Miracle-dz/UniFAR-FTUs huggingface dataset:
Update on clinical role of tamoxifen

Purpose of review Breast cancer is the most common malignancy amongst women in the United States and decreased mortality over the past decade has been attributed to a combination of screening and adjuvant therapies. There has been a resurgence of interest in hormonal therapies and this article discusses the clinical status of tamoxifen in the context of emerging alternative agents for treatment and prevention of breast cancer. Recent findings Tamoxifen has served as a prototype for the development of selective estrogen receptor modulators at the laboratory-clinical interface. Molecular technologies have permitted elucidation of mechanisms for tissue specific action and led to newer selective estrogen receptor modulators with potentially greater antitumour efficacy and attenuated uterotrophic profile. Publications over the past 12 months have emphasized the risks of thromboembolism and endometrial carcinoma associated with tamoxifen use which has accelerated application of other hormonal agents for treatment of advanced disease and as neoadjuvant therapy. This article reviews the current role of tamoxifen in the treatment of early and advanced breast cancer together with its potential for chemoprevention. Models for quantitative risk assessment are being developed to identify women for whom chemoprotection is justified. Summary Recent data showing a survival advantage for the aromatase inhibitor letrozole compared with tamoxifen in the advanced setting and improvement in disease-free survival for the aromatase inhibitor anastrozole versus tamoxifen as adjuvant treatment may herald a major shift in standard first-line endocrine therapies for both advanced and early disease and ultimately chemoprevention of breast cancer. Other agents including newer SERMs and pure antiestrogens are undergoing phase III clinical trials and future endocrine and biological therapies are likely to include more selective and targeted therapies, which may be efficacious in both hormone-sensitive and receptor-negative disease.
New Host Factors Important for Respiratory Syncytial Virus (RSV) Replication Revealed by a Novel Microfluidics Screen for Interactors of Matrix (M) Protein*

Although human respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia in infants and elderly worldwide, there is no licensed RSV vaccine or effective drug treatment available. The RSV Matrix protein plays key roles in virus life cycle, being found in the nucleus early in infection in a transcriptional inhibitory role, and later localizing in viral inclusion bodies before coordinating viral assembly and budding at the plasma membrane. In this study, we used a novel, high throughput microfluidics platform and custom human open reading frame library to identify novel host cell binding partners of RSV matrix. Novel interactors identified included proteins involved in host transcription regulation, the innate immunity response, cytoskeletal regulation, membrane remodeling, and cellular trafficking. A number of these interactions were confirmed by immunoprecipitation and cellular colocalization approaches. Importantly, the physiological significance of matrix interaction with the actin-binding protein cofilin 1, caveolae protein Caveolin 2, and the zinc finger protein ZNF502 was confirmed. siRNA knockdown of the host protein levels resulted in reduced RSV virus production in infected cells. These results have important implications for future antiviral strategies aimed at targets of RSV matrix in the host cell.
Exercise reveals impairments in left ventricular systolic function in patients with metabolic syndrome

• What is the central question of this study? Metabolic syndrome (MetS) is associated with a threefold increase in risk of cardiovascular disease mortality, which may be mediated, in part, by impaired left ventricular systolic function. The severity of left ventricular and arterial dysfunction during dynamic exercise in individuals with MetS without diabetes and/or overt cardiovascular disease has not previously been explored. • What is the main finding and its importance? Cardiovascular function was characterized at rest and during peak exercise using echocardiography and gas exchange. During exercise, individuals with MetS displayed impaired left ventricular contractility, a blunted arterial–ventricular coupling reserve and limited aerobic capacity. These findings provide insight into the pathophysiological changes that may occur to predispose individuals with MetS to an increased risk of cardiovascular disease.
A Prospective Cost-Effectiveness Study of Trigeminal Neuralgia Surgery

Objectives:Approximately 8000 patients with trigeminal neuralgia undergo surgery each year in the United States at an estimated cost exceeding $100 million. We compared 3 commonly performed surgeries (microvascular decompression, glycerol rhizotomy, and stereotactic radiosurgery) to evaluate the relative cost-effectiveness of these operations for patients with idiopathic trigeminal neuralgia. Methods:Prospective nonrandomized trial at a tertiary referral center from July 1999 to December 2001. One hundred twenty-six consecutive patients underwent 153 operations (microvascular decompression, n = 33; glycerol rhizotomy, n = 51; stereotactic radiosurgery, n = 69). Preoperative characteristics were similar between the groups with respect to sex, pain location, duration of pain, and atypical features. Facial pain outcomes were classified as excellent (no pain, no medications), good (no pain, reduced medications), fair (>50% pain reduction), and poor. The cost per quality adjusted pain-free year was compared between the groups. Mean follow-up was 20.6 months. Results:Patients having microvascular decompression more commonly achieved and maintained an excellent outcome (85% and 78% at 6 and 24 months) compared with glycerol rhizotomy (61% and 55%, P = 0.01) and stereotactic radiosurgery (60% and 52%, P < 0.01). No difference was detected between glycerol rhizotomy and stereotactic radiosurgery (P = 0.61). The cost per quality adjusted pain-free year was $6,342, $8,174, and $8,269 for glycerol rhizotomy, microvascular decompression, and stereotactic radiosurgery, respectively. Reduction in the average cost of morbidity and additional surgeries to zero did not make either microvascular decompression or stereotactic radiosurgery more cost-effective than glycerol rhizotomy. Both microvascular decompression and stereotactic radiosurgery would be more cost-effective than glycerol rhizotomy if the cost of additional surgeries after glycerol rhizotomy increased 79% and 83%, respectively. Discussion:This analysis supports the practice of percutaneous surgeries for older patients with medically unresponsive trigeminal neuralgia. At longer follow-up intervals, microvascular decompression is predicted to be the most cost-effective surgery and should be considered the preferred operation for patients if their risk for general anesthesia is acceptable. More data are needed to assess the role that radiosurgery should play in the management of patients with trigeminal neuralgia.
The CareFile Project: a feasibility study to examine the effects of an individualised information booklet on patients after stroke.

INTRODUCTION patients have reported a lack of knowledge and understanding of stroke and its risk factors. Uncertainty remains about the most appropriate and effective method of educating patients after stroke. OBJECTIVE to assess the impact of the CareFile, an individualized information booklet, on patients' knowledge and satisfaction level after stroke. DESIGN randomised pilot study for a controlled trial. SETTING a large teaching hospital in Liverpool, UK. METHODS consecutive stroke patients admitted over a 9-month period, who met the inclusion criteria and consented to participate, were randomised into this study. All patients received the usual stroke information leaflets provided by the stroke unit. In addition, the intervention group received the ;CareFile', a booklet containing general information and patient-specific information on stroke. Patients in both groups completed a stroke knowledge questionnaire at baseline, and at three and six months post-stroke. RESULTS of the 259 admissions, 100 were eligible to participate, and 50 were randomised to each group. There was no significant difference in patient knowledge between the groups at baseline (P>0.05). However, at three (P<0.05) and six (P<0.005) months post-stroke, the intervention group had significantly better knowledge of stroke. There were no differences between the groups regarding satisfaction with the information received. CONCLUSIONS a simple education package, in the form of an individualized information booklet, resulted in a significant improvement in knowledge and recognition of risk factors for stroke. The CareFile should make a valuable contribution in meeting the requirements of the National Sentinel Audit and National Service Framework regarding provision of information to patients after stroke.
Lyme Disease: Clinical Features, Classification, and Epidemiology in the Upper Midwest

Lyme disease can be classified using the terminology of syphilis. In this series of 95 cases from the upper midwest, early cases, defined as an illness of less than 2 months, were more likely to have lived in or recently visited a highly endemic area. Unlike late cases, early cases presented entirely in the nonwinter months (p less than .001). Early disease was further subdivided into primary and secondary disease. Ninety percent of primary and 43% of secondary cases had erythema migrans, while no late cases had active erythema migrans (p less than .001). Clinical manifestations of nonspecific inflammation, except for arthralgia, were more common in early than late disease (p less than .01). In secondary cases, monoarticular arthritis was slightly more common than polyarticular arthritis, with the reverse occurring in late disease (p less than .05). Indirect fluorescent antibody testing revealed a ratio of IgM to IgG antibodies to be helpful in distinguishing early from late disease. Antibacterial therapy in early, primary cases caused Jarisch-Herxheimer reaction 7% of the time. Despite longer and more frequent parenteral therapy, late Lyme disease frequently required retreatment, owing to poor clinical response (p less than .05).
Systematic review of the survival rate and the biological, technical, and aesthetic complications of fixed dental prostheses with cantilevers on implants reported in longitudinal studies with a mean of 5 years follow-up.

OBJECTIVE A systematic review was carried out to evaluate the success and survival rate of implants supporting cantilever prosthesis, as well as the incidence of technical and biological complications. MATERIAL AND METHODS A MEDLINE search was conducted up to December 2011 for studies with a mean follow-up of 5 years or more. Two independent reviewers screened the retrieved articles and extracted the data independently. Data on survival, failure, mechanical/technical and biological complications were analyzed. RESULTS One-hundred and sixty articles were selected as abstract. Only 18 underwent a full-text analysis and only six were included in the study. The estimated cumulative survival rate of implants supporting cantilevered prosthesis was 98.9% (95% CI: 97.4-99.5%), whereas ICFDP survival was estimated to be about 97.1% (95% CI: 90.1-99.2%). Implant failures before prosthetic delivery were not considered. Biological complications were estimated to be 5.7% (95% CI: 4.2-7.6%) at implant level after 5 years. Technical complications were analyzed: the most common complications were veneer fractures (5-year estimate: 10.1%; 95% CI: 3.7-16.5%) and abutment screw fractures (5-year estimate: 1.6%; 95% CI: 0.8-3.5%). Decementation and screw loosening were estimated to be at 5 years 5.9% (95% CI: 1.7-16.8%) and 7.9% (95% CI: 3.2-18.2%), respectively. Implant fracture was rare (5-year estimate: 0.7%; 95% CI: 0.1-4.7%); no framework fracture was reported. Radiographic bone level changes did not yield statistically significant differences. No aesthetic outcome was reported. CONCLUSIONS ICFDPS can be considered a reliable treatment: the systematic review assessed that there is no increase in complication rate due to the presence of the cantilever.
Nipple fluid carcinoembryonic antigen and prostate-specific antigen in cancer-bearing and tumor-free breasts.

PURPOSE Mammograms and breast examinations are established methods for early breast cancer detection. Routine mammography screening reduces breast cancer mortality among women ages > or = 50 years, but additional screening methods are needed. We and others have found high levels of carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA) in nipple aspirate fluids (NAFs), but the usefulness for these bio-markers for early breast cancer detection is unknown. PATIENTS AND METHODS NAFs from one or both breasts of 388 women were analyzed for CEA, PSA, and albumin levels. The study included 44 women with newly diagnosed invasive breast cancers, 67 women with proliferative breast lesions (ductal and lobular carcinoma in situ and atypical ductal hyperplasia), and 277 controls without these breast lesions. Analyses were conducted using the log(10)-transformed CEA and PSA levels to normalize the distributions of these tumor markers. RESULTS Nipple fluid CEAs are significantly higher for cancerous breasts than tumor-free breasts (median 1,830 and 1,400 ng/mL, respectively; P <.01). However, at 90% specificity of the assay (CEA = 11,750 ng/mL), the corresponding sensitivity for cancer detection is 32%. CEA levels are not significantly different for breasts with proliferative lesions compared with tumor-free breasts. Nipple fluid PSAs do not differ by tumor status. Analyses of NAF albumin-standardized CEAs and PSAs yield similar results. Nipple fluid CEA and PSA titers are correlated in the affected and unaffected breast of women with unilateral lesions. CONCLUSION Nipple fluid CEAs are higher for breasts with untreated invasive cancers, but the test sensitivity is low. Nipple fluid PSA titers do not seem to be useful for breast cancer detection.
Emancipación y participación ciudadana de mujeres de una zona urbana con necesidades de transformación social

Se describe el proceso emancipador por el que las mujeres oprimidas de una zona urbana con necesidades de transformacion social de Sevilla desarrollan conciencia critica y asercion para exigir su autodeterminacion, asi como habilidades para participar en la toma de decisiones y el reparto de los recursos. Siguiendo las propuestas de Kieffer (1984), el Area de Igualdad del Ayuntamiento de Sevilla, llevo a cabo un proceso de investigacion-accion participativa cuyos resultados mas sobresalientes fueron: a) muchas mujeres adquirieron conciencia critica y competencia participativa, b) constituyeron asociaciones de mujeres orientadas a promover la igualdad en los procesos de cambio social, y c) realizaron cambios efectivos en el barrio, tales como un centro comunitario, la implementacion de programas de fomento de empleo para mujeres y de respiro a familiares cuidadoras de personas dependientes. Ademas, constituyeron coaliciones con otras asociaciones de mujeres de la ciudad para realizar campanas de sensibilizacion contra la violencia de genero.
Endothelial dysfunction predicts clinical restenosis after percutaneous coronary intervention

Abstract Background. Endothelial dysfunction is associated with increased risk for cardiovascular events in patients with coronary artery disease and may predict in-stent restenosis after percutaneous coronary intervention. We evaluated if endothelial dysfunction could predict clinical and angiographic restenosis in patients after percutaneous coronary intervention with stent implantation for angina pectoris or acute coronary syndrome. Methods. One hundred patients were consecutively included after successful percutaneous coronary intervention with stenting for angiographic single vessel disease. All patients were evaluated with ultrasound detection of brachial artery reactivity at four weeks and with a symptom limited exercise stress test at six months and were followed for the occurrence of clinical or angiographic restenosis for 18 ± 6 months. Results. Twenty patients showed clinical signs of restenosis during 18 months follow-up and were referred to re-angiography. Patients with clinical restenosis had impaired flow mediated vasodilation compared to patients without clinical restenosis (5.8 ± 3.4 vs. 9.0 ± 4.8, p = 0.005). In multivariate analysis flow mediated vasodilation was the only independent predictor for the risk of clinical restenosis (OR 4.5, 95% CI 1.11 to 17.8). Conclusions. Impaired flow mediated vasodilation four weeks after percutaneous coronary intervention independently predicts the risk of clinical restenosis. Trial registration: ClinicalTrials.gov identifier: NCT00999323.
The motor origins of human and avian song structure

Human song exhibits great structural diversity, yet certain aspects of melodic shape (how pitch is patterned over time) are widespread. These include a predominance of arch-shaped and descending melodic contours in musical phrases, a tendency for phrase-final notes to be relatively long, and a bias toward small pitch movements between adjacent notes in a melody [Huron D (2006) Sweet Anticipation: Music and the Psychology of Expectation (MIT Press, Cambridge, MA)]. What is the origin of these features? We hypothesize that they stem from motor constraints on song production (i.e., the energetic efficiency of their underlying motor actions) rather than being innately specified. One prediction of this hypothesis is that any animals subject to similar motor constraints on song will exhibit similar melodic shapes, no matter how distantly related those animals are to humans. Conversely, animals who do not share similar motor constraints on song will not exhibit convergent melodic shapes. Birds provide an ideal case for testing these predictions, because their peripheral mechanisms of song production have both notable similarities and differences from human vocal mechanisms [Riede T, Goller F (2010) Brain Lang 115:69–80]. We use these similarities and differences to make specific predictions about shared and distinct features of human and avian song structure and find that these predictions are confirmed by empirical analysis of diverse human and avian song samples.
EngagedScholarship@CSU EngagedScholarship@CSU

Trypanosoma brucei causes human African try-panosomiasis and regularly switches its major surface antigen, VSG, thereby evading the host’s immune response. VSGs are monoallelically expressed from subtelomeric expression sites (ESs), and VSG switching exploits subtelomere plasticity. However, subtelomere integrity is essential for T. brucei viability. The telomeric transcript, TERRA, was detected in T. brucei previously. We now show that the active ES-adjacent telomere is transcribed. We ﬁnd that TbRAP1, a telomere protein essential for VSG silencing, suppresses VSG gene conversion-mediated switching. Importantly, TbRAP1 depletion increases the TERRA level, which appears to result from longer read-through into the telomere downstream of the active ES. Depletion of TbRAP1 also results in more telomeric RNA:DNA hybrids and more double strand breaks (DSBs) at telomeres and subtelomeres. In TbRAP1-depleted cells, expression of excessive TbRNaseH1, which cleaves the RNA strand of the RNA:DNA hybrid, brought telomeric RNA:DNA hybrids, telomeric / subtelomeric DSBs and VSG switching frequency back to WT levels. Therefore, TbRAP1-regulated appropriate levels of TERRA and telomeric RNA:DNA hybrid are fundamental to subtelomere / telomere integrity. Our study revealed for the ﬁrst time an important role of a long, non-coding RNA in antigenic variation and demonstrated a link between telomeric silencing and subtelomere / telomere integrity through TbRAP1-regulated telomere transcription
Can the propensity of protein crystallization be increased by using systematic screening with metals?

Protein crystallization is one of the major bottlenecks in protein structure elucidation with new strategies being constantly developed to improve the chances of crystallization. Generally, well‐ordered epitopes possessing complementary surface and capable of producing stable inter‐protein interactions generate a regular three‐dimensional arrangement of protein molecules which eventually results in a crystal lattice. Metals, when used for crystallization, with their various coordination numbers and geometries, can generate such epitopes mediating protein oligomerization and/or establish crystal contacts. Some examples of metal‐mediated oligomerization and crystallization together with our experience on metal‐mediated crystallization of a putative rRNA methyltransferase from Sinorhizobium meliloti are presented. Analysis of crystal structures from protein data bank (PDB) using a non‐redundant data set with a 90% identity cutoff, reveals that around 67% of proteins contain at least one metal ion, with ∼14% containing combination of metal ions. Interestingly, metal containing conditions in most commercially available and popular crystallization kits generally contain only a single metal ion, with combinations of metals only in a very few conditions. Based on the results presented in this review, it appears that the crystallization screens need expansion with systematic screening of metal ions that could be crucial for stabilizing the protein structure or for establishing crystal contact and thereby aiding protein crystallization.