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Buccal drug administration may be chosen as a medication route to treat various diseases for local or systemic effects. This study proposes the development of a thermosensitive hydrogel containing curcumin-loaded lipid-core nanocapsules coated with chitosan to increase mucoadhesion, circumventing several limitations of this route of administration. Hydroxypropylmethylcellulose and Poloxamer

Pembrolizumab is licensed for the treatment of pre-treated and PD-L1 positive non-small cell lung cancer (NSCLC), but response is heterogeneous. In this context, the Lung Immune Prognostic Index (LIPI) has been proposed as tool to prognosticate outcome.To investigate the real-world efficacy and safety of pembrolizumab in pre-treated NSCLC patients and the clinical utility of LIPI for patients' selection.Patients with pre-treated NSCLC and PD-L1 ≥ 1% treated with pembrolizumab were included in this retrospective series. The LIPI was used to classify patients in 3 prognostics subgroups according to the pre-treatment dNLR (derived neutrophil to lymphocyte ratio) and LDH in blood. The prognostic impact of the LIPI on progression free survival (PFS) and overall survival (OS) was evaluated with Cox regression. The combined effect of LIPI and other relevant prognostic factors was explored with multivariate regression.In total, 113 consecutive patients were included. Median (mPFS) and mOS was 4.3 (2.6-6.7) and 13.5 (10.3-17.7) months, respectively. Good-, intermediate-, and poor-LIPI was found in 54 (47.8%), 45 (39.8%), and 8 (7.1%) patients, respectively. Median PFS was 5.1 (2.8-9.1), 3.0 (2.5-6.8), and 1.4 (0.5-18.7) months, and mOS was 17.2 (12.0-26.4), 11.8 (8.4-17.1), and 3.7 (0.5-not calculable) months for good-, intermediate-, and poor-LIPI group, respectively. Patients with intermediate-LIPI and poor-LIPI had worse PFS versus good-LIPI, and statistically significant worse OS (p = 0.030 and p = 0.013, respectively). In the multivariate analysis, intermediate- versus good-LIPI (p = 0.190) was not independently associated to PFS or OS. Patients with both good-LIPI and high (≥ 50%) PD-L1 had better OS than all other subgroups defined by LIPI and PD-L1. Immune-related adverse events (irAEs) occurred in 47 (41.6%) patients (12.4% grade ≥ 3). In a time-varying analysis, irAEs were statistically associated with longer OS (HR 0.51, 0.31-0.84; p = 0.008).In our series, the outcome of pembrolizumab in pre-treated NSCLC is consistent with the registration trial. Lung Immune Prognostic Index is a readily available tool able to prognosticate outcome, also in PD-L1-high patients. The positive association between irAEs and OS might aid decision making.

The importance of many mutualistic interactions is poorly understood because information on their frequency and distribution at wide spatial scales is lacking. One such interaction is that between ants and plants bearing diaspores equipped with elaiosomes, which function as a reward for ants in exchange for dispersion. Our aim was to estimate the number of taxa having elaiosome-bearing diaspores in the Ibero-Balearic territory and its relationship to several factors. We estimated that at least 572 species and subspecies, almost one-third endemic, are present, which corresponds to ca. 5.1% of European angiosperms and 9% of Iberian ones. Because this number of elaiosome-bearing taxa is much higher than those given so far for the Northern Hemisphere, the Ibero-Balearic territory should be considered an important center of myrmecochory, with myrmecochorous species richness significantly positively correlated with ruggedness, latitude, and longitude. In contrast to other myrmecochorous territories (Australia and Cape Province), where numerous trees and shrubs develop on acid substrates, most myrmecochores in the Ibero-Balearic area are perennial herbs occupying basic substrates. Such perennial herbs are more frequent in the Eurosiberian floristic region, whereas annuals abound in the Mediterranean region. The enumerated taxa mainly inhabit forests, scrubs, and anthropized sites. Among them, 56.5% carry the elaiosome on seeds (especially strophiole and caruncle types). In 36.7%, the elaiosome is borne on indehiscent fruits, such as achenes in Asteraceae, where they are found either at the base of the style or the basal hilum, and at the base of nutlets (Boraginaceae and Lamiaceae).

The advent of PD-(L)1 and CTLA-4 immune check point inhibitors (CPIs) has dramatically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC). For up to a quarter of patients with advanced NSCLC, CPIs have the potential to induce durable responses with long-term survival outcomes. Since the approval of first-line pembrolizumab for patients whose tumors express a PD-L1 ≥ 50%, several pivotal first-line CPI-based phase 3 studies have been conducted investigating combination treatments combining CPIs with chemotherapy (ChT) or combining different CPIs with or without ChT. As a result, there has been an increase in front-line treatment options for advanced NSCLC, and treatment algorithms are changing very quickly. In fit patients with advanced NSCLC, combination treatments including CPI and ChT are considered the new standard of care with improved clinical outcomes. CPI combination treatments are well tolerated and quality of life also seems to be better when CPIs are implemented in the first-line setting. The aim of this review is to provide a summary of the recently published first-line phase 3 studies investigating CPIs as monotherapy or in combination with other CPIs or ChT in advanced NSCLC, and to suggest possible treatment algorithms.

Phenolic compounds provide important quality attributes to red wines. These compounds are found inside the vacuoles of the plant cells of the skin and seeds of the grape. During maceration, they diffuse to the must/wine, although for this to happen, the vegetal cell walls need to rupture. Pectolytic enzymes and high-power ultrasound (US) may facilitate this objective. Therefore, this study analyzes the extraction efficiency of phenolic compounds using pectolytic enzymes and US (applied at 2 different times of the maceration period) alone and in combination. The chromatic characteristics of the wines were analyzed by spectrophotometry and chromatography at the end of the alcoholic fermentation and after 3 months in bottle. The treatment with enzymes alone increased the concentration of tannins by 13%, but US increased both the extraction of anthocyanins and tannins (7 and 16% respectively). The combination of enzymes and US, both applied at the beginning of the maceration time, did not improve the results of the treatments separately. However, when the enzyme was allowed to act alone during the first days of maceration before US was applied, a statistically significant synergistic effect was observed, increasing the color intensity by 18% and total phenol content by 21%, and especially marked was the effect on tannin extraction, whose concentration increased in the wines by 30% at the end of alcoholic fermentation.

Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling.

An essential factor for the production of nitric oxide by nitric oxide synthase 1 (NOS1), major modulator of cardiac function, is the cofactor tetrahydrobiopterin (BH4). BH4 is regulated by GTP cyclohydrolase 1, the rate-limiting enzyme in BH4 biosynthesis which catalyses the formation of dihydroneopterin 3′triphosfate from GTP, producing BH4 after two further steps catalyzed by 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. However, there are other essential factors involved in the regulation of NOS1 activity, such as protein inhibitor of NOS1 (PIN), calmodulin, heat shock protein 90 and NOS interacting protein. All these molecules have never been analysed in human non-ischemic dilated hearts (DCM). In this study we demonstrated that the upregulation of cardiac NOS1 is not accompanied by increased NOS1 activity in DCM, partly due to the elevated PIN levels and not because of alterations in biopterin biosynthesis. Notably, the PIN concentration was significantly associated with impaired ventricular function, highlighting the importance of this NOS1 activity inhibitor in Ca2+ homeostasis. These results take a central role in the current list of targets for future studies focused on the complex cardiac dysfunction processes through more efficient harnessing of NOS1 signalling.

Amelogenesis imperfecta is a group of genetic conditions that affect the structure and clinical appearance of tooth enamel. The types (hypoplastic, hypocalcified, and hypomature) are correlated with defects in different stages of the process of enamel synthesis. Autosomal dominant, recessive, and X-linked types have been previously described. These disorders are considered clinically and genetically heterogeneous in etiology, involving a variety of genes, such as AMELX, ENAM, DLX3, FAM83H, MMP-20, KLK4, and WDR72. The mutations identified within these causal genes explain less than half of all cases of amelogenesis imperfecta. Most of the candidate and causal genes currently identified encode proteins involved in enamel synthesis. We think it is necessary to refocus the search for candidate genes using biochemical processes. This review provides theoretical evidence that the human SLC4A4 gene (sodium bicarbonate cotransporter) may be a new candidate gene.

In Anagyris foetida, the fruits are disseminated by fall under gravity. No dispersing agent is as yet known, so that the fruits are located near the mother plant. The species presents an important seed bank that differs between the two populations studied, probably due to their different production of seeds/individual and to the livestock pressure. The germination of control seeds was found to be null or very low, with no improvement following exposure to high temperatures, but reaching high values following scarification in all the populations studied. This indicates that the failure in germination must be attributed to the hardness of the testa, with the seeds presenting physical dormancy. Also, the browsing of sheep on ripe fruit increases germination to 48% due to mechanical scarification, with this being the only positive effect those animals have on these plants. There were differences in germination after scarification between populations and years which could have been due to intrinsic characteristics.

A collection of 143 plants arising from crosses from Monastrell × Cabernet Sauvignon is available in our orchards. A 3-year study enabled us to identify the differences between the different plants. In 2005, we had studied the anthocyanin profile and color characteristics of the most promising hybrids as a part of a project to select those plants showing the most interesting enological characteristics. Differences in the anthocyanin profile were observed between Monastrell and Cabernet Sauvignon grapes, the hybrids showing, in general, an anthocyanin profile intermediate between these two varieties, although closer to that of Cabernet Sauvignon grapes. To the best of our knowledge, this is the first work to study how the anthocyanin profile of two premium Vitis vinifera varieties is inherited by the resulting hybrid plants.

The morphology and composition of skin and pulp cell walls of four premium red wine grape (Vitis vinifera L.) varieties were studied to determine whether the technological differences observed in previous studies between the four different varieties during the winemaking process (especially, the anthocyanin extractability) could be partly explained by their respective cell wall compositions. Monastrell grapes showed the highest amount of cell wall material in their skins (55–57 mg cell wall/g skin), while Syrah showed the largest amount of cell wall material in the pulp (5.1 mg cell wall/g pulp). The highest percentage of galactose and cellulosic glucose in skin and pulp cell walls was also found in Monastrell grapes. The cell wall composition of Monastrell grapes, together with their morphology, suggests that the firmer pulp and skin are responsible for the difficulties this variety shows for anthocyanin extraction (extractability index varying from 37 to 60). As cell wall composition may be modulated by the action of enzymes, the activity of pectinmethylesterase, polygalacturonase, cellulase and α- and β-galactosidase was studied. No polygalacturonase and cellulase activity was found. The two galactosidases showed higher activity than pectinmethylesterase (25–290 units/g tissue versus 0.3–0.4 units/g tissue), especially in Cabernet Sauvignon grapes, although in Monastrell grapes α- and β-galactosidase activity was low, which may explain the large amount of galactose in Monastrell grapes cell wall.

Approximately 30 % of the genera of Scrophulariaceae s.str. have a staminode, which is the remnant of a sterile stamen. However, there are no studies of the functionality or evolutionary pattern of staminodes in that family. This paper investigates three Scrophularia species with different staminode sizes to determine if the staminode safeguards nectar from dilution by rainwater and if it influences pollinator behavior. We also study staminode evolution and ancestral state reconstruction onto a phylogeny containing 71 species and subspecies with four different staminode developmental stages: tiny, large, enormous, and absent. The results showed that large staminodes did not hinder nectar collection or modify pollinator-visiting time but acted as a barrier to reduce rainwater entry. The latter reduced the dilution of nectar, which did not occur with tiny staminodes. The phylogenetic study revealed that the ancestral state in the genus corresponds with the presence of a large staminode vs. the tiny and enormous staminodes that are considered as derived. The complete disappearance of the staminode has occurred independently at least twice. Events occurred that increased or reduced the staminode size in one of the clades (Clade II), which includes species of sect. Caninae; most of these events occurred during the Pleistocene (0.6–2.7 Ma).

The neurokinin-1 (NK1) receptor antagonists are a new class of agents designed to reduce the risk of emesis following chemotherapy, particularly with cisplatin. Early data from double-blind randomised trials suggest that an orally administered NK1 antagonist can reduce the absolute risk of acute and delayed emesis following cisplatin by 20 and 30%, respectively.To measure the value that patients with cancer place on improved emesis control and quality of life.Willingness-to-pay analysis.Five study sites in Canada, Italy, Spain and Greece.245 patients with cancer either receiving chemotherapy with cisplatin or who had received cisplatin-based chemotherapy within the previous 6 months.After background information had been presented, patients were asked to define the maximum that they would pay per day for a drug that reduced their risk of acute and delayed (days 2 to 5) emesis by 20 and 30%, respectively. Costs were converted to US dollars ($US) using year 2000 exchange rates.For a 20% improvement in acute emesis, Canadian, Italian and Spanish patients with cancer were willing to pay $US46, $US34 and $US63 per day, respectively, compared with $US8 for patients from Greece (p0.001). For a 30% improvement in delayed emesis, Canadian, Italian and Spanish patients with cancer were also willing to pay more than their Greek counterparts (SUS41, $US31, $US50 and $US9 daily for 4 days, respectively; p0.001). These significant differences in patient value between countries remained, even after adjusting for socioeconomic variables and previous history of emesis.There are substantial cultural differences in how patients with cancer value benefit and improved quality of life. Since the majority of the world's population resides outside North America and Western Europe, there may be a need to re-evaluate perceived levels of patient benefit and measures of quality of life.

Gentamicin monitoring and the selection of the initial dosage are generally based on the relationship between pharmacokinetic parameters of gentamicin (GPP) and patient characteristics and/or clinical data (PC). However, the number of studies about this relationship in cancer patients is limited. Therefore, the main objective of the present study was to evaluate the relationship between GPP and PC in cancer patients and to identify different subgroups within this group of patients with unique relationship models between GPP and PC. A total of 198 cancer patients were included in the study. Firstly, GPP were estimated by the Sawchuk and Zaske regression method. Then, a linear regression analysis was performed to investigate the relationship between GPP and PC, and lastly subgroups with unique models were identified by comparing their regression models. The results revealed that the variable which was the best predictor of the distribution volume of gentamicine was the dosing weight (DW = IBW + (ABW‐IBW), ABW being the actual body weight and IBW the ideal body weight). Creatinine clearance (CLCR) measured by a 24‐hour urine collection (CLCRu) was the best predictor of gentamicin clearance (CL). When this value is not available, the CLCR estimated by the formula of Crockcroft and Gault (C‐G), can be used. When the C‐G formula was used, unique models to predict CL from CLCR were identified for patients who were obese, patients who had received high‐dose chemotherapy and, for subjects who had never developed aplasia following chemotherapy. Whichever the model used, the results showed that some variability in pharmacokinetic parameters of gentamicin was not explained by the models, especially in some groups of patients.

We studied the biology and floral rewards of 34 taxa ofGenisteae from the SW of Europe. Most of the floral attributes show a statistically significant direct relationship. Anther biomass of the lower whorl (lW) is significantly lower than that of the upper whorl (uW), and the ratio of the two (Rv) differs among the taxa. All taxa are polliniferous, andRetama sphaerocarpa also secretes nectar. They can be considered xenogamous or facultative xenogams on the basis of their high pollen/ovule (P/O) ratios. Three principal mechanisms of pollen releasing are identified in this tribe: valvular, pump and explosive; the latter comprises specialized and nonspecialized subtypes. Pollination is sternotribic except in the specialized explosive mechanism, in which it is noto-sternotribic. Thus some pollen serves as food (pollen from the uW, which adheres to the ventral surface of the insect) and part of the pollen fulfils a polliniferous function (pollen from the lW, which adheres to the dorsal surface). Species that use a pump mechanism have very low Rv values (Rv=0.08−0.26); species with valvular or nonspecialized explosive mechanisms have Rv values between 0.24 and 0.58; those with a specialized mechanism of pollen presentation have high Rv values (0.6−0.76). In contrast to expectations, the highest P/O ratios appear in the specialized explosive system, which allows a single visit from the insect.

A cost-evaluation model was applied to clinical trial protocols to estimate their cost for the hospital pharmacy service. The steps taken in the drug management of clinical research were identified. Fixed costs (common to all clinical trials) and variable costs (peculiar to each clinical trial) were determined for each step. The number of patients, the number of operations, the planned services (receptions, storage, drug dispensing), the timing and difficulty of the study (randomization) were included in the variable costs. The economic assessment of these items was based on the costs of the materials and means used, the cost of staff time and finally the cost of drug storage during the clinical trial. This model was applied to 24 clinical trials carried out in the University Clinic of Navarra. 83% of all pharmacy costs of a clinical trial were variable. Drug dispensing, stock management and return drugs account for 94% of the time expended. The approximate cost of the pharmacy providing investigational services was $1,766 per trial or $174 per patient. Drug storage costs were not an important source of expenditure among the variable costs (7.4%). The best way to determine the cost of a trial is to calculate the number of operations.

The genusScrophularia in the Iberian Peninsula and Balearic Islands comprises two sections,Scrophularia andCaninaG. Don. Analyses were carried out on flower production, flower duration and their sexual phases, pollen and nectar production together with observations on their pollinators. Nectar production is correlated with corolla size and pollen production with anther size. The taxa of sect.Scrophularia show greater nectar and pollen production than those of sect.Canina. Also, those of the first section produce more ovules per ovary than those of the second group, production being correlated with the ovary size.

The reproductive biology of someScrophularia species in the Iberian Peninsula and Balearic Islands has been studied. Levels of fruit-set in bagged and unbagged inflorescences, the production of seeds/capsule, the effectiveness of seed-set following cross-pollination in the genus and the pollen/ovule ratios have been analyzed.

The cost of parenteral admixtures has an important impact on the hospital budget. Recently, a Viaflex® with vial adapter (named 'minibag plus' in some countries) has been commercialized in order to facilitate parenteral admixture preparation. In the present study a preparation using Viaflex® with a vial adapter has been economically compared with a preparation with a traditional Viaflex® (without adapter) in a centralized unit or in nursing wards in a unit‐dose drug distribution system. A cost‐analysis was conducted from the hospital point of view. Direct costs were considered: these included supplies and human resources. Differences in the whole process between the two types of Viaflex® were analysed. The process included: purchasing, reception, storage, medical order record, preparation in the Pharmacy Service (PS), delivery from the PS to the nursing unit, preparation by the nurse, return of unused material to the PS. Human resource costs were estimated by time counting and multiplying by the average salary. To estimate wasted material, drug and supplies delivered from the PS and returned to the PS were counted during 26 days. With the new Viaflex® costs are reduced by 30% in comparison with drug dilution using the traditional Viaflex® in a centralized unit of the PS, and by 13.4% in comparison with preparation with the traditional Viaflex® in the nursing ward. In addition it can be estimated that contamination risk with the new Viaflex® is lower than preparation in the nursing ward with the traditional Viaflex®. Therefore, owing to its lower cost we recommend the use of Viaflex® with vial adapter for drug dilution for those vials that are compatible with the system.