-pentyl- thiobenzothiazole an antifungal agent is reported to inhibit hyphal growth (Fabry et al., 1999). Antimetabolite class of anticancer agents are also tested for their hyphal inhibitory activity along with mRNA, DNA synthesis and protein syn- thesis inhibitors. Among all these, cyclohexamide showed most potential activity against hyphal induction (Imanishi et al., 2004). The known actin inhibiting drugs, latrun- culin-A and jasplakinolide inhibited yeast to hyphal form transition in a dose dependent and reversible manner (To- enje et al., 2005). Undecylenic acid inhibits the switch from yeast form to hyphae, in sublethal concentrations (McLain et al., 2000). Earlier we have reported the potential mor- phogenetic role for ethyl alcohol and its first oxidation
Multiple studies considered the perception of affordances of walking infants as well as crawling infants. E. J. Gibson et al. (1987) found a difference between walking and crawling infants in the perception of traversability of different surfaces. Walking in- fants showed longer initiation times and more exploration (both visual and haptic) when facing a deformable surface as compared to a standard surface. Crawling in- fants did not exhibit such differences. When given the choice between the surfaces, walking infants displayed a preference for the standard surface that afforded walking, whereas crawling infants did not exhibit a preference for one type of surface. This shows that infants detected the affordances for locomotion in a particular action mode (E. J. Gibson et al. 1987). The analogous conclusion can be drawn regarding infants’ behaviour on slopes. In a series of experiments, Adolph and colleagues studied how walking and crawling infants adapted their locomotion when facing slopes of varying steepness (e.g., Adolph 1995; Adolph et al. 1993b; Eppler et al. 1996). Walking infants walked down a shallow hill of 10 degrees but slid down or avoided a risky steep hill of 36 degrees which are appropriate choices for the different degrees of the slant (Eppler et al. 1996; see also Adolph 1995). Also, Adolph’s (1997) longitudinal study of infants’ ability of crawling and walking on slopes showed that crawling infants gradually im- proved their judgments of risky slopes until these were near perfect in their last week of crawling. Next, after the transition from crawling to walking, all infants displayed a sharp decline in the accuracy of their judgments of risky slopes, after which their judgments improved again just as when they had been crawling. That is to say, infants became increasingly capable of adapting their mode of locomotion to the properties of the slant relative to their own locomotor proficiency, but this improved ability to judge slopes did not transfer from crawling to walking (Adolph 1997). Interestingly, when loading the infants with extra weight, infants changed their actions in accordance with this change in action capabilities by treating a slope that was a safe one in normal conditions as risky in the extra-weight conditions (Adolph and Avalio 2000).
Genotyping of 574 POSH phase-1 breastcancer cases was conducted using the Illumina 660-Quad SNP array. Genotyping was conducted in two separate batches at two locations. The Mayo Clinic (Rochester, Minnesota, USA) genotyped 274 triple negative breast cancers (negative for ER, PR and HER2) . The remaining 300 POSH patients were genotyped at the Genome Institute of Singapore (GIS), National University of Singapore; these were selected based on either short duration of breastcancer specific survival (,2 years) or long duration of breastcancer specific survival (.4 years). In order to ensure complete harmonisation of genotype calling, the intensity data from GIS and MAYO were combined and the genotyping module of Illumina’s Genome Studio software was used to generate genotypes. A GenCall threshold of 0.15 was selected and the HumanHap660 annotation file was used. Of the 300 samples genotyped in Singapore, 3 were excluded from analysis because they had sample call rates lower than 95%. No individuals among the two hundred and seventy four triple negative cohort genotyped at the Mayo clinic were excluded from analysis based on poor call rate. The genotyping accuracy for SNPs genotyped by GIS and Mayo were over 99%.
3. Early BreastCancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGaleP, Correa C, Taylor C, Arriagada R, Clarke M, Cutter D, Davies C, Ewertz M,Godwin J, Gray R, Pierce L, Whelan T, Wang Y, Peto R. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breastcancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378(9804):1707-16. 4. Veronesi U, Salvadori B, Luini A, Greco M, Saccozzi R, del Vecchio M, et al.
are mono-dispersed with modifiable surface functionality as well as internal cavities. They contain several binding sites for hydrophobic, hydrophilic, cationic and anionic drugs (Fig. 1). Dendrimers can be used as a container which encapsulate drug molecules and carry to different targets in vivo [9,36–38]. It has been shown that dendrimers with a hydrophobic interior and hydrophilic chain ends are able to solubilize hydrophobic compounds in aqueous solutions [38,39]. Attempts have been made to design different dendrimers as drug carriers . For example, anticancer fluorouracil drug was attached to the dendrimers with cyclic core  or using dendrimers having poly(ethylene glycol) grafts to encapsulate antitumor drugs adriamy- cin and methotrexate . The complexation of dendrimers with anti-inflammatrory drug flurbiprofen was studied in vitro and in vivo, while drug biodistribution in different organs has been monitored . Gene delivery targeted to brain has been attempted using transferring-conjugated polyethyleneglycol-modified polyamidoa- mine dendrimer . The purpose of our investigation was to evaluate the potential of dendrimers as nanoscale drug delivery tools to carry hydrophilic (cisplatin) and hydrophobic drugs (resveratrol, genistein and curcumin). Resveratrol and genistein) with three OH groups and two and three phenolic rings, respectively are mainly Figure 7. UV-visible spectra of mPEG-PAMAM-G3, mPEG-PAMAM-G4 and PAMAM-G4 and their complexes with resveratrol and genistein with free dendrimer at 100 mM and complexes b-I at 20 to 130 mM. (A, B and C) Resveratrol with mPEG-PAMAM-G3, mPEG-PAMAM-G4 and PAMAM-G4 respectively. (D, E and F) Genistein with mPEG-PAMAM-G3, mPEG-PAMAM-G4 and PAMAM-G4 respectively. (A9, B9 and C9) Plots of 1/(A-A 0 ) vs (1/pigment concentration) and binding constant (K) for Res-mPEG-PAMAM-G3, Res-mPEG-PAMA-G4,
In the present study, we have carried out in-depth analysis and comparison of POPs from three different species human, porcine and plant (A. thaliana) in terms of ligand specificity and binding. This comparison was done to better understand the differences and conformational dynamics of the protein. We have focused on two main issues firstly, to what extant extrapolation of porcine POP to human POP is correct and secondly investigating the possible passage for substrate/product entry/egress. To unravel the above mentioned questions we have applied computational based approaches like molecular docking and dynamics. We were interested in studying plant POPs as they are distant members of same family so it would be interesting to see from evolutionary perspectives like how a distant member of same family behaves as compared to newly diverged members. Moreover, few naturally occurring plant molecules are reported as POP inhibitors having therapeutic applications but nothing much is known about their function and presence in plant system [21–25]. Three possibilities of substrate entry were considered: (1) Movement of side chains present at b-propeller pore will allow annulus of tunnel to become broad (2) the first and seventh blade will move apart, thereby increasing pore size (3) Hinge-like motion between two domains causing separation, thereby substrate entry . Further compar- ison of all the reported cavities (Figure 1) present in protein, that includes b-propeller, inter-domain (between two domains reported by Polgar and coworkers, ) and a recently reported cavity (by Tarrago and coworkers found using cryo-electron microscopy which is present just above active site ) was carried out for unrevealing the possible entry/exit mechanism.
Imaginemos um tabuleiro Hex que seja feito de papel. Sempre que haja um movimento do jogador negro (a sua vez de jogar uma peça negra num determinado hexágono) pinta-se esse hexágono de preto em vez de colocar uma peça desta cor. Sempre que o jogador de branco se mover (a sua vez de jogar uma peça branca num determinado hexágono) fará desaparecer esse hexágono correspondente, cortando-o, em vez de colocar uma peça branca. Repetimos estes procedimentos até já não ser possível jogar. Peguemos agora no tabuleiro de papel, segurando-o pelos lados pretos e afastemos as mãos. Se o papel impedir que as mãos se afastem, tem necessariamente que haver uma cadeia de peças negras a unir os lados do jogador negro e este jogador ganha. Se conseguirmos, por outro lado, afastar as mãos, significa que existe uma cadeia de “cortes” entre os lados do jogador negro sendo a vitória pertencente ao jogador branco. Na seguinte figura, o jogador negro pega nos seus dois lados e consegue afastar as mãos. A vitória pertence ao jogador branco.
An attribute considered relevant to the concept of nursing care to the patient with breastcanceron chemothe- rapy is related to the observation and appreciation of the signs and symptoms caused by the treatment. Women referred to a sense of awareness of these effects by healthcare professionals, but there is often a short resolution of the services and the identification of its occurrence does not happen at the beginning of its appearance, being later, which makes it increasingly remote the chance to stop or minimize the consequences caused .
The number of apoptotic cells in the CN 500 group was significantly higher than in the CC and CN 250 groups whereas, there was no significant dif- ference compared with the CT group (Fig 10). As in the CN 250 group (Fig 6), the nucleus in the plane of view was not as crowded as in the CC samples. There were small dots of green fluores- cent staining among the chromosome clots in the nucleus overlapping the PI red fluorescent staining of the DNA in the nucleus. Interestingly in the CN 500 group (Fig 7), the majority of the cells had con- densed nuclei with intense red fluorescent staining. Concurrently, there were also a number of con- densed nuclei stained with intense apoptotic green fluorescent staining which were never observed in the CN 250 samples. This green stain was found in the condensed nuclei as well as around the nuclear membrane. Some of the nuclei of the cancer cells were breaking apart into small pieces in contrast to the prominent nuclei found in the CC samples. In the CC group, the PI stain was dominant however, the appearance of the stained nucleus was swol- len and prominent and many dark clots of chromo- somes were observed with the presence of hairy extensions when focusing up and down (Fig 8). In the CT group, the appearance of the red stain- ing (Fig 9) revealed that the nuclei of the cells had broken apart into small pieces and in a number the background staining of the nucleus was green instead of red. The quantitative data for apoptotic cells are presented in Fig 10. The CT group ex-