An integrative taxonomy study reveals a rare new species of the genus Creptotrema (Trematoda: Allocreadiidae) in an endangered frog in South America.

During an ecological study with a near-endangered anuran in Brazil, the Schmidt's Spinythumb frog, Crossodactylus schmidti Gallardo, 1961, we were given a chance to analyze the gastrointestinal tract of a few individuals for parasites. In this paper, we describe a new species of an allocreadiid trematode of the genus Creptotrema Travassos, Artigas & Pereira, 1928, which possesses a unique trait among allocreadiids (i.e., a bivalve shell-like muscular structure at the opening of the ventral sucker); the new species represents the fourth species of allocreadiid trematode parasitizing amphibians. Besides, the new species is distinguished from other congeners by the combination of characters such as the body size, ventral sucker size, cirrus-sac size, and by having small eggs. DNA sequences through the 28S rDNA and COI mtDNA further corroborated the distinction of the new species. Phylogenetic analyses placed the newly generated sequences in a monophyletic clade together with all other sequenced species of Creptotrema. Genetic divergences between the new species and other Creptotrema spp. varied from 2.0 to 4.2% for 28S rDNA, and 15.1 to 16.8% for COI mtDNA, providing robust validation for the recognition of the new species. Even though allocreadiids are mainly parasites of freshwater fishes, our results confirm anurans as hosts of trematodes of this family. Additionally, we propose the reallocation of Auriculostoma ocloya Liquin, Gilardoni, Cremonte, Saravia, Cristóbal & Davies, 2022 to the genus Creptotrema. This study increases the known diversity of allocreadiids and contributes to our understanding of their evolutionary relationships, host-parasite relationships, and biogeographic history.

Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey.

BACKGROUND: Germline BRCA1-2 pathogenic variants (gBRCA1-2pv)-related pancreatic ductal adenocarcinoma (PDAC) showed increased sensitivity to DNA cross-linking agents. This study aimed at exploring safety profile, dose intensity, and activity of different chemotherapy regimens in this setting. PATIENTS AND METHODS: gBRCA1-2pv PDAC patients of any age and clinical tumor stage who completed a first course of chemotherapy were eligible. A descriptive analysis of chemotherapy toxicity, dose intensity, response, and survival outcomes was performed. RESULTS: A total of 85 gBRCA1-2pv PDAC patients treated in 21 Italian centers between December 2008 and March 2021were enrolled. Seventy-four patients were assessable for toxicity and dose intensity, 83 for outcome. Dose intensity was as follows: nab-paclitaxel 72%, gemcitabine 76% (AG); cisplatin 75%, nab-paclitaxel 73%, capecitabine 73%, and gemcitabine 65% (PAXG); fluorouracil 35%, irinotecan 58%, and oxaliplatin 64% (FOLFIRINOX). When compared with the literature, grade 3-4 neutropenia, thrombocytopenia, and diarrhea were increased with PAXG, and unmodified with AG and FOLFIRINOX. RECIST responses were numerically higher with the three- (81%) or four-drug (73%) platinum-containing regimens that outperformed AG (41%) and oxaliplatin-based doublets (56%). Carbohydrate antigen 19.9 (CA19.9) reduction >89% at nadir was reported in two-third of metastatic patients treated with triplets and quadruplets, as opposed to 33% and 45% of patients receiving oxaliplatin-based doublets or AG, respectively. All patients receiving AG experienced disease progression, with a median progression-free survival (mPFS) of 6.4 months, while patients treated with platinum-containing triplets or quadruplets had an mPFS >10.8 months. Albeit still immature, data on overall survival seemed to parallel those on PFS. CONCLUSIONS: Our data, as opposed to figures expected from the literature, highlighted that platinum-based regimens provoked an increased toxicity on proliferating cells, when dose intensity was maintained, or an as-expected toxicity, when dose intensity was reduced, while no change in toxicity and dose intensity was evident with AG. Furthermore, an apparently improved outcome of platinum-based triplets or quadruplets over other regimens was observed.

Germinal BRCA1-2 pathogenic variants (gBRCA1-2pv) and pancreatic cancer: epidemiology of an Italian patient cohort.

OBJECTIVE: Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients. MATERIALS AND METHODS: Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient's family history was considered as potentially BRCA-associated. Patients or disease characteristics were examined using the χ2 test or Fisher's exact test for qualitative variables and the Student's t-test or Mann-Whitney test for continuous variables, as appropriate. RESULTS: Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P = 0.01). The gBRCApv rate was 17.1% among patients <40 years old, 10.4% among patients 41-50 years old, 9.2% among patients 51-60 years old, 6.7% among patients aged 61-70 years, and 6.2% among patients >70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients <74 years old was 9%. Patients with/without a family history of potentially BRCA-associated tumors had 14%/6% mutations. CONCLUSION: Based on our findings of a gBRCApv incidence higher than expected in a real-life series of Italian patients with incident PDAC, we recommend screening all PDAC patients <74 years old, regardless of family history and stage, due to the therapeutic implications and cancer risk prevention in patients' relatives.

Longitudinal Study of Foraging Networks in the Grass-Cutting Ant Atta capiguara Gonçalves, 1944.

Colonies of leaf-cutting ants of the genus Atta need to collect large quantities of vegetal substrate in their environment to ensure their growth. They do so by building and extending over time a foraging network that consists of several underground tunnels extending above ground by physical trails. This paper presents a longitudinal study of the foraging network of two mature colonies of the grass-cutting ant Atta capiguara (Gonçalves) located in a pasture in central Brazil. Specifically, we investigated whether the extension of the foraging area of the colonies required to reach new resources occurs by building new and longer underground tunnels or by building new and longer physical trails. Each nest was surveyed at intervals of approximately 15 days during 1 year. At each survey we mapped the position of the tunnel entrances and foraging trails at which activity was observed. In addition, we assessed the excavation effort of the colonies since the last survey by the number and distance to the nest of new tunnel entrances, and the physical trail construction effort by the number and length of newly built physical trails. Our study reveals that in A. capiguara the collection of new resources around the nest required to ensure the continuous growth of the colonies is achieved mainly through the excavation of new underground tunnels, opening at greater distance from the nest, not through the building of longer aboveground physical trails.

Do Workers from Subspecies Acromyrmex subterraneus Prepare Leaves and Toxic Baits in Similar Ways for Their Fungus Garden?

Toxic baits are the most efficient method to control leaf-cutter ants in eucalyptus forests for paper and cellulose production. For the proper use of these baits, insecticide compounds must reach workers and contaminate them. Thus, understanding how these baits are processed inside the nests is vital for a successful control, especially when it comes to genus Acromyrmex. Lack of information on toxic baits and on contamination of Acromyrmex workers raises the question: do workers from subspecies Acromyrmex subterraneus (Forel) prepare leaves and toxic baits in similar ways for their fungus garden? To answer it, this study described and analyzed the behavioral repertoire executed by A. subterraneus workers during the preparation of leaf disks and baits and their incorporation into the fungus garden. Results show that the act of licking the substrate was the most frequently executed behavior, regardless of subspecies or size categories. Moreover, additional behaviors have been observed when workers processed the baits, such as licking and scraping their jaws on the surface of the bait pellet, as well as licking and biting fragments of bait pellets, moistening them. Thus, it is concluded that the preparation of baits is different from that of leaves; baits are more processed and can therefore contribute to contaminating workers via insecticides.

Fat-Soluble Substance Flow During Symbiotic Fungus Cultivation by Leaf-Cutter Ants.

Leaf-cutter ants perform a series of specialized behaviors in preparing plant substrates for their symbiotic fungus. This process may be related to contamination of workers by substances such as insecticides, leading us to hypothesize that substances are spread among workers through behaviors they perform to grow the fungus. To test this hypothesis, we analyzed the behavioral acts of workers during the processing of the pellets by using a fat-soluble tracing dye, since the active ingredient that composes toxic baits, used for control of leaf-cutter ants, is fat-soluble. The frequencies of performed behaviors were recorded and the number of dyed workers was assessed after fungus cultivation. The most frequent behavior is allogrooming and corresponds to 45.87% of the contamination process in workers, followed by holding, licking, and cutting pellets, which account for 40.22% of the process. After pellet processing, the workers had their external and internal morphological structures marked by the tracing dye-93.75% and 79.25%, respectively. These results confirm that behaviors performed during fungus cultivation contribute to dispersing substances such as insecticides, causing the contamination of workers.

Contamination Route of Leaf-Cutting Worker Ants Analyzed Through a Fat-Soluble Tracer Dye in Toxic Bait.

Our study seeks to discover contamination routes of leaf-cutting worker ants during chemical control by formicide baits. To do so, toxic baits containing fat-soluble tracer dye were provided to colonies of three subspecies of Acromyrmex under laboratory conditions, in order to assess the proportion of dyed workers by size category, as well as dyed internal morphological structures. Results showed that nearly 50% of the workers come into contact with the active ingredient, since the internal structures of their bodies are dyed by the fat-soluble tracer dye within the first 24 h from contact with the toxic bait. In addition, the three subspecies of leaf-cutting ants present a similarity as to the contamination of their workers, probably due to their specialized behavior performed during the growth of the fungus garden with the baits. We conclude that the workers' pattern of behavior during fungus garden growth was the main means for dispersion of a fat-soluble substance among approximately half of the nest mates in our experiments, serving as a model for further studies on contamination of worker ants with insecticides.

High Versus Low Load Resistance Training: The Effect of 24 Weeks Detraining on Serum Brain Derived-Neurotrophic Factor (BDNF) in Older Adults.

BACKGROUND: Previously we showed that 12 weeks of mixed-low resistance training (LOW+) significantly increased circulating BDNF in older male individuals. OBJECTIVES: To examine the impact of 24 weeks detraining on circulating BDNF. DESIGN: Randomized intervention study. SETTING: Community-dwelling older adults. PARTICIPANTS AND METHODS: Forty-seven out of 56 participants stopped training (detraining) after 12 weeks of resistance exercise (3x/week) at either HIGH-resistance (5 Males, 5 Females, 2x10-15 repetitions at 80%1RM), LOW-resistance (6 Males, 7 Females, 1x80-100 repetitions at 20%1RM), or mixed-low LOW+-resistance (6 Males, 8 Females, 1x60 repetitions at 20%1RM followed by 1x10-20 repetitions at 40%1RM), of whom 37 (aged 68±5 years) provided sufficient serum samples for BDNF analysis at baseline, 12 week and at 36 weeks (24 weeks detraining). RESULTS: BDNF had initially increased by 31% (from 33.4±10.9 ng/mL to 44.5±13.2 ng/mL, p=0.005) after 12 weeks in the LOW+ exercise group in males and decreased by 26% (from 44.5±13.2 ng/mL to 32.9±10.7 ng/mL) after detraining, though not statistically significant (p=0.082). In females, no significant change in BDNF was found in any of the intervention groups (p>0.05), neither after training, nor detraining. At 36 weeks all of the subgroups showed BDNF levels comparable (all p>0.10) to baseline (before the exercise intervention). CONCLUSIONS: Our results show that a 12-weeks LOW+ resistance exercise increases circulating BDNF in older male subjects but that this reduces back to baseline levels after 24 weeks of detraining. Continuous exercise adherence seems to be needed to sustain the training-induced effects on BDNF in older persons. Additional studies are needed to unravel the underlying mechanisms, as well as to confirm the observed sex difference.

Prevalence of the genus Cladosporium on the integument of leaf-cutting ants characterized by 454 pyrosequencing.

The relationship of attine ants with their mutualistic fungus and other microorganisms has been studied during the last two centuries. However, previous studies about the diversity of fungi in the ants' microenvironment are based mostly on culture-dependent approaches, lacking a broad characterization of the fungal ant-associated community. Here, we analysed the fungal diversity found on the integument of Atta capiguara and Atta laevigata alate ants using 454 pyrosequencing. We obtained 35,453 ITS reads grouped into 99 molecular operational taxonomic units (MOTUs). Data analysis revealed that A. capiguara drones had the highest diversity of MOTUs. Besides the occurrence of several uncultured fungi, the mycobiota analysis revealed that the most abundant taxa were the Cladosporium-complex, Cryptococcus laurentii and Epicoccum sp. Taxa in the genus Cladosporium were predominant in all samples, comprising 67.9 % of all reads. The remarkable presence of the genus Cladosporium on the integument of leaf-cutting ants alates from distinct ant species suggests that this fungus is favored in this microenvironment.

Circannual variation of efficacy outcomes in patients with newly diagnosed metastatic colorectal cancer and treated with first-line chemotherapy.

Seasonal variation of baseline diagnosis (or clinical suspect) of stage I-III colorectal cancer patients has been repeatedly reported as an independent variable influencing overall survival. However, data are conflicting and no information is available about such a rhythm in advanced stage patients. To test whether a circannual rhythm of efficacy outcomes can be detected in this setting, we collected data about response rate (RR), progression-free survival (PFS), and overall survival (OS) to first-line chemotherapy of 1610 newly diagnosed metastatic patients treated at four independent centers. Responses to first-line chemotherapy were available for 1495 patients. A strong circannual rhythm in RR was evident, with the higher proportion of responding patients in the subgroup diagnosed in January (acrophase). At the time of data cutoff, 1322 patients progressed and 986 died, with median PFS and OS of 11 and 25.6 months, respectively. A circannual rhythmicity of the proportion of patients progressing at 6 months and surviving at 1 year was demonstrated, with acrophases located both in winter (February and January, respectively), similar to what reported for RR. Several interpretations about the genesis of this cyclic variation could be claimed: the rhythm in sunlight exposure and, as a consequence, of vitamin D serum levels and folate degradation, the variability in toxic effect intensity of chemotherapy, and the rhythm in the biological behavior of tumor cells. This observation is worth of further investigation both in preclinical and in clinical settings in order to better elucidate the underlying mechanisms.

Use of Seeds as Fungus Garden Substrate Changes the Organization of Labor Among Leaf-Cutting Ant Workers.

Seeds of different plant species constitute an alternative but also significant substrate that leaf-cutting ants use to cultivate their fungus garden. However, how they are processed inside the nest and if their use implies differential allocation of worker size classes are still poorly known. Using laboratory colonies of Acromyrmex subterraneus (Forel) as a model, the behaviors related to the processing of three different seeds (sesame, guava, and grape) as fungus substrate were listed. At the same time, we measured how each worker size class contributed to the execution of these behaviors by registering their respective frequency. It was found that medium-sized (1.2 > head width < 1.6 mm) and minimum-sized (head width <1.1 mm) workers assumed the role of incorporation for sesame and grape seeds, respectively. Major-sized workers (head width >1.7 mm) were concentrated on licking and holding guava seeds. Tegument removal was the only task observed that differs between treatment of seeds and treatment of leaves before their incorporation, as described in the literature. It was verified that different species of seeds imply a differential allocation of worker size classes and the inclusion or exclusion of some tasks from the behavioral repertoire. Regardless of the substrate type, leaf-cutting ant workers follow a coordinated and specialized procedure to cultivate the fungus garden but always maintain a high degree of cooperation.

The prognostic role of baseline CEA and CA 19-9 values and their time-dependent variations in advanced colorectal cancer patients submitted to first-line therapy.

Serum marker evaluation is an easily available prognostic indicator that may help clinicians to discriminate patients with an aggressive disease; there are few and small-sized studies exploring the prognostic role of baseline carcinoembryonic antigen (CEA) values and their variations during first-line therapy, and even fewer data are available for carbohydrate antigen 19-9 (CA 19-9). Our aim was to analyze the role of those prognostic markers to exploit them in daily clinical practice. Data of 892 patients with marker determination before and 3 and/or 6 months during therapy were extracted from two institutional databases. Patients were grouped according to single marker variation as always negative (G0), decreasing (G1), stable (G2), or increasing (G3). We evaluated the progression-free survival (PFS) and the overall survival (OS) of all the patents and correlated them with CEA and CA 19-9 values. A concordance between response to therapy and marker decrease was evident in 50.2% and in 34.4% of the patients for CEA and CA 19-9. Patients with low CEA or CA 19-9 baseline values had a longer PFS (15.1 vs. 10.5; 13.6 vs. 10.2 months) and OS (32.0 vs. 22.3; 30.5 vs. 20.1 months). The same results of PFS and OS were obtained by analyzing the data of the four different groups. Multivariate analyses confirmed the independent prognostic role of CEA and CA 19-9. Baseline CEA and CA 19-9 levels and their kinetics demonstrated to be independent prognostic factors. CA 19-9 dosage is not recommended; a possible role of CA 19-9 in patients with negative CEA could be worth further evaluation.

Leaf-cutting ants: an unexpected microenvironment holding human opportunistic black fungi.

Fungus-growing ants of the genus Atta are known for their leaf-cutting habit, a lifestyle they have maintained since their 50-million-year-old co-evolution with a mutualistic fungus, cultivated as food. Recent studies have highlighted that, in addition to the mutualistic fungus, nests of ants harbor a great diversity of microbial communities. Such microorganisms include the dematiaceous fungi, which are characterized by their melanized cell walls. In order to contribute to the knowledge of fungal ecology, as well as opportunistic strains that may be dispersed by these social insects, we isolated and identified fungi carried by gynes of Atta capiguara and Atta laevigata, collected from colonies located in Fazenda Santana, Botucatu (São Paulo, Brazil). The isolation was carried out using the oil flotation technique, which is suitable for the growth of black fungi. Inoculated plates were incubated at 25 and 35 °C until black cultures were visible (20-45 days). Isolates were identified based on microscopic and molecular characteristics. Some isolated genera were: Cladophialophora, Cladosporium, Exophiala, Ochroconis, Phaeococcomyces, Phialophora and Penidiella. Hyaline species were also found. The results obtained from this work showed that leaf-cutting gynes may contribute to the dispersal of opportunistic dematiaceous fungi. It is suggested that more attention should be paid to this still unexplored subject.

Prey-capture efficiency between juveniles and adults, feeding habitat and abundance of Wattled Jacana foragers in northern Pantanal, Mato Grosso state, Brazil.

The choice of foraging strategies implies an attempt at gaining energy by predators. Supposedly, the difference in employing the "sit and wait" or "active foraging" behavior lays in hunter skills, experience and the kind of prey consumed. With the hypothesis that "active foraging" demands no learning, in this study we compared the prey capture efficiency among Wattled Jacana juveniles and adults, and also present descriptive information about feeding habitat and the abundance variation of foragers throughout the day in the northern Pantanal. Prey capture efficiency did not differ significantly among juveniles and adults, corroborating our initial hypothesis that "active foraging" is an instinctive behavior and demands no experience to be effective. However, future work is necessary to compare the energetic quality of consumed items by juveniles and adults, searching for differences explained by adults' experience. Foraging individuals were found at an average distance of 14 m ranging from 2 to 42 m) from the margin of the sampled swamps, however 64% of the foragers were found closer to the margins. The average depth of foraging sites was 17 cm, ranging from 5 to 40 cm, although no preference for specific classes of depth was found (p > 0,05). Despite the accepted general pattern of birds being more active in the early morning, the largest number of individuals foraging was observed between 11:00 and 12:00 AM, but no significant difference was found in the abundance of foraging individuals among different periods of the day. Factors, which were not analyzed, such as food availability and presence of competitors and predators need to be studied to reveal the main factors of the spatial and temporal distribution of the Wattled Jacana.

Side effects associated with ultrarapid cytochrome P450 2D6 genotype among women with early stage breast cancer treated with tamoxifen.

BACKGROUND: The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultra-metabolizers, UMs). The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects. METHODS: 61 women with ER+ breast cancer receiving tamoxifen monotherapy were investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genotyping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology. RESULTS: A highly significant difference was detected (41.2% of difference, 95% CI 6 - 61%, Fisher's exact test, p = 0.030) between the numbers of Ultrarapid Metabolizer patients (UM; high activity) with two or more adverse drug reactions to tamoxifen (7/9; 77.8%), compared to the number of Extensive Metabolizers (EM; normal activity), Intermediate Metabolizers (IM; reduced activity), and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5%). A similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM/EM/IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005). CONCLUSIONS: Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence.

Diet of Ameerega braccata (Steindachner, 1864) (Anura: Dendrobatidae) from Chapada dos Guimarães and Cuiabá, Mato Grosso State, Brazil.

The understanding of feeding habits is important for anurans in general, both from an ecological and a phylogenetic perspective. For diurnal poison frogs belonging to the Dendrobatidae family, diet aspects play a crucial role in their defense and survival. Herein, we investigated feeding habits, foraging behaviour, and overall effects of habitat, sex, and body size on the diet of individuals of Ameerega braccata, a poorly known dendrobatid species. Specimens were observed and collected in the type-locality, Chapada dos Guimarães, and in the neighbouring municipality of Cuiabá, both in the State of Mato Grosso, Midwestern Brazil. The most important prey categories for A. braccata were Formicidae, Isoptera, and Acari, whose representatives were caught during active foraging. Individuals from Chapada dos Guimarães population consumed more Acari but fewer Isoptera than individuals from Cuiabá. Despite this, niche breadth values were narrow and similar for the two populations. Individuals from two distinct habitats (campo sujo and cerrado stricto sensu) showed differences in their diet, probably as an effect of differential prey availability. Females consumed more Isoptera than males. The number of prey categories used as food was not influenced by the variation of body size of the target species. However, the abundance and the volume of consumed Acari were statistically correlated with body size. The main results suggest that Ameerega braccata has a narrow niche breadth, as well as a specialised diet in ants, termites, and mites, which reinforces the hypotheses of close association between Acari consumption and the presence of skin toxic alkaloids, already found in other species of Dendrobatidae. Although differences in prey consumption between sexes are uncommon among poisonous frogs, differences in the diet composition between age classes, which probably reduce intraspecific competition, are frequently reported.

Acoustic communication and vocalization microhabitat in Ameerega braccata (Steindachner, 1864) (Anura, Dendrobatidae) from midwestern Brazil.

Ameerega braccata is an aposematic, small dendrobatid anuran known from its type-locality, Chapada dos Guimarães, in the State of Mato Grosso, and from a few additional localities in Mato Grosso do Sul and Goiás States, Brazil. The advertisement call of A. braccata is composed of a single unpulsed note, with a frequency range from 3.5 to 4.2 KHz (N = 110), and average duration of 65.8 ms (N = 110, SD = 11.6). The territorial call is composed of five or six repeated notes, structurally similar to advertisement call notes. The courtship call is emitted in close-range interactions between male-female during the courtship event and may reach frequencies of 2.2 to 5.3 KHz (N = 10), with shorter notes (average duration 43 ms; N = 10; SD = 4.9). Call duration, note duration and call rate of the advertisement call showed high variation (>15% of coefficient of variation), and dominant frequency showed low variation (<4%). The properties with higher variation possibly respond to climatic features and male social position. When producing advertisement calls, males were usually found at an average height of 31.4 cm (N = 19, SD = 12.2 cm), mainly on leaves of shrubs and herbaceous plants (59%). Individuals of A. braccata were found in open physiognomies in the Cerrado ('campo sujo' and 'cerrado stricto sensu'), as opposed to that found by previous researchers, who reported an association of the species with gallery forests in the Cerrado.

The resveratrol analogue 4,4'-dihydroxy-trans-stilbene inhibits cell proliferation with higher efficiency but different mechanism from resveratrol.

Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a natural phytoalexin found in grapes and wine, which shows antiproliferative activity. We previously found that 4-hydroxy group in the trans conformation was absolutely required for the inhibition of cell proliferation. In the present work we have synthesized the resveratrol analogue 4,4'-dihydroxy-trans-stilbene, which contains two OH in 4' and 4 positions, with the aim of developing a compound with an antiproliferative potential higher than that of resveratrol, on the basis of the correlation between structure and activity previously observed. In comparison with resveratrol, 4,4'-dihydroxy-trans-stilbene inhibited cell clonogenic efficiency of fibroblasts nine times more although with a different mechanism. First, 4,4'-dihydroxy-trans-stilbene induced predominantly an accumulation of cells in G1 phase, whereas resveratrol perturbed the G1/S phase transition. Second, although both compounds were able to inhibit DNA polymerase (pol) delta in an in vitro assay, 4, 4'-dihydroxy-trans-stilbene did not affect pol alpha activity. Finally, 4,4'-dihydroxy-trans-stilbene increased p21(CDKN1A) and p53 protein levels, whereas resveratrol led to phosphorylation of the S-phase checkpoint protein Chk1. Taken together, our results demonstrated for the first time that the two hydroxyl groups on 4- and 4'- positions of the stilbenic backbone enhance the antiproliferative effect and introduce additional targets in the mechanism of action of resveratrol. In conclusion, 4,4'-dihydroxy-trans-stilbene has potent antiproliferative activities that differ from the effect of resveratrol shown in this system, suggesting that it warrants further development as a potential chemopreventive or therapeutic agent.

The CAP-CR study: direct medical costs in Italian metastatic colorectal cancer patients on first-line infusional 5-fluorouracil or oral capecitabine.

AIM: To describe the healthcare resource consumption of metastatic colorectal cancer (MCRC) patients in the Italian healthcare setting. METHODS: A retrospective chart analysis estimating direct medical costs of first-line infusional 5-Fluorouracil (5-FU) or oral Capecitabine (CAP), associated or not with other chemotherapies, from the Italian Healthcare Service (IHCS) and Hospital (H) perspectives. RESULTS: 202 subjects were analysed. CAP patients (N=66) were older, with a more compromised clinical status and received less chemotherapy agents in association than 5-FU patients (N=136). From the IHCS perspective, mean total costs per patient were 12,029 euro and 5,781 euro in the 5-FU and CAP arms respectively; 7,338 euro and 4,688 euro from the H perspective. The infusional administration route of 5-FU was a cost driver from both perspectives. Sensitivity analyses found the results to be robust to variations in base case parameters. CONCLUSIONS: Management of MCRC by oral chemotherapies may be an economically advantageous option to both IHCS and hospitals.