Resistance to anti-HER2 (human epithelial growth factor receptor 2) trastuzumab therapy occurs commonly in HER2-positive breast cancer and involves overactivation of HER2 and/or AKT1. Using the model ...of trastuzumab-sensitive or trastuzumab-resistant HER2-positive cells with wild-type PTEN, negative regulator of AKT1, we explore the involvement of cysteine protease calpain in mechanisms of trastuzumab resistance. Overexpression of calpain1 or activation of endogenous calpain during adhesion or trastuzumab treatment of trastuzumab-sensitive cells induces cleavage of cytoplasmic domains of HER2/phospho-HER2; cleavage occurs in HER2-positive tumors. Expression of the catalytically inactive mutant of calpain1 reduces the cleavage to enhance the activity of HER2, inactivates PTEN to enhance the activation of AKT1, induces desensitization to trastuzumab and promotes survival of trastuzumab-sensitive cells. In the model of trastuzumab resistance, constitutive overactivation of HER2 and AKT1 correlates with reduced activation of calpain. Moreover, inhibitors of the catalytic site of calpain reduce the increase in constitutive activity of AKT1 and survival of trastuzumab-resistant cells selectively. Together, by regulating the activation of HER2 and PTEN/AKT1, calpain regulates trastuzumab sensitivity and survival, and the deregulation of the activation of calpain promotes trastuzumab resistance. Trastuzumab-resistant cells activate AKT1 in a mechanism dependent on the residual calpain activity, inhibition of which restores trastuzumab sensitivity and rescues resistance. These data identify calpain as a new therapeutic target in HER2-positive breast cancer.
The aim of this study was to determine the association between occurrence and intensity of estrous expression with pregnancy success in recipient lactating dairy cows subjected to embryo transfer ...(ET). Two observational studies were conducted. Holstein cows were synchronized using the same timed ET protocol, based on estradiol and progesterone in both experiments. At 9 d after the end of the timed ET protocol only animals that had ovulated were implanted with a 7-d embryo experiment 1 (Exp. 1); n = 1,401 ET events from 1,045 cows, and experiment 2 (Exp. 2); n = 1,147 ET events from 657 cows. Embryos were produced in vivo (Exp. 1 and Exp. 2) and in vitro (only Exp. 2), then transferred to recipient cows as fresh or frozen-thawed. Pregnancy was confirmed at 29 and 58 d after the end of timed ET protocol. In Exp. 1, animals had their estrous expression monitored through a tail chalk applied on the tail head of the cows and evaluated daily for chalk removal (no estrus: 100% of chalk remaining; estrus: <50% of chalk remaining). In Exp. 2, cows were continuously monitored by a leg-mounted automated activity monitor. Estrous expression was quantified using the relative increase in physical activity at estrus in relation to the days before estrus. Estrous expression was classified as no estrus <100% relative increase in activity (RI), weak intensity (100–299% RI), and strong intensity (≥300% RI). Data were analyzed by analysis of variance using mixed linear regression models (GLIMMIX) in SAS (SAS Institute Inc.). A total of 65.2% (914/1,401) and 89.2% (1,019/1,142) of cows from Exp. 1 and Exp. 2, respectively, displayed estrus at the end of the ovulation synchronization protocol. In Exp. 1, cows expressing estrus before to ET had greater pregnancy per ET than those that did not 41.0 ± 2.3% (381/914) vs. 31.5 ± 2.9% (151/487), respectively. Similarly, in Exp. 2, cows classified in the strong intensity group had greater pregnancy per ET compared with cows in the weak intensity and no estrus groups 41.3 ± 2.2% (213/571) vs. 32.7 ± 2.7% (115/353) vs. 11.3 ± 3.5% (26/218), respectively. There was no effect of ET type on pregnancy per ET in Exp. 1. However, in Exp. 2, cows that received an in vivo-produced embryo, either fresh or frozen, had greater pregnancy per ET compared with cows that received in vitro-produced embryo. Cows receiving embryos in the early blastocyst and blastocyst stage had greater fertility compared with cows receiving embryos in the morula stage. There was an interaction between the occurrence of estrus and the stage of embryo development on pregnancy per ET, cows which displayed estrus and received a morula or early blastocyst had greater pregnancy per ET than cows that did not display estrus. In conclusion, the occurrence and the intensity of estrous expression improved pregnancy per ET in recipient lactating dairy cows and thus could be used as a tool to assist in the decision making of reproduction strategies in dairy farms.
Understanding Nature's Design for a Nanosyringe Lopez, Carlos F.; Nielsen, Steve O.; Moore, Preston B. ...
Proceedings of the National Academy of Sciences - PNAS,
03/2004, Letnik:
101, Številka:
13
Journal Article
Recenzirano
Odprti dostop
Synthetic and natural peptide assemblies can possess transport or conductance activity across biomembranes through the formation of nanopores. The fundamental mechanisms of membrane insertion ...necessary for antimicrobial or synthetic pore formation are poorly understood. We observe a lipid-assisted mechanism for passive insertion into a model membrane from molecular dynamics simulations. The assembly used in the study, a generic nanotube functionalized with hydrophilic termini, is assisted in crossing the membrane core by transleaflet lipid flips. Lipid tails occlude a purely hydrophobic nanotube. The observed insertion mechanism requirements for hydrophobic-hydrophilic matching have implications for the design of synthetic channels and antibiotics.
SuperCDMS is an experiment designed to directly detect weakly interacting massive particles (WIMPs), a favored candidate for dark matter ubiquitous in the Universe. In this Letter, we present ...WIMP-search results using a calorimetric technique we call CDMSlite, which relies on voltage-assisted Luke-Neganov amplification of the ionization energy deposited by particle interactions. The data were collected with a single 0.6 kg germanium detector running for ten live days at the Soudan Underground Laboratory. A low energy threshold of 170 eVee (electron equivalent) was obtained, which allows us to constrain new WIMP-nucleon spin-independent parameter space for WIMP masses below 6 GeV/c2.
Background
The objective of this study was to test the hypothesis that exercise would be more effective than a support group plus Fitbit (SG+Fitbit) program in improving functional outcomes in older ...breast cancer survivors (BCSs) and that race would moderate the exercise effect on outcomes.
Methods
Older African American (AA) and non‐Hispanic White (NHW) BCSs were purposively recruited and enrolled into the 52‐week randomized controlled trial. The interventions included 20 weeks of supervised moderate‐intensity aerobic and resistance training followed by 32 weeks of unsupervised exercise called IMPROVE (n = 108) and a 20‐week SG+Fitbit program followed by 32 weeks of unsupervised activity (n = 105). Study outcomes were assessed at 20 and 52 weeks. The primary outcome was the change in Short Physical Performance Battery (SPPB) scores 20 weeks from the baseline between arms. Secondary outcomes included change in the 6‐Minute Walk Test (6MWT) in meters 20 weeks from the baseline between arms. General linear regression and multivariable logistic regression analyses were used.
Results
The mean age was 71.9 years (SD, 5.9 years), and 44% were AA. SPPB scores did not differ between arms (adjusted difference in mean change, 0.13; 95% CI, –0.28 to 0.55; P = .53). However, the exercise arm (vs the SG+Fitbit arm) improved on the 6MWT (21.6 m; 95% CI, 2.5‐40.6 m; P = .03). Race moderated the exercise effect on the 6MWT (adjusted interaction effect, 43.3 m; 95% CI, 6.3‐80.2 m; P = .02); this implied that the change in the adjusted mean for the 6MWT at 20 weeks from the baseline was 43.3 m higher in AA exercise participants versus NHW exercise participants.
Conclusions
Combined aerobic and resistance exercise appears to improve physical performance in older BCSs, and the exercise effect might be moderated by race, with AAs appearing to derive larger benefits in comparison with NHWs. Larger studies are warranted to confirm the study findings.
Combined aerobic and resistance exercise appears to improve functional outcomes in older African American and non‐Hispanic White breast cancer survivors. The exercise effect might be moderated by race.
Purpose
Survivorship care is an essential component in the management of cancer patients. Optimal delivery of survivorship care requires an understanding of patient concerns and factors associated ...with treatment-related symptoms and comorbidities.
Methods
We conducted a retrospective cohort study evaluating 34 patient-reported conditions (symptoms and comorbidities) as well as self-reported health habits of stage 0–III breast cancer patients using a questionnaire completed at the time of the initial survivorship visit (SV). Logistic regression analysis was used to assess effects of treatment, age, body mass index, health habits, and timing of SV on these 34 conditions.
Results
Data from 1126 patients seen between April 2009 and November 2015 were analyzed. Hot flashes/night sweats (44%) and numbness/tingling (34%) were the most commonly reported conditions. Significant associations (
P
< 0.05) were observed with chemotherapy and increased prevalence of 26 conditions, as well as higher BMI and increased prevalence of 10 conditions. Age and timing of SV were associated (
P
< 0.05) with 20 and 17 conditions, and the direction of associations varied. Exercise was associated (
P
< 0.05) with reduced reporting of 8 conditions.
Conclusions
Symptom burden is high in this group of breast cancer survivors, particularly following chemotherapy and in those who are overweight or obese. Health concerns vary by patient age and time since treatment. Exercise appears to attenuate patient-reported concerns.
Implications for cancer survivors
Survivorship care models should account for a variety of patient needs. Survivors who are overweight or obese and those who received chemotherapy appear to be at higher risk for adverse consequences of treatment.
OMICS technologies are relatively new biomarker discovery tools that can be applied to study large sets of biological molecules. Their application in human observational studies (HOS) has become ...feasible in recent years due to a spectacular increase in the sensitivity, resolution and throughput of OMICS-based assays. Although, the number of OMICS techniques is ever expanding, the five most developed OMICS technologies are genotyping, transcriptomics, epigenomics, proteomics and metabolomics. These techniques have been applied in HOS to various extents. However, their application in occupational environmental health (OEH) research has been limited. Here, we will discuss the opportunities these new techniques provide for OEH research. In addition we will address difficulties and limitations to the interpretation of the data that is generated by OMICS technologies. To illustrate the current status of the application of OMICS in OEH research, we will provide examples of studies that used OMICS technologies to investigate human health effects of two well-known toxicants, benzene and arsenic.
This paper integrates themes from psychology and economics to analyze pro-environmental behavior. Increasingly, both disciplines share an interest in understanding internal and external influences on ...behavior. In this study, we analyze data from a mail survey of participants and non-participants in a premium-priced, green electricity program. Internal variables consist of a newly developed scale for altruistic attitudes based on the Schwartz norm-activation model, and a modified version of the New Ecological Paradigm scale to measure environmental attitudes. External variables consist of household income and standard socio-demographic characteristics. The two internal variables and two external variables are significant in a logit model of the decision to participate in the program. We then focus on participants in the program and analyze their specific motives for participating. These include motives relating to several concerns: ecosystem health, personal health, environmental quality for residents in southeastern Michigan, global warming, and warm-glow (or intrinsic) satisfaction. In a statistical ranking of the importance of each motive, a biocentric motive ranks first, an altruistic motive ranks second, and an egoistic motive ranks third.
The aim of this study was to evaluate the effect of different progesterone (P4) concentrations during the follicular growth on the intensity of estrous expression, ovarian response to the ...superovulatory treatment, and embryo production and quality in superovulated heifers. A total of 63 Holstein heifers were randomly assigned into 2 experimental groups: Low P4 (n = 31) and High P4 (n = 32). Animals received a pre-synchronization protocol followed by a protocol of superovulation that included the allocated P4 treatment. Activity was monitored continuously by an automated activity monitor, and estrus characteristics (maximum intensity and duration) were recorded. Embryo collection was performed 7 d post artificial insemination (AI). Embryos were counted and graded from good or excellent (1) to degenerated (4). The outcomes of interest were: number and diameter of follicles at the time of AI, ovulation success (confirmed 7 d post-AI), time to estrus event, maximum intensity and duration of estrus, number and quality of embryos. Data were analyzed according to the type of outcome variable using logistic, linear, or Poisson regression models. A total of 105 embryos (High P4: n = 42; Low P4: n = 63) were graded for quality. Different P4 levels did not affect the maximum intensity (High P4 = 497.8 ± 23.9%; Low P4 = 542.2 ± 23.5%) or the duration (High P4 = 13.5 ± 1.5 h; Low P4 = 14.3 ± 1.4 h) of estrus. Heifers in the High P4 treatment had greater number of follicles at time of AI (High P4 = 16.6 ± 1.6 follicles; Low P4 = 13.9 ± 1.2 follicles), but with smaller diameter (High P4 = 11.3 ± 0.1 mm; Low P4 = 12.0 ± 0.1 mm) compared with Low P4. High P4 heifers tended to have better embryo quality compared with Low P4 heifers (odds ratio = 1.98; 95% CI = 0.90-4.35). High P4 heifers had less embryos than Low P4 heifers, but this was modified by the CIDR (intravaginal implant of P4) removal to estrus interval (interval 0-21 h: mean ratio = 1.15, 95% CI = 0.42-1.87; interval 22-46 h: mean ratio = 0.58, 95% CI = 0.27-0.96). Although estrous expression was not associated with embryo quality, as the duration and the maximum intensity of estrous expression increased, the number of embryos recovered 7 d post-AI increased (duration: mean ratio = 1.04; 95% CI = 1.03-1.05; maximum intensity: mean ratio = 1.50; 95% CI = 1.42-1.58). In conclusion, P4 during the follicular growth, and intensity of estrus, are playing a role in regulating the quality and the number of embryos produced by superovulated heifers. This study was supported by contributions from Resilient Dairy Genome Project and the Natural Sciences and Engineering Research Council.
Gallbladder mucocele (GBM) is a common extra-hepatic biliary syndrome in dogs with death rates ranging from 7 to 45%. Therefore, the aim of this study was to identify the association of survival with ...variables that could be utilized to improve clinical decisions. A total of 1194 dogs with a gross and histopathological diagnosis of GBM were included from 41 veterinary referral hospitals in this retrospective study.
Dogs with GBM that demonstrated abnormal clinical signs had significantly greater odds of death than subclinical dogs in a univariable analysis (OR, 4.2; 95% CI, 2.14–8.23; P<0.001). The multivariable model indicated that categorical variables including owner recognition of jaundice (OR, 2.12; 95% CI, 1.19–3.77; P=0.011), concurrent hyperadrenocorticism (OR 1.94; 95% CI, 1.08–3.47; P=0.026), and Pomeranian breed (OR, 2.46; 95% CI 1.10–5.50; P=0.029) were associated with increased odds of death, and vomiting was associated with decreased odds of death (OR, 0.48; 95% CI, 0.30–0.72; P=0.001). Continuous variables in the multivariable model, total serum/plasma bilirubin concentration (OR, 1.03; 95% CI, 1.01–1.04; P<0.001) and age (OR, 1.17; 95% CI, 1.08–1.26; P<0.001), were associated with increased odds of death. The clinical utility of total serum/plasma bilirubin concentration as a biomarker to predict death was poor with a sensitivity of 0.61 (95% CI, 0.54–0.69) and a specificity of 0.63 (95% CI, 0.59–0.66). This study identified several prognostic variables in dogs with GBM including total serum/plasma bilirubin concentration, age, clinical signs, concurrent hyperadrenocorticism, and the Pomeranian breed. The presence of hypothyroidism or diabetes mellitus did not impact outcome in this study.
PDF
