Profiling and targeting HER2-positive breast cancer using trastuzumab emtansine.

PurposeThis article reviews the mechanism of action of trastuzumab emtansine (T-DM1), existing clinical data relating to its use for human growth factor receptor 2 (HER2)-positive breast cancer, potential pathways of resistance, and ongoing studies evaluating this novel agent.BackgroundThe development of HER2-targeted therapies has dramatically improved clinical outcomes for patients with any stage of HER2-positive breast cancer. Although the positive effect of these treatments cannot be overstated, treatment resistance develops in the vast majority of those diagnosed with stage IV HER2-positive breast cancer. Moreover, HER2-directed therapies are most effective when combined with cytotoxic chemotherapy. The need for chemotherapy leads to significant adverse effects and a clear decrease in quality of life for those dealing with a chronic incurable disease. T-DM1 is a recently developed, novel antibody-drug conjugate in which highly potent maytanisinoid chemotherapy is stably linked to the HER2-targeted monoclonal antibody, trastuzumab.ResultsPreclinical and phase 1-3 clinical data support the significant antitumor activity of T-DM1. Importantly, several randomized studies also now demonstrate its clear superiority in terms of tolerability compared with standard chemotherapy-containing regimens. Its role in the treatment of trastuzumab-resistant metastatic breast cancer has now been established on the basis of the results of two phase 3 randomized studies, EMILIA (An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) and TH3RESA (A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy). The most common toxicities seen with T-DM1 are thrombocytopenia and an elevation in liver transaminases. Significant cardiac toxicity has not been demonstrated. Both in vitro cell line-based studies as well as exploratory analyses of archived tumor samples from the clinical trials are seeking to understand potential mechanisms of resistance to T-DM1. Ongoing studies are also evaluating the use of T-DM1 in the first-line metastatic, neoadjuvant, and adjuvant settings, as well as in combination with other targeted therapies.ConclusionT-DM1 represents the first successfully developed antibody drug conjugate for the treatment of HER2-positive advanced breast cancer

The analysis of the relationship between organizational values and commitment with regard to the knowledge management of Kermanshah’s tax department staff

The present research has been carried out under the title of “The analysis of the relationship between organizational values and commitment with regard to the knowledge management of Kermanshah’s Tax Department staff”. The study is descriptive from the viewpoint of its aim and method of data collection.The Statistical population of this study consists of chief administrative officers, middle-ranked officers and operating officers, a total number of whom reaches 396 individuals.195 individuals were chosen as statistical samples. The means of data collection is three types of questionnaire concerning organizational values, knowledge management, and organizational commitment. The results of data analysis prove that there is a meaningful correspondence between organizational values and knowledge management but not a meaningful relationship between organizational commitment and knowledge management. Likewise, there is a correlation between the variable that predicts organizational values and the variable of knowledge management, while there is no meaningful relationship between the variable of organizational commitment and that of knowledge management. Keywords: organizational values; organizational commitment; knowledge management

Hexagonal-boron nitride substrates for electroburnt graphene nanojunctions

We examine the effect of a hexagonal boron nitride (hBN) substrate on electron transport through graphene nanojunctions just before gap formation. Junctions in vacuum and on hBN are formed using classical molecular dynamics to create initial structures, followed by relaxation using density functional theory. We find that the hBN only slightly reduces the current through the junctions at low biases. Furthermore due to quantum interference at the last moments of breaking, the current though a single carbon filament spanning the gap is found to be higher than the current through two filaments spanning the gap in parallel. This feature is present both in the presence of absence of hBN

Electron and heat transport in porphyrin-based single-molecule transistors with electro-burnt graphene electrodes

We have studied the charge and thermal transport properties of a porphyrin-based single-molecule transistor with electro-burnt graphene electrodes (EBG) using the nonequilibrium Green’s function method and density functional theory. The porphyrin-based molecule is bound to the EBG electrodes by planar aromatic anchor groups. Due to the efficient π–π overlap between the anchor groups and graphene and the location of frontier orbitals relative to the EBG Fermi energy, we predict HOMO-dominated transport. An on–off ratio as high as 150 is predicted for the device, which could be utilized with small gate voltages in the range of ±0.1 V. A positive thermopower of +280 μV/K is predicted for the device at the theoretical Fermi energy. The sign of the thermopower could be changed by tuning the Fermi energy. By gating the junction and changing the Fermi energy by +10 meV, this can be further enhanced to +475 μV/K. Although the electrodes and molecule are symmetric, the junction itself can be asymmetric due to different binding configurations at the electrodes. This can lead to rectification in the current–voltage characteristic of the junction

Oligoyne molecular junctions for efficient room temperature thermoelectric power generation

Understanding phonon transport at a molecular scale is fundamental to the development of high-performance thermoelectric materials for the conversion of waste heat into electricity. We have studied phonon and electron transport in alkane and oligoyne chains of various lengths and find that, due to the more rigid nature of the latter, the phonon thermal conductances of oligoynes are counterintuitively lower than that of the corresponding alkanes. The thermal conductance of oligoynes decreases monotonically with increasing length, whereas the thermal conductance of alkanes initially increases with length and then decreases. This difference in behavior arises from phonon filtering by the gold electrodes and disappears when higher-Debye-frequency electrodes are used. Consequently a molecule that better transmits higher-frequency phonon modes, combined with a low-Debye-frequency electrode that filters high-energy phonons is a viable strategy for suppressing phonon transmission through the molecular junctions. The low thermal conductance of oligoynes, combined with their higher thermopower and higher electrical conductance lead to a maximum thermoelectric figure of merit of ZT = 1.4, which is several orders of magnitude higher than that of alkanes

Enhancing the thermoelectric figure of merit in engineered graphene nanoribbons

We demonstrate that thermoelectric properties of graphene nanoribbons can be dramatically improved by introducing nanopores. In monolayer graphene, this increases the electronic thermoelectric figure of merit ZTe from 0.01 to 0.5. The largest values of ZTe are found when a nanopore is introduced into bilayer graphene, such that the current flows from one layer to the other via the inner surface of the pore, for which values as high as ZTe = 2.45 are obtained. All thermoelectric properties can be further enhanced by tuning the Fermi energy of the leads

Assessing Child Obesity and Physical Activity in a Hard-to-Reach Population in California's Central Valley, 2012-2013.

IntroductionIn California's agricultural Central Valley, the rate of childhood obesity is higher than the national average. Adequate physical activity contributes to obesity prevention and its assessment is useful to evaluate the impact of interventions.MethodsNiños Sanos, Familia Sana (Healthy Children, Healthy Family [NSFS]) uses community-based participatory research to implement an intervention program to reduce childhood obesity among people of Mexican origin in the Central Valley. Anthropometric measurements were conducted on more than 650 children enrolled in NSFS. Physical activity data from a subgroup of children aged 4 to 7 years (n = 134) were collected via a wearable accelerometer.ResultsChildren were classified on the basis of age and sex-adjusted body mass index as healthy weight (57.7%); overweight (19.3%), or obese (23%). Logistic regression showed that moderate to vigorous physical activity (MVPA) was associated with a child's likelihood of having a healthy BMI (odds ratio: 1.03; 95% CI, 1.01-1.05; P = .017).ConclusionNSFS's community-based participatory approach resulted in successful use of a commercial electronic device to measure physical activity quantity and quality in this hard-to-reach population. Promotion of adequate daily MVPA is an appropriate and necessary component of NSFS's childhood obesity prevention strategy

99mTc-DMSA Scintigraphy Revealed A Unilateral Multicystic Anomaly In A Horseshoe Kidney

The multicystic dysplastic pattern in a half of a horseshoe kidney is a very uncommon presentation. We present a 6-month-old male infant with a history of antenatally unilateral cystic abnormality in the right kidney which was reevaluated after birth by ultrasonography (US) and 99m Tc-DMSA scintigraphy. The US showed a horseshoe kidney with the multicystic dysplastic area on the right side, which proved to be non-functional on 99m Tc-DMSA scintigraphy

Comparison of the Effects of Concept Mapping and Conventional Teaching Methods on Critical Thinking of Nursing Students‏

Introduction: Development of critical thinking and Procedural skills has remained a serious and considerable challenge throughout the nursing educational system in Iran. Conventional methods of teaching such as lecture, as the dominant method used in higher educational systems, is a passive style which ignores critical thinking. Therefore, the aim of this study was to compare the effects of instruction by concept-mapping and conventional methods in fundamentals of nursing on critical thinking skills in Tehran nursing students in 2014. Methods: This quasi-experimental study was carried out on 70 nursing students, who were selected through convenient sampling method, then divided randomly into two equal experimental and control groups, in the Clinical Skills Center of Tehran Nursing and Midwifery School. Educational content was presented in the forms of concept-mapping for the experimental group and lecture in the control group. Data collection included a demographic information and California Critical Thinking Skills (form B) questionnaire; They were filled at the beginning and end of the fourth week of the Instructional period. Data were analyzed using SPSS software (v. 21), using descriptive and analytical statistics, at the significance level of 0.05. Results: Before the intervention, the mean of the total critical thinking skill score was 9.71 ± 2.66 in the concept mapping group and 9.64 ± 2.14 in the lecture group, and the difference was not significant (P = 0.121); but, after the intervention, the critical thinking skill score was 15.20 ± 2.71 in the intervention group and 10.25 ± 2.06 in the control group, which had a significant difference (P = 0.003). Conclusions: Using concept mapping strategy in the education of nursing students may lead to developing critical thinking skills as one of the important missions of higher level education. Therefore, it is recommended to employ this method in clinical nursing education. Keywords: Concept mapping, Critical Thinking Skills, Fundamentals of Nursing, Nursing Student