Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular characterization of anastrozole resistance in breast cancer: Pivotal role of the Akt/mTOR pathway in the emergence of de novo or acquired resistance and importance of combining the allosteric Akt inhibitor MK‐2206 with an aromatase inhibitor

Acquisition of resistance to aromatase inhibitors (AIs) remains a major drawback in the treatment of estrogen receptor alpha (ERα)‐positive breast cancers. The Res‐Ana cells, a new model of acquired resistance to anastrozole, were established by long‐term exposure of aromatase‐overexpressing MCF‐7 cells to this drug. These resistant cells developed ER‐independent mechanisms of resistance and decreased sensitivity to the AI letrozole or to ERα antagonists. They also displayed a constitutive activation of the PI3K/Akt/mTOR pathway and a deregulated expression of several ErbB receptors. An observed increase in the phospho‐Akt/Akt ratio between primary and matched recurrent breast tumors of patients who relapsed under anastrozole adjuvant therapy also argued for a pivotal role of the Akt pathway in acquired resistance to anastrozole. Ectopic overexpression of constitutively active Akt1 in control cells was sufficient to induce de novo resistance to anastrozole. Strikingly, combining anastrozole with the highly selective and allosteric Akt inhibitor MK‐2206 or with the mTOR inhibitor rapamycin increased sensitivity to this AI in the control cells and was sufficient to overcome resistance and restore sensitivity to endocrine therapy in the resistant cells. Our findings lead to us proposing a model of anastrozole‐acquired resistance based on the selection of cancer‐initiating‐like cells possessing self‐renewing properties, intrinsic resistance to anastrozole and sensitivity to MK‐2206. Altogether, our work demonstrated that the Akt/mTOR pathway plays a key role in resistance to anastrozole and that combining anastrozole with Akt/mTOR pathway inhibitors represents a promising strategy in the clinical management of hormone‐dependent breast cancer patients.
Smad3 Inhibits Transforming Growth Factor-β and Activin Signaling by Competing with Smad4 for FAST-2 Binding*

Transcriptional regulation by transforming growth factor-β and activin is mediated by interaction of Smad2 and Smad3 with specific transcription factors and/or DNA elements. However, Smad3 behaves differently from Smad2 in regulating transcription by a winged-helix transcription factor, FAST-2, on an activin-responsive element (ARE) in the Xenopus Mix.2 promoter. Smad3 alone was able to stimulate the ARE through FAST-2, but inhibited the ARE transactivation mediated by Smad2/Smad4 following receptor activation. We characterized the functional domains that are involved in these two activities of Smad3. Deletion of the MH1 domain as well as mutations of four lysine residues in the MH1 domain abrogated the inhibitory activity of Smad3, but did not compromise the self-stimulatory function. In contrast, deletion of the MH2 domain or a point mutation of glycine 379 within this domain obliterated the self-stimulatory activity of Smad3, but not the inhibitory activity. In an electrophoretic mobility shift assay, we found that Smad3 was able to associate with the FAST-2·ARE complex and that this association was dependent on FAST-2. In addition, Smad3 was not able to directly bind the ARE in a DNase I protection assay, in which FAST-2 binds the ARE around a motif (TGTGTATT) previously characterized to associate with the human FAST-1 protein. Interestingly, Smad4 was also able to directly associate with the FAST-2·ARE complex through binding with FAST-2. In a gel shift assay, the association of FAST-2 with Smad4 was mutually exclusive from the association with Smad3. Taken together, these data indicate that Smad3 exerts the inhibitory activity by competitive association with FAST-2.
Mdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53*

Mdm2 has been shown to regulate p53 stability by targeting the p53 protein for proteasomal degradation. We now report that Mdm2 is a ubiquitin protein ligase (E3) for p53 and that its activity is dependent on its RING finger. Furthermore, we show that Mdm2 mediates its own ubiquitination in a RING finger-dependent manner, which requires no eukaryotic proteins other than ubiquitin-activating enzyme (E1) and an ubiquitin-conjugating enzyme (E2). It is apparent, therefore, that Mdm2 manifests an intrinsic capacity to mediate ubiquitination. Mutation of putative zinc coordination residues abrogated this activity, as did chelation of divalent cations. After cation chelation, the full activity could be restored by addition of zinc. We further demonstrate that the degradation of p53 and Mdm2 in cells requires additional potential zinc-coordinating residues beyond those required for the intrinsic activity of Mdm2 in vitro. Replacement of the Mdm2 RING with that of another protein (Praja1) reconstituted ubiquitination and proteasomal degradation of Mdm2. However, this RING was ineffective in ubiquitination and proteasomal targeting of p53, suggesting that there may be specificity at the level of the RING in the recognition of heterologous substrates.
Neuroprotective effect of hypothermia at defined intraischemic time courses in cortical cultures

Many experimental and clinical studies have shown that hypothermia confers cerebroprotective benefits against ischemic insults. Because of the many conflicting reports on hypothermic neuroprotection, we undertook this cellular study to identify the optimal temperature or a range of temperatures for maximal neuroprotection at different times (6–24 hr) during ischemic insults. Cultured Wistar rat cortical neurons were exposed to oxygen deprivation at defined times and temperatures (37°C normothermia, 32°C mild hypothermia, 27°C moderate hypothermia, 22°C deep hypothermia, and 17°C profound hypothermia). The survival rate of neurons was evaluated by assessing viable neurons on photomicrographs. The normothermic group demonstrated a significantly lower survival rate of cultured neurons (6 hr, 80.3% ± 2.7%; 12 hr, 56.1% ± 2.1%; 18 hr, 34.2% ± 1%; 24 hr, 18.1% ± 2.2%) compared to hypothermic groups (P < 0.001). The survival rate for the profound hypothermic group was significantly reduced (P < 0.01) compared to other hypothermic groups (at 17°C: 12 hr, 85.9% ± 2.5%, 18 hr, 74.7% ± 3.7%, 24 hr, 58.7% ± 2.7%). Almost equal survival rates were observed among mild, moderate, and deep hypothermic groups following <18 hr exposure to hypoxia, but the deep hypothermic group showed a significantly higher survival rate (84.1% ± 1.6%; P < 0.001) when subjected to hypoxia for 24 hr. In conclusion, hypothermia offers marked neuroprotection against hypoxia, but attenuation of neuronal cell death was less with profound hypothermia compared to mild, moderate, and deep hypothermia. Deep hypothermia affords maximal protection of neurons compared to mild and moderate hypothermia during long‐lasting hypoxia (>18 hr). J. Neurosci. Res. 65:583–590, 2001. © 2001 Wiley‐Liss, Inc.
Pharmacogenetic study of atypical antipsychotic drug response: Involvement of the norepinephrine transporter gene

The identification of genetic factors underlying individual differences in antipsychotic drug response is of major interest. We investigated the involvement of two norepinephrine transporter gene polymorphisms in response to antipychotics, comparing patients with strong and weak response to olanzapine and risperidone. We prospectively assessed short‐term drug response in 75 Caucasian schizophrenic patients treated with these drugs, using the Positive and Negative Syndrome Scale. We then assessed the association between two SLC6A2 gene polymorphisms and drug response in this sample. No significant difference in genotype distribution was found between responders and non‐responders, for the G1287A or T‐182C polymorphism. The improvement in PANSS positive subscore was significantly greater in patients homozygous for the A1287 allele than in other patients, and significantly smaller in patients homozygous for the C‐182 allele than in other patients. Our results suggest that these polymorphisms are specifically involved in the variation of positive symptoms in schizophrenic patients. © 2007 Wiley‐Liss, Inc.
Incidence of retinoblastoma in the USA: 1975–2004

Background: The purpose of this study was to determine the age-adjusted incidence of retinoblastoma in the USA over a 30-year period from 1975 to 2004 using a review of existing databases. Methods: Six hundred and fifty-eight patients with retinoblastoma (International Classification of Oncology (ICDO-3) codes C69.2 (retina) and C69.9 (eye, NOS)) were derived from the Surveillance, Epidemiology, and End Results (SEER) program database in the USA from 1975 to 2004. Nine historical SEER registries were utilised. The significance of trend in age-adjusted incidence rate was determined using the χ2 test, and 95% CIs were calculated. The patients were stratified according to age at diagnosis, laterality, gender and race. Results: There were a total of 658 cases of retinoblastoma, representing 6.1% of all childhood cancers under age 5 years. The mean age-adjusted incidence of retinoblastoma in the USA was 11.8 per million children aged 0–4 years (95% CI 10.9 to 12.8). There was no significant trend in age-adjusted incidence for all races/genders, nor was there any significant variation of incidence between races or between genders. The proportion of bilateral cases (26.7%) versus unilateral cases (71.9%) remained stable over the 30-year period. Conclusions: The mean age-adjusted incidence rate of retinoblastoma of 11.8 cases per million children aged 0–4 years in the USA is similar to rates reported from European countries. The age-adjusted incidence rate of retinoblastoma in the USA has remained stable for the last 30 years.
Enhanced Lycopene Productivity by Manipulation of Carbon Flow to Isopentenyl Diphosphate in Escherichia coli

Lycopene is a useful phytochemical that holds great commercial value. In our study the lycopene production pathway in E. coli originating from the precursor isopentenyl diphosphate (IPP) of the non‐mevalonate pathway was reconstructed. This engineered strain of E. coli accumulated lycopene intracellularly under aerobic conditions. As a next step, the production of lycopene was enhanced through metabolic engineering methodologies. Various competing pathways at the pyruvate and acetyl‐CoA nodes were inactivated to divert more carbon flux to IPP and subsequently to lycopene. It was found that the ackA‐pta, nuo mutant produced a higher amount of lycopene compared to the parent strain. To further enhance lycopene production, a novel mevalonate pathway, in addition to the already existing non‐mevalonate pathway, was engineered. This pathway utilizes acetyl‐CoA as precursor, condensing it to form acetoacetyl‐CoA and subsequently leading to formation of IPP. Upon the introduction of this new pathway, lycopene production increased by over 2‐fold compared to the ackA‐pta, nuo mutant strain.
Defective propeptide processing and abnormal activation underlie the molecular pathology of factor IX Troed‐y‐Rhiw

Summary. Affected members of a South Wales haemophilia B family (from Troed‐y‐Rhiw) were shown by Western blotting and immunoperoxidase detection to have a factor IX molecule of higher than normal molecular weight which also shows impaired calcium binding. Gene cloning and DNA sequencing revealed the same arginine to glutamine mutation at position ‐ 4 of the propeptide that has been found in two previously described factor IX variants which circulate with the propeptide still attached. The mutation also abolishes a HaeIII restriction enzyme recognition site. A potential carrier was shown to be normal both by Western blotting and DNA studies. The way in which the attached propeptide interferes with normal factor IX function was investigated by activation studies with crude normal and patient factor IX Troed‐y‐Rhiw preparations using Western blotting and detection with iodinated immunopurified polyclonal anti‐factor IX serum. We demonstrate that the −4 mutation appears to block cleavage between the Arg 145‐Ala146 peptide bond in the activation peptide, thus preventing the normal activation of factor IX Troed‐y‐Rhiw. A small amount of normally processed factor IX is produced, implying that the −4 mutation does not completely prevent propeptide cleavage, thus accounting for the low levels of factor IX activity measured in the plasma of affected family members.
A hybrid approach for mobile security threat analysis

Research on effective and efficient mobile threat analysis becomes an emerging and important topic in cybersecurity research area. Static analysis and dynamic analysis constitute two of the most popular types of techniques for security analysis and evaluation; nevertheless, each of them has its strengths and weaknesses. To leverage the benefits of both approaches, we propose a hybrid approach that integrates the static and dynamic analysis for detecting security threats in mobile applications. The key of this approach is the unification of data states and software execution on critical test paths. The approach consists of two phases. In the first phase, a pilot static analysis is conducted to identify potential critical attack paths based on Android APIs and existing attack patterns. In the second phase, a dynamic analysis follows the identified critical paths to execute the program in a limited and focused manner. Attacks shall be detected by checking the conformance of the detected paths with existing attack patterns. The method will report the types of detected attack scenarios based on types of sensitive data that may be compromised, such as web browser cookie.
Validity and Reliability of Agility Tests in Junior Australian Football Players

Young, W, Farrow, D, Pyne, D, McGregor, W, and Handke, T. Validity and reliability of agility tests in junior Australian football players. J Strength Cond Res 25(12): 3399–3403, 2011—The importance of sport-specific stimuli in reactive agility tests (RATs) compared to other agility tests is not known. The purpose of this research was to determine the validity and reliability of agility tests. Fifty junior Australian football players aged 15–17 years, members of either an elite junior squad (n = 35) or a secondary school team (n = 15), were assessed on a new RAT that involved a change of direction sprint in response to the movements of an attacking player projected in life size on a screen. These players also underwent the planned Australian Football League agility test, and a subgroup (n = 13) underwent a test requiring a change of direction in response to a left or right arrow stimulus. The elite players were significantly better than the school group players on the RAT (2.81 ± 0.08 seconds, 3.07 ± 0.12 seconds; difference 8.5%) but not in the arrow stimulus test or planned agility test. The data were log transformed and the reliability of the new RAT estimated using typical error (TE) expressed as a coefficient of variation. The TE for the RAT was 2.7% (2.0–4.3, 90% confidence interval) or 0.07 seconds (0.5–1.0), with an intraclass correlation coefficient (ICC) of 0.33. For the test using the arrow stimulus, the TE was 3.4% (2.4–6.2), 0.09 (0.06–0.15) seconds, and ICC was 0.10. The sport-specific stimulus provided by the new RAT is a crucial component of an agility test; however, adoption of the new RAT for routine testing is likely to require more accessible equipment and several familiarization trials to improve its reliability.
Moebius syndrome: a review of the anaesthetic implications

Moebius syndrome is a rare congenital anomaly characterized by multiple cranial nerve palsies, orofacial malformations and limb anomalies. This study retrospectively reviewed the anaesthetic records of 19 children with Moebius syndrome who had anaesthesia at the Royal Alexandra Hospital for Children over a 15 year period and analysed the complications which occurred. Affected children most commonly present for anaesthesia for correction of strabismus, or for orthopaedic procedures to improve limb function. Despite the abnormal facies and drooling of saliva, these children are almost always of normal intelligence. Problems can arise during anaesthesia, with a high incidence of difficult or failed intubation. The use of a facemask and spontaneous breathing technique, where appropriate, seems to present no problems and maintaining an airway in this way appears to be safe. However, the potential for problems with aspiration of oral secretions should be remembered and the use of antisialogogue premedication is recommended. Affected children have a high incidence of other anomalies, including congenital cardiac disease, spinal anomalies, corneal abrasions and peripheral neuropathies and a careful preoperative assessment is essential.
Asymmetric Dimethylarginine and Augmentation Index in Newly Diagnosed Patients With Hypertension

Pulse wave velocity (PWV), augmentation index (Aix), and central aortic pressure (CAP) are arterial stiffness markers of endothelial dysfunction (ED). We investigated the relationship between arterial stiffness parameters and asymmetric dimethylarginine (ADMA; a marker of ED), in newly diagnosed patients with hypertension (n = 101; 61 females). These patients were investigated in accordance with the recommendations of hypertension guidelines. Arterial stiffness was measured, and serum ADMA and C-reactive protein (CRP; a marker of inflammation) levels were determined. In both women and men, there was no difference in terms of age, body mass index, systolic and diastolic blood pressures, PWV, CAP and the levels of ADMA, while Aix and CRP levels were significantly higher in women (P = .004, P = .046, respectively). In the whole group, ADMA levels correlated with Aix (Pearson r = .237, P = .024). Our findings provide further evidence of a link between arterial stiffness and ED in newly diagnosed patients with hypertension.
Ultrasound texture analysis: Association with lymph node metastasis of papillary thyroid microcarcinoma

This retrospective study aimed to evaluate whether ultrasound texture analysis is useful to predict lymph node metastasis in patients with papillary thyroid microcarcinoma (PTMC). This study was approved by the Institutional Review Board, and the need to obtain informed consent was waived. Between May and July 2013, 361 patients (mean age, 43.8 ± 11.3 years; range, 16–72 years) who underwent staging ultrasound (US) and subsequent thyroidectomy for conventional PTMC ≤ 10 mm between May and July 2013 were included. Each PTMC was manually segmented and its histogram parameters (Mean, Standard deviation, Skewness, Kurtosis, and Entropy) were extracted with Matlab software. The mean values of histogram parameters and clinical and US features were compared according to lymph node metastasis using the independent t-test and Chi-square test. Multivariate logistic regression analysis was performed to identify the independent factors associated with lymph node metastasis. Tumors with lymph node metastasis (n = 117) had significantly higher entropy compared to those without lymph node metastasis (n = 244) (mean±standard deviation, 6.268±0.407 vs. 6.171±.0.405; P = .035). No additional histogram parameters showed differences in mean values according to lymph node metastasis. Entropy was not independently associated with lymph node metastasis on multivariate logistic regression analysis (Odds ratio, 0.977 [95% confidence interval (CI), 0.482–1.980]; P = . 949). Younger age (Odds ratio, 0.962 [95% CI, 0.940–0.984]; P = .001) and lymph node metastasis on US (Odds ratio, 7.325 [95% CI, 3.573–15.020]; P < .001) were independently associated with lymph node metastasis. Texture analysis was not useful in predicting lymph node metastasis in patients with PTMC.
Depression and cognitive function in maintenance hemodialysis patients.

BACKGROUND Both depression and cognitive impairment are common in hemodialysis patients, are associated with adverse clinical outcomes, and place an increased burden on health care resources. STUDY DESIGN Cross-sectional cohort. SETTING & PARTICIPANTS 241 maintenance hemodialysis patients in the Boston, MA, area. PREDICTOR Depressive symptoms, defined as a Center for Epidemiological Studies Depression Scale (CES-D) score ≥16. OUTCOME Performance on a detailed neurocognitive battery. RESULTS Mean age was 63.8 years, 49.0% were women, 21.6% were African American, and median dialysis therapy duration was 13.8 months. There were 57 (23.7%) participants with significant depressive symptoms. In multivariable analysis adjusting for age, sex, education, and other comorbid conditions, participants with and without depressive symptoms performed similarly on the Mini-Mental State Examination (P = 0.4) and tests of memory. However, participants with greater depressive symptoms performed significantly worse on tests assessing processing speed, attention, and executive function, including Trail Making Test B (P = 0.02) and Digit-Symbol Coding (P = 0.01). Defining depression using a CES-D score ≥18 did not substantially change results. LIMITATIONS Cross-sectional design, absence of brain imaging. CONCLUSIONS Hemodialysis patients with a greater burden of depressive symptoms perform worse on tests of cognition related to processing speed and executive function. Further research is needed to assess the effects of treating depressive symptoms on cognitive performance in dialysis patients.
In-Situ Method for TSV Delay Testing and Characterization Using Input Sensitivity Analysis

In this paper, we propose a method and the required architecture for characterizing the propagation delays of the through Silicon vias (TSVs) in a 3-D IC. First of all, every two TSVs are paired up to form an oscillation ring with some peripheral circuits. Their joint performance can thus be measured roughly by the oscillation period of the ring. Next, we utilize a technique called sensitivity analysis to further derive the propagation delay of each individual TSV participating in an oscillation ring-a distilling process. In this process, we perturb the strength of the two TSV drivers, and then measure their effects in terms of the change of the oscillation ring's period. By some following analysis, the propagation delay of each TSV can be revealed. On top of scheme, we also present an architecture that can activate the performance characterization process of each test unit - that consists of two TSVs - one at a time in a proper sequence. The area overhead is only 18.97 equivalent two-input NAND gate per TSV, by which one can gain the ability to profile the capacitances and the propagation delays of the TSVs on a 3-D IC.
Localization and Quantification of Carbonic Anhydrase Activity in the Symbiotic Scyphozoan Cassiopea xamachana

The relationship between density and location of zooxanthellae and levels of carbonic anhydrase (CA) activity was examined in Cassiopea xamachana. In freshly collected symbiotic animals, high densities of zooxanthellae corresponded with high levels of CA activity in host bell and oral arm tissues. Bleaching resulted in a significant loss of zooxanthellae and CA activity. Recolonization resulted in full restoration of zooxanthellar densities but only partial restoration of CA activity. High levels of CA activity were also seen in structures with inherently higher zooxanthellar densities, such as oral arm tissues. Similarly, the oral epidermal layer of bell tissue had significantly higher zooxanthellar densities and levels of CA activity than did aboral bell tissues. Fluorescent labeling, using 5-dimethylaminonapthalene-1-sulfonamide (DNSA) also reflected this tight-knit relationship between the presence and density of zooxanthellae, as DNSA-CA fluorescence intensity was greatest in host oral epithelial cells directly overlying zooxanthellae. However, the presence and density of zooxanthellae did not always correspond with enzyme activity levels. A transect of bell tissue from the margin to the manubrium revealed a gradient of CA activity, with the highest values at the bell margin and the lowest at the manubrium, despite an even distribution of zooxanthellae. Thus, abiotic factors may also influence the distribution of CA and the levels of CA activity.