197 research outputs found
The role of ligand efficiency metrics in drug discovery
The judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates
Do airway metallic stents for benign lesions confer too costly a benefit?
<p>Abstract</p> <p>Background</p> <p>The use of self-expanding metallic stents (SEMAS) in the treatment benign airway obstruction is controversial.</p> <p>Methods</p> <p>To evaluate the safety and efficacy of SEMAS for this indication, we conducted a 10-year retrospective review at our tertiary medical centre.</p> <p>Results</p> <p>Using flexible bronchoscopy, 82 SEMAS (67% Ultraflex, 33% Wallstent) were placed in 35 patients with inoperable lesions, many with significant medical comorbidities (88%). 68% of stents were tracheal, and 83% of patients showed immediate symptomatic improvement. Reversible complications developed in 9% of patients within 24 hrs of stent placement. Late complications (>24 hrs) occurred in 77% of patients, of which 37% were clinically significant or required an interventional procedure. These were mainly due to stent migration (12.2%), fracture (19.5%), or obstructive granulomas (24.4%). The overall granuloma rate of 57% was higher at tracheal sites (59%) than bronchial ones (34%), but not significantly different between Ultraflex and Wallstents. Nevertheless, Wallstents were associated with higher rates of bleeding (5% vs. 30%, p = 0.005) and migration (7% vs. 26%, p = 0.026). Of 10 SEMAS removed using flexible bronchoscopy, only one was associated with incomplete removal of fractured stent wire. Median survival was 3.6 Β± 2.7 years.</p> <p>Conclusion</p> <p>Ill patients with inoperable lesions may be considered for treatment with SEMAS.</p
ADP Ribosylation Factor Like 2 (Arl2) Regulates Breast Tumor Aggressivity in Immunodeficient Mice
We have previously reported that ADP ribosylation factor like 2 (Arl2), a small GTPase, content influences microtubule dynamics and cell cycle distribution in breast tumor cells, as well as the degree and distribution of phosphorylated P53. Here we show, in two different human breast adenocarcinoma models, that Arl2 content has a major impact on breast tumor cell aggressivity both in vitro and in vivo. Cells with reduced content of Arl2 displayed reduced contact inhibition, increased clonogenic or cluster formation as well as a proliferative advantage over control cells in an in vitro competition assay. These cells also caused larger tumors in SCID mice, a phenotype which was mimicked by the in vivo administration of siRNA directed against Arl2. Cells with increased Arl2 content displayed reduced aggressivity, both in vitro and in vivo, with enhanced necrosis and were also found to contain increased PP2A phosphatase activity. A rt-PCR analysis of fresh human tumor breast samples suggested that low Arl2 expression was associated with larger tumor size and greater risk of lymph node involvement at diagnosis. These data underline the role of Arl2, a small GTPase, as an important regulator of breast tumor cell aggressivity, both in vitro and in vivo
The Barreiras Group in the Northeastern coast of the State of Bahia, Brazil: depositional mechanisms and processes
A Deficiency of Ceramide Biosynthesis Causes Cerebellar Purkinje Cell Neurodegeneration and Lipofuscin Accumulation
Sphingolipids, lipids with a common sphingoid base (also termed long chain base) backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid changes in these diseases are pathological events or homeostatic responses. Furthermore, how changes in sphingolipid homeostasis shape the progression of aging and neurodegeneration remains to be clarified. We identified two mouse strains, flincher (fln) and toppler (to), with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration. Positional cloning demonstrated that these mutations reside in the Lass1 gene. Lass1 encodes (dihydro)ceramide synthase 1 (CerS1), which is highly expressed in neurons. Both fln and to mutations caused complete loss of CerS1 catalytic activity, which resulted in a reduction in sphingolipid biosynthesis in the brain and dramatic changes in steady-state levels of sphingolipids and sphingoid bases. In addition to Purkinje cell death, deficiency of CerS1 function also induced accumulation of lipofuscin with ubiquitylated proteins in many brain regions. Our results demonstrate clearly that ceramide biosynthesis deficiency can cause neurodegeneration and suggest a novel mechanism of lipofuscin formation, a common phenomenon that occurs during normal aging and in some neurodegenerative diseases
Lumbar segmental mobility disorders: comparison of two methods of defining abnormal displacement kinematics in a cohort of patients with non-specific mechanical low back pain
BACKGROUND: Lumbar segmental rigidity (LSR) and lumbar segmental instability (LSI) are believed to be associated with low back pain (LBP), and identification of these disorders is believed to be useful for directing intervention choices. Previous studies have focussed on lumbar segmental rotation and translation, but have used widely varying methodologies. Cut-off points for the diagnosis of LSR & LSI are largely arbitrary. Prevalence of these lumbar segmental mobility disorders (LSMDs) in a non-surgical, primary care LBP population has not been established. METHODS: A cohort of 138 consecutive patients with recurrent or chronic low back pain (RCLBP) were recruited in this prospective, pragmatic, multi-centre study. Consenting patients completed pain and disability rating instruments, and were referred for flexion-extension radiographs. Sagittal angular rotation and sagittal translation of each lumbar spinal motion segment was measured from the radiographs, and compared to a reference range derived from a study of 30 asymptomatic volunteers. In order to define reference intervals for normal motion, and define LSR and LSI, we approached the kinematic data using two different models. The first model used a conventional Gaussian definition, with motion beyond two standard deviations (2sd) from the reference mean at each segment considered diagnostic of rotational LSMD and translational LSMD. The second model used a novel normalised within-subjects approach, based on mean normalised contribution-to-total-lumbar-motion. An LSMD was then defined as present in any segment that contributed motion beyond 2sd from the reference mean contribution-to-normalised-total-lumbar-motion. We described reference intervals for normal segmental mobility, prevalence of LSMDs under each model, and the association of LSMDs with pain and disability. RESULTS: With the exception of the conventional Gaussian definition of rotational LSI, LSMDs were found in statistically significant prevalences in patients with RCLBP. Prevalences at both the segmental and patient level were generally higher using the normalised within-subjects model (2.8 to 16.8% of segments; 23.3 to 35.5% of individuals) compared to the conventional Gaussian model (0 to 15.8%; 4.7 to 19.6%). LSMDs are associated with presence of LBP, however LSMDs do not appear to be strongly associated with higher levels of pain or disability compared to other forms of non-specific LBP. CONCLUSION: LSMDs are a valid means of defining sub-groups within non-specific LBP, in a conservative care population of patients with RCLBP. Prevalence was higher using the normalised within-subjects contribution-to-total-lumbar-motion approach
Patient-reported outcome measures of the impact of cancer on patientβs everyday lives: a systematic review
Purpose: Patients with advanced disease are living longer and commonly used patient-reported outcome measures (PROMs) may miss relevant elements of the quality of extended survival. This systematic review examines the measures used to capture aspects of the quality of survival including impact on patientsβ everyday lives such as finances, work and family roles.
Methods: Searches were conducted in MEDLINE, EMBASE,
CINAHL and PsycINFO restricted to English language articles. Information on study characteristics, instruments and outcomes was systematically extracted and synthesised. A predefined set of criteria was used to rate the quality of studies.
Results: From 2761 potentially relevant articles, 22 met all inclusion criteria, including 10 concerning financial distress, 3 on roles and responsibilities and 9 on multiple aspects of social well-being. Generally, studies were not of high quality; many lacked bias free participant selection, had confounding factors and had not accounted for all participants. High levels of financial distress were reported and were associated with multiple demographic factors such as age and income. There were few reports concerned with impacts on patientsβ roles/responsibilities in everyday life although practical and emotional struggles with parenting were identified. Social difficulties were common and associated with multiple factors including being a caregiver. Many studies were single time-point surveys and used non-validated measures. Exceptions were employment of the COST and Social Difficulties Inventory (SDI), validated measures of financial and social distress respectively.
Conclusions: Impact on some important parts of patientsβ everyday lives is insufficiently and inconsistently captured. Further PROM development focussing on roles and responsibilities, including work and caring for dependents, is warranted.
Implications for Cancer Survivors: Factors such as finances, employment and responsibility for caring for dependents (e.g. children and elderly relatives) can affect the well-being of cancer survivors. There is a need to ensure that any instruments used to assess patientsβ social well-being are broad enough to include these areas so that any difficulties arising can be better understood and appropriately supported
Distinct Effects of IL-18 on the Engraftment and Function of Human Effector CD8+ T Cells and Regulatory T Cells
IL-18 has pleotropic effects on the activation of T cells during antigen presentation. We investigated the effects of human IL-18 on the engraftment and function of human T cell subsets in xenograft mouse models. IL-18 enhanced the engraftment of human CD8+ effector T cells and promoted the development of xenogeneic graft versus host disease (GVHD). In marked contrast, IL-18 had reciprocal effects on the engraftment of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in the xenografted mice. Adoptive transfer experiments indicated that IL-18 prevented the suppressive effects of Tregs on the development of xenogeneic GVHD. The IL-18 results were robust as they were observed in two different mouse strains. In addition, the effects of IL-18 were systemic as IL-18 promoted engraftment and persistence of human effector T cells and decreased Tregs in peripheral blood, peritoneal cavity, spleen and liver. In vitro experiments indicated that the expression of the IL-18RΞ± was induced on both CD4 and CD8 effector T cells and Tregs, and that the duration of expression was less sustained on Tregs. These preclinical data suggest that human IL-18 may have use as an adjuvant for immune reconstitution after cytotoxic therapies, and to augment adoptive immunotherapy, donor leukocyte infusions, and vaccine strategies
Multiple Determinants of Whole and Regional Brain Volume among Terrestrial Carnivorans
Mammalian brain volumes vary considerably, even after controlling for body size. Although several hypotheses have been proposed to explain this variation, most research in mammals on the evolution of encephalization has focused on primates, leaving the generality of these explanations uncertain. Furthermore, much research still addresses only one hypothesis at a time, despite the demonstrated importance of considering multiple factors simultaneously. We used phylogenetic comparative methods to investigate simultaneously the importance of several factors previously hypothesized to be important in neural evolution among mammalian carnivores, including social complexity, forelimb use, home range size, diet, life history, phylogeny, and recent evolutionary changes in body size. We also tested hypotheses suggesting roles for these variables in determining the relative volume of four brain regions measured using computed tomography. Our data suggest that, in contrast to brain size in primates, carnivoran brain size may lag behind body size over evolutionary time. Moreover, carnivore species that primarily consume vertebrates have the largest brains. Although we found no support for a role of social complexity in overall encephalization, relative cerebrum volume correlated positively with sociality. Finally, our results support negative relationships among different brain regions after accounting for overall endocranial volume, suggesting that increased size of one brain regions is often accompanied by reduced size in other regions rather than overall brain expansion
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