When Macrocyclic Peptides Meet the Crystal Structure of a Melanocortin Receptor

This work reveals some key factors for the design of a novel generation of selective melanocortin ligands at the MC4 receptor

Metronomic Chemotherapy with Vinorelbine Produces Clinical Benefit and Low Toxicity in Frail Elderly Patients Affected by Advanced Non-Small Cell Lung Cancer

Lung cancer is the leading cause of death worldwide. The treatment choice for advanced stage of lung cancer may depend on histotype, performance status (PS), age, and comorbidities. In the present study, we focused on the effect of metronomic vinorelbine treatment in elderly patients with advanced unresectable non-small cell lung cancer (NSCLC). Methods. From January 2016 to December 2016, 44 patients affected by non-small cell lung cancer referred to our oncology day hospital were progressively analyzed. The patients were treated with oral vinorelbine 30 mg x 3/wk or 40 mg x 3/wk meaning one day on and one day off. The patients were older than 60, stage IIIB or IV, ECOG PS ≥ 1, and have at least one important comorbidity (renal, hepatic, or cardiovascular disease). The schedule was based on ECOG-PS and comorbidities. The primary endpoint was progression-free survival (PFS). PFS was used to compare patients based on different scheduled dosage (30 or 40 mg x3/weekly) and age (more or less than 75 years old) as exploratory analysis. We also evaluated as secondary endpoint toxicity according to Common Toxicity Criteria Version 2.0. Results. Vinorelbine showed a good safety profile at different doses taken orally and was effective in controlling cancer progression. The median overall survival (OS) was 12 months. The disease control rate (DCR) achieved 63%. The median PFS was 9 months. A significant difference in PFS was detected comparing patients aged below with those over 75, and the HR value was 0.72 (p<0.05). Not significant was the difference between groups with different schedules. Conclusions. This study confirmed the safety profile of metronomic vinorelbine and its applicability for patients unfit for standard chemotherapies and adds the possibility of considering this type of schedule not only for very elderly patients

Ecological niche model of Phlebotomus alexandri and P. papatasi (Diptera: Psychodidae) in the Middle East

<p>Abstract</p> <p>Background</p> <p>The purpose of this study is to create distribution models of two sand fly species, <it>Phlebotomus papatasi </it>(Scopoli) and <it>P. alexandri </it>(Sinton), across the Middle East. <it>Phlebotomus alexandri </it>is a vector of visceral leishmaniasis, while <it>P. papatasi </it>is a vector of cutaneous leishmaniasis and sand fly fever. Collection records were obtained from literature reports from 1950 through 2007 and unpublished field collection records. Environmental layers considered in the model were elevation, precipitation, land cover, and WorldClim bioclimatic variables. Models were evaluated using the threshold-independent area under the curve (AUC) receiver operating characteristic analysis and the threshold-dependent minimum training presence.</p> <p>Results</p> <p>For both species, land cover was the most influential environmental layer in model development. The bioclimatic and elevation variables all contributed to model development; however, none influenced the model as strongly as land cover.</p> <p>Conclusion</p> <p>While not perfect representations of the absolute distribution of <it>P. papatasi </it>and <it>P. alexandri</it>, these models indicate areas with a higher probability of presence of these species. This information could be used to help guide future research efforts into the ecology of these species and epidemiology of the pathogens that they transmit.</p

Attention modulates psychophysical and electrophysiological response to visual texture segmentation in humans

none5noTo investigate whether processing underlying texture segmentation is limited when texture is not attended, we measured orientation discrimination accuracy and visual evoked potentials (VEPs) while a texture bar was cyclically alternated with a uniform texture, either attended or not. Orientation discrimination was maximum when the bar was explicitly attended, above threshold when implicitly attended, and fell to just chance when unattended, suggesting that orientation discrimination based on grouping of elements along texture boundary requires explicit attention. We analyzed tsVEPs (variations in VEP amplitude obtained by algebraic of uniform-texture from segmented-texture VEPs) elicited by the texture boundary orientation discrimination task. When texture was unattended, tsVEPs still reflected local texture segregation. We found larger amplitudes of early tsVEP components (N75, P100, N150, N200) when texture boundary was parallel to texture elements, indicating a saliency effect, perhaps at V1 level. This effect was modulated by attention, disappearing when the texture was not attended, a result indicating that attention facilitates grouping by collinearity in the direction of the texture boundary.openCasco, C; Grieco, A; Campana, G; CORVINO M., P; Caputo, GIOVANNI BATTISTACasco, C; Grieco, A; Campana, G; CORVINO M., P; Caputo, GIOVANNI BATTIST

Monitoring and ming bio-physical parameters for hypoxia hazard in a coastal sand pit

Management of coastal areas requires monitoring and modeling of the anthropogenic drivers and the bio-physical processes affecting water quality. To assess the range of hydrographic conditions controlling oxygen distribution in the bottom layers of sand pits, a multi-year oceanographic survey has been conducted in a coastal area with several extraction pits. Hydrographic data including profiles of temperature, salinity and oxygen were collected and related to local wind conditions and circulation. Moreover, 1D and 3D high-resolution non-hydrostatic ocean models were used to describe turbulent mixing regimes and to obtain the range of wind speeds for which the critical anoxic conditions may occur. It is shown that wind speed appears to control the dynamics of oxygen concentrations, with oxygen depleted zones developing in a short time in low wind speed conditions. Moreover, the depth and the shape of the extraction pit contribute to decrease the mixing of the bottom layers and increase the water retention in the hole increasing the output and the persistence of oxygen depleted zones in the excavated area. The results of the numerical simulations show that the risk of hypoxia at the bottom of the sand pits is associated with higher temperatures and wind speed lower than 5 m/s, which is not infrequent during the summer season. However, the number of consecutive days of oxygen depletion can be considered lower than the danger threshold level assumed in the literature

An Atypical Cutaneous Reaction to Rivastigmine Transdermal Patch

Rivastigmine is a cholinesterase inhibitor which improves cognitive function and is currently being used in patients with mild to moderate Parkinson's and Alzheimer's dementia. This drug can be given orally or topically, as transdermal patch. The latter form is currently used for most excellent compliance and few side effects. The most common cutaneous side effects are irritative dermatitis. We report the second case of active sensitization by the rivastigmine-patch in a patient suffering from Alzheimer's dementia

Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study

BACKGROUND: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age 10 and 22 years, cerebellar atrophy, peripheral neuropathy, oculomotor apraxia (OMA), and elevated serum alpha-fetoprotein (AFP) levels. Recessive mutations in SETX have been described in AOA2 patients. OBJECTIVE: To describe the clinical features of AOA2 and to identify the SETX mutations in 10 patients from four Italian families. METHODS: The patients underwent clinical examination, routine laboratory tests, nerve conduction studies, sural nerve biopsy, and brain MRI. All were screened for SETX mutations. RESULTS: All the patients had cerebellar features, including limb and truncal ataxia, and slurred speech. OMA was observed in two patients, extrapyramidal symptoms in two, and mental impairment in three. High serum AFP levels, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI were detected in all the patients who underwent these examinations. Sural nerve biopsy revealed a severe depletion of large myelinated fibers in one patient, and both large and small myelinated fibers in another. Postmortem findings are also reported in one of the patients. Four different homozygous SETX mutations were found (a large-scale deletion, a missense change, a single-base deletion, and a splice-site mutation). CONCLUSIONS: The clinical phenotype of oculomotor apraxia type 2 is fairly homogeneous, showing only subtle intrafamilial variability. OMA is an inconstant finding. The identification of new mutations expands the array of SETX variants, and the finding of a missense change outside the helicase domain suggests the existence of at least one more functional region in the N-terminus of senataxin

Novel anti-inflammatory and chondroprotective effects of the human melanocortin MC1 receptor agonist BMS-470539 dihydrochloride and human melanocortin MC3 receptor agonist PG-990 on lipopolysaccharide activated chondrocytes

Human melanocortin MC1 and MC3 receptors expressed on C-20/A4 chondrocytes exhibit chondroprotective and anti-inflammatory effects when activated by melanocortin peptides. Nearly 9 million people in the UK suffer from osteoarthritis, and bacterial infections play a role in its development. Here, we evaluate the effect of a panel of melanocortin peptides with different selectivity for human melanocortin MC1 (alpha-MSH, BMS-470539 dihydrochloride) and MC3 receptors ([DTrp8]-g-MSH, PG-990) and C-terminal peptide alpha-MSH11-13(KPV), on inhibiting LPS-induced chondrocyte death, pro-inflammatory mediators and induction of anti-inflammatory proteins. C-20/A4 chondrocytes were treated with a panel of melanocortin peptides prophylactically and therapeutically in presence of LPS (0.1 ug/ml). The chondroprotective properties of these peptides determined by cell viability assay, RT-PCR, ELISA for detection of changes in inflammatory markers (IL-6, IL-8 and MMP-1, -3 and -13) and western blotting for expression of the anti-inflammatory protein heme-oxygenase-1. C-20/A4 expressed human melanocortin MC1 and MC3 receptors and melanocortin peptides elevated cAMP. LPS stimulation caused a reduction in C-20/A4 viability, attenuated by the human melanocortin MC1 receptor agonist BMS-470539 dihydrochloride, and MC3 receptor agonists PG-990 and [DTrp8]-g-MSH. Prophylactic and therapeutic regimes of [DTrp8]-g-MSH significantly inhibited LPS-induced modulation of cartilage-damaging IL-6, IL-8, MMPs -1,-3 and -13 mediators both prophylactically and therapeutically, whilst human melanocortin MC1 and MC3 receptor agonists promoted an increase in HO-1 production. In the presence of LPS, activation of human melanocortin MC1 and MC3 receptors provided potent chondroprotection, upregulation of anti-inflammatory proteins and downregulation of inflammatory and proteolytic mediators involved in cartilage degradation, suggesting a new avenue for osteoarthritis treatment