Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety profile of biological therapies for treating rheumatoid arthritis

ABSTRACT Introduction: Biological agents such as tumor necrosis factor inhibitors (TNFi), abatacept, rituximab and tocilizumab have proven efficacy in RA. However, these agents are also associated with adverse events so further data is essential to detect them at the earliest stage possible. Areas covered: Herein, the authors review the safety profile of biological therapy, including TNFi and non-TNF agents including abatacept (ABA), rituximab (RTX) and tocilizumab (TCZ). The authors analyze both published articles and congress communications including clinical trials, meta-analyses, observational studies, data from registries and spontaneous clinical reports. The authors classify studies according to the most common and relevant adverse events associated with biological agents. Expert opinion: Biological therapies have a reasonable safety profile and, globally, the benefits far outweigh the possible risk of adverse events. Currently, the risk of serious infections is low and no increased risk in solid malignancies or cardiovascular events have been found after a long clinical experience with these therapies. However, there are still potential risks as well as concerns of immunogenicity induced by TNFi. More studies are required to understand these risks, design safer drugs, and implement pharmacogenomics into the clinic. This will lead to a more personalized medicine in the future.
Etanercept for treating axial spondyloarthritis

ABSTRACT Introduction: Axial spondyloarthritis is an inflammatory rheumatic disease causing back pain, functional impairment and potential ankylosis in the advanced stage. In this context, TNF blockers have been a major therapeutic advance. Etanercept is a soluble recombinant TNF receptor fusion protein in this vain. Areas covered: The aim of this review is to summarize the current published data concerning the efficacy and tolerance of etanercept in axial spondyloarthrits. The authors performed a systematic review on PubMed, using ‘etanercept’ and ‘spondyloarthritis’, ‘axial spondyloarthritis’ or ‘ankylosing spondylitis’ keywords. Expert opinion: Etanercept showed clinical efficacy on the axial (non-radiographic and radiographic) and peripheral manifestations (peripheral arthritis and enthesitis) of axial spondyloarthritis (Ax-SpA). Among the extra-articular manifestations, it works on psoriasis but not on inflammatory bowel disease, with a lack of efficacy data in anterior uveitis. Etanercept also demonstrated an interesting tolerance profile and good drug survival rates after 5 years. Etanercept was also shown to reduce MRI inflammation on the spine and the sacroiliac joints. However, like other TNF blockers, its impact on radiographic progression could not be fully demonstrated. In the context of upcoming new biologic targeted treatments, head-to-head and longer-term randomized controlled trials are now required to further define the role of etanercept in spondyloarthritis treatment strategies.
Geographical variation of persistent organic pollutants in eggs of threatened loggerhead sea turtles (Caretta caretta) from southeastern United States

Persistent organic pollutants (POPs) are recognized manmade threats to sea turtle populations, but substantial uncertainty exists surrounding their exposure to contaminants and their sensitivity to toxic effects. This uncertainty creates difficulty for conservation managers to make informed decisions for the recovery of these threatened species. To provide baseline concentrations and spatial comparisons, we measured a large suite of POPs in loggerhead sea turtle (Caretta caretta) egg yolk samples collected from 44 nests in three distinct U.S. locations: North Carolina (NC), eastern Florida (E FL), and western Florida (W FL). The POPs included polychlorinated biphenyls (PCBs), organochlorine pesticides such as dichlorodiphenyltrichloroethanes (DDTs), chlordanes, mirex, dieldin, hexachlorocyclohexanes (HCHs), hexachlorobenzene, and toxaphene congeners, as well as polybrominated diphenyl ether congeners (PBDEs). Persistent organic pollutant concentrations were lowest in W FL, intermediate in E FL, and highest in NC egg samples, with several statistically significant spatial differences. This increasing gradient along the southeast coast around the Florida peninsula to North Carolina was explained partly by the foraging site selection of the nesting females. Data from previous tracking studies show that NC nesting females feed primarily along the U.S. eastern coast, whereas W FL nesting females forage in the Gulf of Mexico and Caribbean Sea. The E FL nesting females forage in areas that overlap these two. The foraging site selection also results in exposure to different patterns of POPs. An unusual PBDE pattern was seen in the NC samples, with nearly equal contributions of PBDE congeners 47, 100, and 154. These findings are important to managers assessing threats among different stocks or subpopulations of this threatened species. Environ. Toxicol. Chem. 2011; 30:1677–1688. © 2011 SETAC
Spatial trends of polybrominated diphenyl ethers in Canadian fish and implications for long‐term monitoring

A nationwide study was conducted to examine concentrations of polybrominated diphenyl ethers (PBDEs) in top predatory fish, with a focus on lake trout (Salvelinus namaycush), across Canada, and to explore possible influences of food web processes. Concentrations of the three most abundant PBDE homolog groups (tetra‐, penta‐, and hexa‐PBDEs) were, for the most part, higher in Great Lakes and Lake Champlain fish compared with fish from other systems. The Canadian Federal Environmental Quality Guideline for the penta‐homolog was exceeded in 70% of the fish examined. However, virtually no guideline exceedances were found for other congeners. In general, PBDE‐47 (a representative lower brominated congener) was significantly and positively correlated with fish length, weight, age, lipid content, and stable isotopes of nitrogen and carbon. Significant differences in the slopes of the PBDE‐47/covariate relationships between sites prevented concentrations from being adjusted using an analysis of covariance (ANCOVA). However, plots showed that elevated concentrations of PBDE‐47 in Great Lakes and Lake Champlain fish remained after accounting for the influence of covariates. In contrast, for PBDE‐183 (a representative higher brominated congener), the relationships between fish concentrations and covariates were not consistent, which could be a result of biotransformation being more important in controlling its bioaccumulation. The data from the current study show an overall disconnect between fish PBDE concentrations and likely loadings, which may be caused by differences in food web processes between systems. Continued long‐term fish contaminant monitoring is needed to evaluate potential risk to fish and their consumers. However, we also recommend sediment sampling and focused food web studies to provide information on PBDE inputs to the systems and mechanisms of biomagnification, respectively. Environ. Toxicol. Chem. 2011; 30:1564–1575. © 2011 SETAC
Nurses' Perceptions concerning Patient Records in Swedish Nursing Homes

The aim of this study is to compare nurses' perceptions concerning the documentation of nursing care in patient records in nursing homes and other comparable facilities in six Swedish municipalities. Nurses who recently received training in care-planning and recording were compared with nurses that did not receive such training. A postal questionnaire was answered by 165 (86%) of the nurses. Of these, 80 had participated in an intervention program (study group) to improve their nursing recording. The remaining 85 nurses were allocated to a reference group. In contrast to the reference group, significantly fewer nurses in the study group reported dissatisfaction with their documentation and significantly more nurses reported always documenting nursing history and nursing status. The main purpose of the patient record was described by both groups as the daily basis for care delivery and as a means of establishing the security of the patient. The nurses in the study group mentioned the record as a legal document with greater frequency than the reference group. The reference group reported spending more time on the oral reports. Conclusions from the study are that nurses have difficulties in integrating the structured approach of the nursing process and in expressing the contents of nursing care in writing.
Emerging molecular target antagonists for the treatment of biliary tract cancer

ABSTRACT Introduction: Biliary tract cancers (BTCs) are a heterogeneous group of cancers, characterized by low incidence but poor prognosis. Even after complete surgical resection for early stage, relapse is frequent and the lack of effective treatments contributes to the dismal prognosis. To date, the only standard treatment in first-line is cisplatin/gemcitabine combination, whereas no standard in 2nd-line has been defined. Hence, the current goal is to better understand the biology of BTCs, discovering new treatment methods and improving clinical outcomes. Areas covered: The development of next-generation-sequencing has unveiled the picture of the molecular signatures characterizing BTCs, leading to the identification of actionable mutations in biomarker-driven clinical trials. In this review we will cover the genetic landscape of BTC, focusing on the efficacy of existing treatments. Furthermore, we will discuss emerging molecular targets and evaluate the findings of pre-clinical studies. Finally, the encouraging results of clinical trials involving targeted therapies or immunotherapy will be reviewed. Expert opinion: FGFR fusion rearrangements and IDH1 or IDH2 mutations are the most promising targeted treatments under evaluation. In addition, innovative trial design will allow to offer a chance for tailored medicine to infrequent subgroups of BTCs patients based on their molecular features rather than their histology.
Health‐related quality of life in adults with transfusion‐independent thalassaemia intermedia compared to regularly transfused thalassaemia major: new insights

Background: In patients with β thalassaemia intermedia (TI), the milder anaemia and transfusion independence imply better health‐related quality of life (HR‐QoL). However, the unbalanced pathophysiology of the disease allows for several serious clinical complications to manifest, which may have a negative impact on HR‐QoL. Methods: This was a cross‐sectional study on adult patients with transfusion‐ and iron chelation‐independent TI and β thalassaemia major (TM) attending the Chronic Care Center, Hazmieh, Lebanon. A total of 80 patients agreed to participate in the study [32 TI (median age 24 yr) and 48 TM (median age 23 yr)]. The RAND SF‐36 survey was used to assess HR‐QoL. Data on patient demographics, clinical complications and socioeconomic status were collected. Results: Patients with TI and TM were comparable with age and gender, but patients with TM had a significantly longer median duration with a known thalassaemia diagnosis. Patients with TI had a higher proportion of multiple complications. Socioeconomic parameters were comparable, except for patients with TI being more commonly married. The mean Total, Physical Health and Mental Health Scores were significantly lower in patients with TI compared to TM, indicating poorer HR‐QoL. There was a statistically significant positive correlation between the duration with a known thalassaemia diagnosis and a higher Mental Health Score (rs = 0.73, P = 0.020). The mean Physical Health Score was significantly lower in patients with multiple clinical complications compared to patients with single or no complications (P = 0.012). Associations remained independently significant at multivariate analysis. Conclusion: Patients with transfusion‐independent TI have lower HR‐QoL compared to TM patients. At a comparable age, the shorter duration since diagnosis and the multiplicity of complications may explain these findings.
Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases

ABSTRACT Introduction: Asparagine endopeptidase (AEP) is a pH-dependent endolysosomal cysteine protease that cleaves its substrates after asparagine residues. Our most recent study identifies that it possesses the delta-secretase activity, and that it is implicated in numerous neurological diseases such as Alzheimer’s disease (AD) and stroke. Accumulating evidence supports that the inhibition of AEP exhibits beneficial effects for treating these devastating diseases. Areas covered: Based on recent evidence, it is clear that AEP cleaves its substrate, such as amyloid precursor protein (APP), tau and SET, and plays a critical role in neuronal cell death in various neurodegenerative diseases and stroke. In this article, the basic biology of AEP, its knockout phenotypes in mouse models, its substrates in neurodegenerative diseases, and its small peptidyl inhibitors and prodrugs are discussed. In addition, we discuss the potential of AEP as a novel therapeutic target for neurodegenerative diseases. Expert opinion: AEP plays a unique role in numerous biological processes, depending on both pH and context. Most striking is our most recent finding; that AEP is activated in an age-dependent manner and simultaneously cleaves both APP and tau, thereby unifying both major pathological events in AD. Thus, AEP acts as an innovative trigger for neurodegenerative diseases. Inhibition of AEP will provide a disease-modifying treatment for neurodegenerative diseases including AD.
Treatment of consecutive patients with chronic myeloid leukaemia in the cooperating centres from the Czech Republic and the whole of Slovakia after 2000 – a report from the population‐based CAMELIA Registry

Background: Most results on the treatment of chronic myeloid leukaemia (CML) with imatinib were obtained from clinical trials that may differ from the routine practice. We report the results of treatment of consecutive patients with CML at ten major centres during 2000–2008. Patients and methods: Data reporting was retrospective in 2000–2004 and prospective from 2005 on. A total of 661 patients [301 women and 360 men; median age 51 (range, 15–83)] with Ph + CML were registered. The median follow‐up was 46.1 months (0–122.2). Results: Most patients were treated with first‐ (379; 57.3%) or second‐line (193; 29.2%) imatinib; some of the patients underwent allogeneic hematopoietic stem cell transplantation (AHSCT) (83; 12.6%), but 6.1% were treated with other modalities [40 patients; median age 66 (range, 32–83)]. The probability of overall survival (OS) at 5 years, according to Kaplan and Meier, was 88.9%, 77.5% and 68.7% for chronic‐phase patients treated with first‐line imatinib, second‐line imatinib and first‐line AHSCT, respectively, but only 25.2% for patients receiving other modalities. The OS was dependent on the disease phase and Sokal, Hasford and European group for blood and marrow transplantation (EBMT) risk scores (P < 0.001; each). Only 46.2% of deaths in patients treated with other modalities were attributable to CML. Elderly patients over 65 years achieved similar response rates and progression‐free survival to the younger ones. There was a trend for inferior results of AHSCT performed after the failure of imatinib (P = 0.075), probably as a result of differences in EBMT risk scores (P < 0.001). Conclusions: The ability to achieve results comparable to those of previous clinical studies in our CML cohort was influenced by centralised care. Decisions not to initiate imatinib or to delay AHSCT may have a negative impact on OS, but comorbidities may limit the treatment potential of imatinib in the elderly.
INTRAOCULAR TRANSMISSIBLE VENEREAL TUMOR IN A DOG

Canine transmissible venereal tumor (TVT) is a round cell neoplasm occurring on the external genital mucosa of male and female dogs. Transmission is by cell implantation during coitus, licking, or other interaction between an affected dog and a susceptible host. Metastasis of the tumor rarely occurs. This report describes an unusual presentation of TVT with intraocular involvement and inguinal lymph nodes metastasis. The subject was a six-year-old, intact, male, Brazilian Terrier dog with a history of abnormal masses in the right eye, penis and several subcutaneous nodules in the inguinal area. Histopathological examination of the eye specimens as well as cytologic examination of penile mass and subcutaneous nodules revealed similar findings. The examination revealed round cells containing a large nuclei with prominent, central located nucleoli and a pale cytoplasm containing few small, clear round vacuoles. Histologically, the subcutaneous nodules in the inguinal area were lymph nodes. The diagnosis of TVT with intraocular involvement and lymph nodes metastasis was based on clinical, cytologic and histopathologic findings.
Hypoxia improves expansion potential of human cord blood–derived hematopoietic stem cells and marrow repopulation efficiency

Objectives: In bone marrow, hematopoietic stem cells (HSCs) reside in the most hypoxic endosteum niche, whereas the proliferating progenitors are located near the relatively oxygen‐rich vascular region. High oxygen tension is potentially detrimental to HSCs. The objective of this investigation was to compare cellular, functional, and molecular responses of human umbilical cord blood (UCB)‐derived hematopoietic stem and progenitor cells in culture under hypoxic and normoxic conditions.
The novel, orally bioavailable HSP90 inhibitor NVP‐HSP990 induces cell cycle arrest and apoptosis in multiple myeloma cells and acts synergistically with melphalan by increased cleavage of caspases

Heat shock protein 90 (HSP90) binds and stabilizes numerous proteins and kinases essential for myeloma cell survival and proliferation. We and others have recently demonstrated that inhibition of HSP90 by small molecular mass inhibitors induces cell death in multiple myeloma (MM). However, some of the HSP90 inhibitors involved in early clinical trials have shown limited antitumor activity and unfavorable toxicity profiles. Here, we analyzed the effects of the novel, orally bioavailable HSP90 inhibitor NVP‐HSP990 on MM cell proliferation and survival. The inhibitor led to a significant reduction in myeloma cell viability and induced G2 cell cycle arrest, degradation of caspase‐8 and caspase‐3, and induction of apoptosis. Inhibition of the HSP90 ATPase activity was accompanied by the degradation of MM phospho‐Akt and phospho‐ERK1/2 and upregulation of Hsp70. Exposure of MM cells to a combination of NVP‐HSP990 and either melphalan or histone deacetylase (HDAC) inhibitors caused synergistic inhibition of viability, increased induction of apoptosis, and was able to overcome the primary resistance of the cell line RPMI‐8226 to HSP90 inhibition. Combined incubation with melphalan and NVP‐HSP990 led to synergistically increased cleavage of caspase‐2, caspase‐9, and caspase‐3. These data demonstrate promising activity for NVP‐HSP990 as single agent or combination treatment in MM and provide a rationale for clinical trials.
GRK2 as a therapeutic target for heart failure

ABSTRACT Introduction: G protein-coupled receptor (GPCR) kinase-2 (GRK2) is a regulator of GPCRs, in particular β-adrenergic receptors (ARs), and as demonstrated by decades of investigation, it has a pivotal role in the development and progression of cardiovascular disease, like heart failure (HF). Indeed elevated levels and activity of this kinase are able to promote the dysfunction of both cardiac and adrenal α- and β-ARs and to dysregulate other protective signaling pathway, such as sphingosine 1-phospate and insulin. Moreover, recent discoveries suggest that GRK2 can signal independently from GPCRs, in a ‘non-canonical’ manner, via interaction with non-GPCR molecule or via its mitochondrial localization. Areas covered: Based on this premise, GRK2 inhibition or its genetic deletion has been tested in several disparate animal models of cardiovascular disease, showing to protect the heart from adverse remodeling and dysfunction. Expert opinion: HF is one of the leading cause of death worldwide with enormous health care costs. For this reason, the identification of new therapeutic targets like GRK2 and strategies such as its inhibition represents a new hope in the fight against HF development and progression. Herein, we will update the readers about the ‘state-of-art’ of GRK2 inhibition as a potent therapeutic strategy in HF.
High Ki‐67 expression in diffuse large B‐cell lymphoma patients with non‐germinal center subtype indicates limited survival benefit from R‐CHOP therapy

Objectives: Rituximab has significantly improved the survival of patients with DLBCL, especially those with non‐germinal center B‐cell‐like (non‐GCB) subtype. The impact of Ki‐67 expression, an index of proliferation, on the clinical outcomes of patients with DLBCL has largely been unexplored. This study aimed to investigate whether Ki‐67 expression is an indicator of outcome in DLBCL patients (especially non‐GCB DLBCL patients) treated with standard chemotherapy combined with rituximab.
Critical appraisal of prognostic studies: an introduction

This article explores questions and the theoretical framework that surround prognostic research. After setting definitions and providing examples, it provides guidelines for assessing prognosis, which in turn can serve as key points for performing small scale prognostic research in a physiotherapy setting. The guidelines for prognosis are illustrated by working through an example.
Comparison of V/Q SPECT and planar V/Q lung scintigraphy in diagnosing acute pulmonary embolism

PurposePlanar ventilation/perfusion (V/Q) scintigraphy is currently the standard method for the diagnosis of pulmonary embolism (PE) in most nuclear medicine centers. However, recent studies have shown a superior sensitivity and specificity when applying V/Q single photon emission computed tomography (SPECT) in diagnosing PE. This study evaluated the diagnostic performance of three-dimensional V/Q SPECT in comparison with planar V/Q scintigraphy. Materials and methodsConsecutive patients suspected of acute PE from June 2006 to February 2008 were referred to the Department of Nuclear Medicine at Frederiksberg Hospital, Denmark to a V/Q SPECT, as the first-line imaging procedure. Patients with positive D-dimer (>0.5 mg/l) or after clinical assessment with a Wells score of more than 2 were included and had a V/Q SPECT, low-dose CT, planar V/Q scintigraphy, and pulmonary multidetector computer tomography angiography performed the same day. Ventilation studies were performed using 81mKr. Patient follow-up was at least 6 months. ResultsA total of 36 patient studies were available for analysis, of which 11 (31%) had PE. V/Q SPECT had a sensitivity of 100% and a specificity of 87%. Planar V/Q scintigraphy had a sensitivity of 64% and a specificity of 72%. ConclusionWe conclude that V/Q SPECT has a superior diagnostic performance compared with planar V/Q scintigraphy and should be preferred when diagnosing PE.