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Islands host high numbers of endemic species, and the latter are especially exposed to human-driven habitat alteration because their population size is constrained by the limited space and resources found in insular systems. Extreme events linked with climate change and direct anthropogenic stressors may synergistically affect endemic species, and even push them to the brink of extinction. Bats include many insular endemics whose life traits make them excellent candidates to test the effects of both climate-change driven events and direct human disturbance. The Mediterranean island of Sardinia is home to the endemic long-eared bat Plecotus sardus. Within the island, this recently described species is restricted to a limited range where suitable habitat is present. This makes the species extremely vulnerable to human action. Here we use Plecotus sardus as a model to assess the response of insular endemic bats to climate change and human disturbance, exploring demographic trends across two decades. Overall, roost count data for all known reproductive sites showed a steep (-63.4% between 2003 and 2020) population decline, so that the current estimated population size is only 36.5% of that observed in 2003. Colony growth rates are strongly affected by recurring wildfires around reproductive sites, summer precipitation and temperature extremes, pointing to climate change as a primary threat to the species along with direct human interference. Such anthropogenic pressures may therefore rapidly expose island endemic bats to a high extinction risk. Based on our analysis, Plecotus sardus is among the most threatened mammals, and likely the rarest bat species, in Europe. Thus, we urge that (1) similar assessments are conducted on other insular endemic bats in Mediterranean Europe, (2) IUCN Redlist categories are revised according to new analyses, and (3) recovery action plans are immediately developed and implemented to revert the current population trends. [ABSTRACT FROM AUTHOR]

Objectives: To report outcomes of stereotactic body radiotherapy (SBRT) in metastatic castration-resistant prostate cancer (mCRPC) patients with oligoprogression (≤ 5 metastases) during first-line treatment with androgen receptor-targeted therapy (ARTT). Patients and methods: Retrospective multi-institutional analysis of mCRPC patients treated with SBRT to oligoprogressive lesions during ARTT. End-points were time to next-line systemic treatment (NEST), radiological progression-free survival (r-PFS) and overall survival (OS). Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Survival analysis was performed using the Kaplan–Meier method, univariate and multivariate analysis (MVA) were performed. Results: Data from 34 patients were analyzed. Median NEST-free survival, r-PFS, and OS were 16.97, 13.47, and 38.3 months, respectively. At MVA, factors associated with worse NEST-free survival and r-PFS were polymetastatic burden at diagnosis of metastatic hormone-sensitive disease (hazard ratio [HR] 3.66, p = 0.009; HR 3.03, p = 0.034), PSA ≤ 7 ng/ml at mCRPC diagnosis (HR 0.23, p = 0.017; HR 0.19, p = 0.006) and PSADT ≤ 3 months at mCRPC diagnosis (HR 3.39, p = 0.026; HR 2.79, p = 0.037). Polymetastatic state at mHSPC diagnosis was associated with a decreased OS (HR 4.68, p = 0.029). No patient developed acute or late grade ≥ 2 toxicity. Conclusion: Our results suggest that SBRT in oligoprogressive mCPRC is safe, effective and seems to prolong the efficacy of the ongoing systemic treatment positively affecting disease progression. Prospective trials are needed. [ABSTRACT FROM AUTHOR]

Preserving species within protected areas (PAs) does not guarantee adequate levels of protection if not coupled with conservation of functional connectivity for a target species. We propose an analytical framework to assess the effectiveness of PAs in preserving habitat and functional connectivity for mobile vertebrates. We implemented it in central Italy by using as a case study a bat species (common noctule, Nyctalus noctula) to: (i) determine suitable areas by means of Species Distribution Models (SDMs); (ii) identify potential commuting corridors through a functional connectivity analysis; (iii) develop a new tool to rank corridors according to their functional irreplaceability; (iv) implement a gap analysis on both suitable areas and functional corridors; and (v) propose management recommendations for the conservation of N. noctula. The SDM output and a set of proxies of commuting routes were used to build a resistance layer for the connectivity analysis. The resulting functional corridors were ranked according to their isolation (distance to other corridors and to suitable areas) to obtain an irreplaceability index, with isolated corridors scoring high values. The PA effectiveness assessed by overlapping the PA map with the SDM and the ranked functional corridors highlighted that PAs cover just a small portion of suitable sites (20.3%) and functional corridors for the species (20.8%). The irreplaceability index allowed us to identify those areas inside and outside the PAs that critical for persistence of the species in question require immediate protection regimes. The approach we present could be easily extended to other taxa and offers sound insight on how to promote the conservation at landscape scale. [ABSTRACT FROM AUTHOR]

Introduced species represent a threat to native wildlife worldwide, due to predation, competition, and disease transmission. Concurrent introduction of parasites may also add a new dimension of competition, i.e. parasite-mediated competition, through spillover and spillback dynamics. Urban areas are major hotspots of introduced species, but little is known about the effects of urban habitat structure on the parasite load and diversity of introduced species. Here, we investigated such environmental effects on the ectoparasite load, richness, and occurrence of spillback in two widespread invasive parakeets, Psittacula krameri and Myiopsitta monachus, in the metropolitan area of Rome, central Italy. We tested 231 parakeets and found that in both species parasite load was positively influenced by host abundance at local scale, while environmental features such as the amount of natural or urban habitats, as well as richness of native birds, influenced parasite occurrence, load, and richness differently in the two host species. Therefore, we highlight the importance of host population density and habitat composition in shaping the role of introduced parakeets in the spread of both native and introduced parasites, recommending the monitoring of urban populations of birds and their parasites to assess and manage the potential occurrence of parasite-mediated competition dynamics as well as potential spread of vector-borne diseases. [ABSTRACT FROM AUTHOR]

Urbanisation and climate change are two global change processes that affect animal distributions, posing critical threats to biodiversity. Due to its versatile ecology and synurbic habits, Kuhl's pipistrelle ( Pipistrellus kuhlii) offers a unique opportunity to explore the relative effects of climate change and urbanisation on species distributions. In a climate change scenario, this typically Mediterranean species is expected to expand its range in response to increasing temperatures. We collected 25,132 high-resolution occurrence records from P. kuhlii European range between 1980 and 2013 and modelled the species' distribution with a multi-temporal approach, using three bioclimatic variables and one proxy of urbanisation. Temperature in the coldest quarter of the year was the most important factor predicting the presence of P. kuhlii and showed an increasing trend in the study period; mean annual precipitation and precipitation seasonality were also relevant, but to a lower extent. Although urbanisation increased in recently colonised areas, it had little effect on the species' presence predictability. P. kuhlii expanded its geographical range by about 394 % in the last four decades, a process that can be interpreted as a response to climate change. [ABSTRACT FROM AUTHOR]

Although open landscapes are typically regarded as inhospitable matrix for several species of forest bats, their role may be crucial for maintaining gene flow among otherwise isolated populations occurring in distant forest fragments. The barbastelle ( Barbastella barbastellus) is a bat species previously known to depend on mature forest and dead trees in its wide yet fragmented range. We tested the general hypothesis that viable populations of this bat may persist in open landscapes whose current structure is the result of historical deforestation. We unveiled the roosting and foraging ecology of B. barbastellus in a clay badland area of central Italy where forested habitats are absent and woody vegetation is scarce. Bats in badlands used rock crevices in lieu of the typical maternity tree-roosts and largely foraged in non-forest habitat, alongside riparian vegetation, where they found moth-rich hunting sites. Body condition and sex ratio did not differ from those documented in a source population found in mature forest in the same region. Our study identifies the hitherto overlooked importance of apparently unsuitable landscapes for the conservation of bats regarded as forests specialists and highlights that such environments and the associated occurrence of favoured prey should be carefully considered in management plans. [ABSTRACT FROM AUTHOR]

The presence of the sodium/iodide symporter (NIS) is the prerequisite for the use of the radioiodine in the treatment of thyroid cancer. Thus, stimulators of NIS expression and function are currently investigated in cellular models of various human malignancies, also including extrathyroid cancers. In this study, we analyzed the effects of the histone deacetylase inhibitors (HDACi), suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA), on NIS expression and function in rat Leydig testicular carcinoma cells (LC540). LC540 cells were exposed to SAHA 3 μM and VPA 3 mM (alone and in combination), and cell viability evaluated by MTT assay and cell counting, NIS mRNA and protein levels by using, respectively, real-time RT-PCR and western blotting. NIS function was evaluated by iodide uptake assay. We found that both HDACi were able to stimulate the transcription of NIS gene, but not its protein expression, while the association of SAHA and VPA increased both NIS transcript and protein levels, resulting in significant sixfold enhancement of radioiodine uptake capacity of LC540 cells. These data demonstrate the presence of an epigenetic control of NIS expression in Leydig tumor cells, suggesting the possibility to use the combination of these two HDACi for a radioiodine-based treatment of these malignancies. [ABSTRACT FROM AUTHOR]

Dear Editor, We read with great interest the article by Kontopoulou et al. [[1]] describing the study of the dsDNA carried by extracellular vesicles (EVs) in pediatric acute myeloid leukemia (AML) patients. We enrolled 7 AML patients and 1 healthy control (Table 1) and collected peripheral blood (PB) and bone marrow (BM) specimens from AML patients, while only PB was collected from healthy donor. In 2/7 (29%) AML cases, no leukemia-specific mutation was sequenced neither on exoDNA nor on PB and BM genomic DNA (Table 1). [Extracted from the article]

Human oncogenes involved in the development of hematological malignancies have been widely used to model experimental leukemia. However, models of myeloid leukemia rarely reproduce the human disease in full, due to genetic complexity or to difficulties in targeting leukemia initiating cells. Here, we used a zebrafish genetic model to induce the expression of oncogenic RAS in endothelial cells, including the hemogenic endothelium of the dorsal aorta that generates hematopoietic cells, and observed the development of a myelo-erythroid proliferative disorder. In larvae, the phenotype is characterized by disruption of the vascular system and prominent expansion of the caudal hematopoietic tissue. In few surviving juveniles, increased number of immature hematopoietic cells and arrest of myeloid maturation was found in kidney marrow. Peripheral blood showed increased erythroblasts and myeloid progenitors. We found that the abnormal phenotype is associated with a downregulation of the Notch pathway, whereas overexpressing an activated form of Notch together with the oncogene prevents the expansion of the myelo-erythroid compartment. This study identifies the downregulation of the Notch pathway following an oncogenic event in the hemogenic endothelium as an important step in the pathogenesis of myelo-erythroid disorders and describes a number of potential effectors of this transformation. [ABSTRACT FROM AUTHOR]

Genetic heterogeneity in drug-metabolizing enzyme/transporter (DMET) genes affects specific drug-related cancer phenotypes. To investigate the relationships between genetic variation and response to treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-Ozogamicin (GO) with Fludarabine-Cytarabine-Idarubicin (FLAI) regimen, with the DMET Plus platform. Two ADH1A variants showed statistically significant differences (odds ratio (OR)=5.68, P=0.0006; OR=5.35, P=0.0009) in allele frequencies between patients in complete/partial remission and patients without response, two substitutions on CYP2E1 (OR=0.13, P=0.001; OR=0.09, P=0.003) and one on SLCO1B1 (OR=4.68, P=0.002) were found to differently influence liver toxicity, and two nucleotide changes on SULTB1 and SLC22A12 genes correlated with response to GO (OR=0.24, P=0.0009; OR=2.75, P=0.0029). Genetic variants were thus found for the first time to be potentially associated with differential response and toxicity in AML patients treated with a combination of GO-FLAI regimen. [ABSTRACT FROM AUTHOR]

Wind farms are steadily growing across Europe, with potentially detrimental effects on wildlife. Indeed, cumulative impacts in addition to local effects should be considered when planning wind farm development at a regional scale, and mapping the potential risk to bats at this scale would help in the large-scale planning of wind turbines and focus field surveys on vulnerable areas. Although modelling offers a powerful approach to tackle this goal, its application has been thus far neglected. We developed a simple regional-scale analysis in an area of central Italy (Molise region) that is undergoing considerable wind farm development. We implemented species distribution models (SDMs) for two bat species vulnerable to wind farm impact, Nyctalus leisleri and Pipistrellus pipistrellus. We developed risk maps by overlaying SDMs for the two species with turbine locations, assessed the alteration of the landscape patterns of foraging habitat patches determined by the wind turbines, and identified highly vulnerable areas where wind farm construction would be particularly risky. SDMs were statistically robust (AUC ≥0.8 for both species) and revealed that 41 % of the region offers suitable foraging habitat for both species. These areas host over 50 % of the existing or planned wind farms, with 21 % of the turbines located within 150 m of forest edges, suggesting an increase in fatality risk. The alterations in suitable foraging patches consisted of a 7.7 % increase in the number of patches, a 10.7 % increase in the shape index, and a 8.1 % decrease in the mean patch area. The region's western portion, which is most suitable to both species, requires careful consideration with regard to future wind farm planning. [ABSTRACT FROM AUTHOR]

Phosphoinositide-phospholipase C (PI-PLC) beta1 can be considered a specific target for demethylating therapy in high-risk myelodysplastic syndrome (MDS) patients, as azacitidine treatment has been associated with a PI-PLCbeta1-specific promoter demethylation, and induction of PI-PLCbeta1 gene and protein expression. However, little is known about the molecular effect of azacitidine in low-risk MDS or the functional mechanisms linked with azacitidine effect on PI-PLCbeta1 promoter. In the present study, we further investigated the role of epigenetic regulation of PI-PLCbeta1, mainly focusing on the structure of the PI-PLCbeta1 promoter. We first examined the effect of azacitidine on PI-PLCbeta1 promoter methylation and gene expression in low-risk MDS. Moreover, we studied the expression of key molecules associated with the nuclear inositide signaling pathways, such as cyclin D3. By applying a chromatin immunoprecipitation method, we also studied the correlation between the demethylating effect of azacitidine and the degree of recruitment to PI-PLCbeta1 promoter of some transcription factors implicated in hematopoietic stem cell proliferation and differentiation, as well as of the methyl-CpG-binding domain proteins, which specifically interact with methylated DNA. Taken together, our results hint at a specific involvement of PI-PLCbeta1 in epigenetic mechanisms, and are particularly consistent with the hypothesis of a role for PI-PLCbeta1 in azacitidine-induced myeloid differentiation. [ABSTRACT FROM AUTHOR]

This work was undertaken to investigate thermal and dynamic transitions observed in the temperature range close to the bulk ice melting temperature in sucrose solutions. Measurements of thermal (differential calorimetry) and dynamic (neutron scattering) properties were compared in order to give a physical interpretation of the thermal transitions observed during the thawing of amorphous sucrose solutions. In fact, the freezing of biological material leads to the distinction between different pools of water: bulk water which becomes ice after freezing, unfrozen water trapped in the glassy matrix or close to the interface of solutes can be considered, and finally freezable confined water with a lower melting point than bulk water and with properties depending on both the ice presence and the microstructure of the material. The transition temperatures such as glass transition or melting are dependent on the freezing protocol used and examples of annealing effects are presented, in order to underline the necessity of a good temperature control during freezing for the study of biological material with freezable water. [ABSTRACT FROM AUTHOR]

The role of different cytokines and cells of immune system in the pathogenesis of chronic GVHD (cGVHD) is still controversial. Earlier studies, which were either retrospective or analysed one or a few factors, did not show unequivocal results. We prospectively evaluated cytokine levels and lymphocyte subsets in 30 patients who underwent Allo-SCT to investigate their possible correlation with cGVHD. Levels of IL-4, IL-6, IL-10, IFN-γ, tumour necrosis factor-alpha (TNF-α) and its soluble receptors were assessed by ELISA in 30 patients at different times after SCT. Lymphocyte subsets were evaluated by flow cytometry in peripheral blood at the same times as cytokines. A multivariate analysis was performed using principal component analysis and multi-factor ANOVA (analysis of variance). Eighteen patients developed cGVHD at a median time of 6 months (range, 5–9) after SCT. In multivariate analysis, we observed a correlation between cGVHD and clusters of cytokines and lymphocyte subsets from the third to the sixth month after SCT. These clusters changed their composition over time, but they constantly included natural killer (NK) and CD152+ T cells as negative predictors of cGVHD. TNF-α prevailed among other cytokines before the onset of cGVHD. This prevalence could be related partly to the defect of immunoregulatory cells. [ABSTRACT FROM AUTHOR]

Adhesion molecules are intimately involved in the process of tumour progression. Among them, E-selectin is an inducible endothelial cell adhesion molecule that plays a role in the interactions of neoplastic cells with the endothelium. These interactions are required for the trans-endothelial migration of tumour cells that leads to the growth at the new sites. Since the detailed events in the early phase of metastasis still remain poorly defined, our study has undertaken an electron-microscopic analysis of the interactions of human colon carcinoma cells with endothelial cells as well as an analysis of the effect of recombinant purified E-selectin in the cell signalling involved in colon cancer cell malignant phenotype. Results revealed that SW480 and T84 colon cancer cell lines show different features, different adhesion kinetics, a different cytoskeletal organization, and a different tyrosine phosphorylation pattern when seeded on an endothelial cell monolayer or recombinant E-selectin. In particular T84 cancer cells adhere more efficiently to the E-selectin and this interaction is associated with pronounced morphological changes, actin redistribution and filopodial processes, and an increase in tyrosine phosphorylation of different proteins. These data support the hypothesis that E-selectin ligand is not only a cell-cell adhesion molecule but also initiates a signalling transduction pathway inside the cells. [ABSTRACT FROM AUTHOR]

YNK01 (Starasid) is a prodrug that is adsorbed in the gut and is transformed in the liver in arabinosyl cytosine (AC). Low-dose AC (LDAC) is useful for the treatment of Philadelphia positive (Ph+) chronic myeloid leukemia (CML), especially in combination with alpha-interferon (alphaIFN). The use of YNK01 can avoid the daily s.c. injection of conventional AC. To assess the safety and the efficacy of alphaIFN and YNK01, we enrolled 86 consecutive previously untreated chronic phase Ph+ CML patients in a phase II study of alphaIFN (Intron-A) 5 MIU/m(2) daily and YNK01 600 mg daily 14 days a month. The 6-month complete hematologic response and the 12-month major cytogenetic response rates were 78 and 28%, respectively. In a prior study of alphaIFN and conventional LDAC, they were 62 and 22%, respectively. However, the compliance to the treatment was poor, with 25% of cases discontinuing the treatment within the first year. This was not because of the severity of the side effects but because of the frequency, duration and repetition of the side effects, for an overall frequency of 13.17 adverse events, mostly grade 1 and 2, per patient per year. Therefore, the study of this effective combination is being pursued, testing lower doses of alphaIFN and YNK01. [ABSTRACT FROM AUTHOR]

Toxicity limits the use of anthracyclines in elderly sick patients and in heavily pretreated patients. Since the liposomal preparation of daunorubicin (DNR) (DaunoXome, or DNX) is expected to be less toxic than conventional DNR, we tested DNX combined with high-dose arabinosyl cytosine (HDAC) in 42 adult poor-risk acute leukemia patients. Thirty-one patients had acute non-lymphocytic leukemia (ANLL). Of these, 12 patients were newly diagnosed but were not eligible for standard induction treatment, 13 were in first relapse, and 6 were in second or subsequent relapse. Eleven patients had acute lymphocytic leukemia (ALL), in first (eight cases) or second (three cases) relapse. DNX was given i.v. in three doses of 80 or 100 mg/m2 each (days 1–3) by a 60-min infusion in glucose 5%, followed by a 4-h infusion of HDAC 2 g/m2 (days 1–5). Among 31 ANLL patients there were 16 (51%) complete remissions (CR), 5 deaths during induction, and 10 failures. Among 11 ALL patients there were 10 CRs and 1 failure. The response rate was not affected by the overexpression of MDR-related proteins (PgP, MRP-1, and LRP). Non-hemopoietic toxicity was negligible, with no intestinal toxicity and only one case of gram-negative bacteremia. We conclude that DNX, in combination with HDAC, is an effective treatment for poor-risk adult AL. Because of the low non-hematologic toxicity, it can be used to reinduce remission in poor-risk patients who are candidates for allogeneic bone marrow transplantation. The high CR rate observed in ALL requires confirmation. [ABSTRACT FROM AUTHOR]

Constitutive activating mutations of the TSHR gene, have been detected in about 30 per cent of hyperfunctioning human thyroid adenomas and in a minority of differentiated thyroid carcinomas. The mutations activating the TSHR gene(s) in the thyroid carcinomas, were located at the codon 623 changing an Ala to a Ser (GCC→TCC) or in codon 632 changing a Thr to Ala or Ile (ACC→GCC or ACC→ATC). In order to study if the constitutively activated TSHR gene(s) has played a role in the determination of the malignant phenotype presented by these tumors, we investigated: (1) the transforming capacity after transfection of mouse 3T3 cells, of a TSHR cDNA activated by an Ala→Ser mutation in codon 623 or an Thr→lle mutation in codon 632 and (2) the pathway(s) eventually responsable(s) for the malignant phenotype of the cells transformed by these constitutively activated TSHR cDNAs. Our results show that (1) the TSHRM623 orM632 cDNAs give rise to 3T3 clones presenting a fully neoplastic phenotype (growth in agar and nude mouse tumorigenesis); this phenotype was weaker in the cells transformed by the 632 cDNA; (2) suggest that the fully transformed phenotype of our 3T3 cells, may be the consequence of the additive effect of the activation of at least two different pathways: the cAMP pathway through Gαs and the Ras dependent MAPK pathway through Gβγ and PI3K and (3) show that the PI3K isoform playing a key role as an effector in the MAPK pathway activation in our 3T3-transformed cells is PI3Kγ. Signaling from PI3Kγ to MAPK appears to require in our murine cellular system a tyrosine kinase (still not characterized), Shc, Grb2, Sos, Ras and Raf. It is proposed that the constitutively activated TSHR genes detected in the thyroid carcinomas, may have played an oncogenic role, participating in their development through these two pathways. Oncogene (2000) 19, 4896–4905 [ABSTRACT FROM AUTHOR]

We measured using a competitive quantitative polymerase chain reaction-capillary electrophoresis (PCR-CE)-based assay, the levels of bcr-abl transcripts in 44 patients with chronic myeloid leukemia (CML) after interferon-α (IFN-α) therapy, who achieved a major (10 patients, MCR group) or complete (34 patients, CCR group) cytogenetic response. All 34 CCR patients had molecular evidence of residual disease detected in bone marrow samples at the time of best karyotypic response. The median number of bcr-abl transcripts of 34 evaluable patients in the CCR group at the time of complete cytogenetic remission was 4/μg RNA (range 3–4600), while the median number of bcr-abl transcripts of 10 patients in the MCR group at the time of best cytogenetic response was 4490/μg RNA (range 600–23 900) (P = 0.000024). In nine CCR and five MCR patients we were able to quantify the amount of bcr-abl transcript both at diagnosis and after interferon therapy: no statistical difference (P = 0.18) was found between the two groups at diagnosis (median bcr-abl transcripts/μg RNA was 30 000 vs 39 650, respectively). During IFN-α therapy, the two groups were evaluable at the time of major karyotypic conversion: at this point, there was a statistical difference of expression of bcr-abl transcript between the CCR group (17 patients) (median 2700; range 76–40 000) and the MCR group (10 patients) (median 4490; range 600–23 900), respectively (P = 0.046). No differences of bcr-abl amount of transcript were found in patients with CCR obtained either by IFN-α therapy alone (20 patients) vs IFN-α plus ABMT (13 patients) (P = 0.47). We firstly demonstrated that although the CCR and MCR groups were clinically, cytogenetically and molecularly indistinguishable at diagnosis, the two groups could be recognized successfully during interferon therapy based on the level of bcr-abl transcript. Bone Marrow Transplantation (2000) 25,... [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of the coadministration of the multidrug resistance (MDR) modulators cyclosporin A (CyA) alone or plus dexverapamil (D-Ver) on idarubicin (IDA) pharmacokinetics in patients with acute leukemia. Methods: Pharmacokinetic studies were performed in 27 patients with a diagnosis of acute myelogenous leukemia (AML), who were being treated with a combination chemotherapy regimen including idarubicin and cytarabine for the induction of a first remission ( n = 14), or of a second remission ( n = 7), or for remission consolidation ( n = 6). Of these 27 patients, nine were coadministered CyA and seven were coadministered CyA plus D-Ver as MDR modulators. Blood was sampled at appropriate intervals after each of the three IDA daily administrations. IDA and idarubicinol (IDAOL) were assayed by HPLC. Pharmacokinetic evaluations were performed by means of a two-compartment open model with zero-order absorption and first-order elimination using the WinNonlin pharmacokinetic software package. Results: CyA markedly increased the area under the concentration time-curve (AUC) of both IDA [558.26 (197.25) μg · h · l−1 vs 315.44 (158.28) μg · h · l−1; P < 0.01] and IDAOL [2896.60 (736.38) μg · h · l−1 vs 1028.49 (603.95) μg · h · l−1; P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l · h−1 · m−2 vs 139.65 (69.45) l · h−1 · m−2; NS]. When patients received two MDR modulators simultaneously (D-Ver plus CyA), IDA exposure was essentially the same as in those of the no inhibitor group [331.29 (95.49) μg · h · l−1 vs 315.44 (158.28) μg · h · l−1; NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) μg · h · l−1 vs 1028.49 (603.95) μg · h · l−1; P < 0.01], even if less than in patients receiving CyA as a single MDR modulator (IDA + CyA group) [AUC 2030.32 (401.11) μg · h · l−1 vs 2896.60 (736.38) μg · h · l−1; P < 0.05], suggesting an antagonistic effect against those of CyA on IDA and IDAOL elimination and/or an unpredictable redistribution. The main pharmacokinetic parameters of IDA, such as CL and volume of distribution at steady state (Vdss), were remarkably affected by the coadministration of CyA or CyA plus D-Ver, but no statistically significant difference was noted because of IDA pharmacokinetic interpatient variation. Conclusion: The results show that CyA alone at a dose of 10 mg · kg−1 daily significantly increased systemic body exposure to both IDA and IDAOL in acute leukemia, and suggest that these pharmacokinetic effects were at least partially decreased when D-Ver was coadministered with CyA. Our findings raise important questions concerning the need for a dosage adjustment of IDA when MDR modulators are coadministered. [ABSTRACT FROM AUTHOR]

Since in vitro observations indicated that all-trans retinoic acid (ATRA), especially in combination with IFNalpha, can exert significant suppressive effects on Ph+ cells, we investigated the effects and the pharmacokinetic profile of ATRA in a selected cohort of patients with Ph+ chronic myeloid leukemia (CML) in chronic phase. Eighteen patients were treated with ATRA at a dose of 80 mg/m2/day (p.o.), divided into two equal doses after meals, for 7 consecutive days every other week for a maximum of 12 courses (1 course = 1 week on and 1 week off). Pharmacokinetic profiles of ATRA were evaluated during intermittent therapy on days 1 and 7 of course 1; on day 1 of course 2; on day 1 of course 6. Out of the 18 patients treated with ATRA, 11 (61%) went off study before the sixth course of treatment because of progressive hyperleukocytosis (seven cases), or thrombocytosis (one case), or refusal (three cases). Seven (39%) patients completed the first six courses (12 weeks) of treatment with ATRA and two of them (11%) maintained a white blood cell (WBC) <10 x 10[9]/l which was induced by the pretreatment with hydroxyurea. One patient completed the 12th course of ATRA maintaining WBC <10 x 10(9)/l, platelets <500 x 10(9)/l and spleen not palpable. The treatment with ATRA was well tolerated and only one patient discontinued the therapy because of non-hematological side-effects. The area under the concentration-time curve (AUC) decreased significantly (P< 0.001) during the first week of therapy. By adopting an intermittent dosing regimen, 1 week on/ 1 week off (1 course), at the start of courses 2 and 6, we obtained the ATRA AUCs equivalent to the ones achieved on day 1 of course 1. In conclusion, our results showed that ATRA alone appeared to be unable to control the WBC expansion in the CML patients in chronic phase. Moreover, it did not induce any remarkable cytoreductive effects on the platelet count and on the hemoglobin level. The major interest of ATRA would be in combination with other therapies. If ATRA was given in combination with IFNalpha or other agents, dose reduction of these would not be planned. On the basis of the pharmacokinetic profile, ATRA should be administered intermittently rather than continuously. [ABSTRACT FROM AUTHOR]

Homoharringtonine (HHT) is a cephalotaxine alkaloid that showed clinical efficacy in the chronic phase of chronic myeloid leukemia (Ph1+CML). As a single agent, it resulted in effectively controlling leukocytosis and in producing sporadic karyotypic conversions; its clinical use in combination with interferon (IFN-alpha) for the treatment of CML could thus be considered. In this study we evaluated the growth inhibition and the induction of apoptosis determined by HHT alone and in combination with IFN-alpha and cytosine arabinoside (Ara-C) on normal and CML (both in chronic, CML-CP and in blastic phase; CML-BP) hematopoietic progenitors. HHT is able to determine a dose-dependent cell growth inhibition; evaluation of cytotoxic activity on semisolid cultures showed an activity significantly higher on CML-CP than on normal cells (P = 0.02 for HHT 50 ng/ml and P = 0.01 for HHT 200 ng/ml). HHT exerted a synergistic effect with IFN-alpha, Ara-C and IFN-alpha + Ara-C in inhibiting CML-CP colony growth; the same activity was demonstrated by the combination of HHT with Ara-C and by the triple combination, but not by HHT + IFN-alpha, on normal myeloid progenitors. The triple combination only was able to exert a synergistic effect in CML-BP. The induction of apoptosis resulted HHT dose-dependent in CML-CP and normals; at higher drug concentrations (100-200-1000 ng/ml), HHT induced a significant increase of apoptotic cells (for normals: P = 0.04, P = 0.02 and P = 0.04; for CML-CP: P = 0.01, P = 0.01 and P = 0.04, respectively); no significant changes were observed in CML-BP. In conclusion, the differences in cytotoxic effect and apoptosis induction observed, depending on the various phases of CML, add experimental evidence to the different clinical results between the chronic phase, where the clone is responsive to HHT, and the acute phase, where the drug is ineffective. The in vitro synergism of HHT with Ara-C and IFN-alpha in CML-CP suggests further evaluation in the clinical setting. [ABSTRACT FROM AUTHOR]

P-glycoprotein (Pgp)-related multidrug resistance (MDR) is frequently observed in acute non-lymphocytic leukemia (ANLL) and is associated with a poor response to standard chemotherapy. Cyclosporin A (CsA) is an effective downmodulator of Pgp-related MDR in vitro and has already been tested for that purpose in vivo also. Since Pgp is expressed in several normal cells and tissues, the modulation of Pgp can also modify total body exposure to antileukemic drugs and can alter and increase the toxicity of the antileukemic treatment. We report here the results of a study where 46 consecutive adult patients with ANLL were assigned to receive the same standard chemotherapy regimen of arabinosyl cytosine and idarubicin (IDA) for remission induction or consolidation, without or with CsA. Twenty-eight patients received 36 courses of chemotherapy without CsA and 18 patients received 32 courses of chemotherapy with CsA. CsA dose was 10-12.5 mg/kg/day and was given as a continuous i.v. infusion for 72 h. Whole blood CsA steady-state concentration ranged between 0.61 and 1.14 microM. The IDA area-under-the-curve was about twice as high in the cases that received CsA than in the other cases. CsA had no detectable effects on renal function and fluid balance, but significantly increased systemic blood diastolic pressure and conjugated bilirubine concentration. Furthermore, CsA-treated patients had greater, and more severe, oral and intestinal mucosal toxicity, with more severe adverse events, including more cases of gram-negative bacteremia, and with a delayed hemopoietic recovery. In conclusion, this study showed that an attempt at an effective downmodulation of Pgp-mediated MDR would substantially increase the hemopoietic and mucosal toxicity of antileukemic treatment and that the increase is accounted for, at least in part, by an increase of total body exposure to IDA. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the pharmacokinetics of tretinoin during alternating cycles of 1 week of tretinoin treatment and 1 week drug-free in patients with Ph1+ chronic myelogenous leukaemia (CML) in the chronic phase. Patients: Eighteen patients with CML were treated with tretinoin 80 mg/m/day (in two divided doses) for 7 consecutive days every other week (one cycle = 1 week on/1 week off). Results: Body systemic exposure to tretinoin as determined by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from (mean ± SD) 678.3 ± 498.1 to 258.7 ± 272.4 µg/L·h. In about 40% of the patients the decline in plasma concentrations was ≥80%, while 17% of the population did not experience any decline. On day 7 of cycle 1, the mean apparent oral clearance (CL/F) was 2.6 times the corresponding value on day 1. After 1 week without tretinoin, the mean AUC on day 1 of cycle 2 was lower (down 15%) but not statistically different from the corresponding value observed on day 1 of cycle 1; 62% of patients showed an increase in the AUC, which was 40% higher than the corresponding value on day 7 of cycle 1. On day 1 of cycle 6, the AUC and CL/F of tretinoin during a dosage interval were not statistically different from those observed on day 1 of cycle 1 and cycle 2. On all occasions the peak plasma concentration (C) was strongly correlated to the corresponding AUC. No significant change in the time to observed C (t) and in the elimination half-life (t) was observed during the whole study. These results confirmed that the metabolism of tretinoin is rapidly up-regulated in CML patients, with significant declines in plasma drug exposure during the first week of drug administration. After tretinoin was discontinued, a return to the noninduced state followed a mean time-cycle similar to the induction. The strong decrease in the apparent oral drug clearance and the absence of significant variations in the drug half-life demonstrated that the presystemic extraction of tretinoin is the main cause of the marked decline in plasma drug exposure. Conclusion: The favourable pharmacokinetic profile of tretinoin obtained by an intermittent regimen, 1 week on/1 week off therapy (vs continuous administration), suggests that such a therapeutic schedule is the most appropriate for the assessment of clinical efficacy in those pathologies in which its use is suitable. [ABSTRACT FROM AUTHOR]

• Background: Adult-onset foveomacular vitelliform dystrophy (AOFVD) represents a heterogeneous group of disorders with different clinical, angiography, and histopathological features. The most common form is characterized by a yellow, round to oval subretinal macular lesion with or without central pigmented spot. • Methods: Eight patients affected by typical AOFVD underwent fluorescein an giography and indocyanine green videoangiography (ICGV). • Results: Fluorescein angiography showed a central hypofluorescent spot surrounded by an irregular hyperfluorescentring ICGV demonstrated a foveal nonfluorescent spot, visible during the entire examination, and a hyperfluorescent area surrounding the central spot, which became evident soon after the beginning of the examination. • Conclusions: In light of previous histopathological studies, the central nonfluorescent spot may be interpreted as a masking effect of a pigment clump, whereas the hyper-fluorescent area may represent dye pooling or staining of the subretinal pigment epithelial material. [ABSTRACT FROM AUTHOR]

PTT-119, a new synthetic alkylating compound, has shown a marked 'in vitro' inhibitory effect on chronic myeloid leukemia (CML) granulo-monocytic precursors (CFU-GM) at doses greater than 5 µg/ml. Based on previous experiences of synergistic associations between alkylating drugs and biological modifiers, we tested the effects of low doses of PTT-119 (from 0.1 to 1 µg/ml) in concert with alpha, gamma, or alpha + gamma interferons and compared to IFNs alone, in order to investigate an alternative choice for treatment of CML patients in chronic phase. Our results showed a significantly higher CFU-GM cloning inhibition after addition of 100 or 1,000 U/ml of alpha IFN to 0.1 µg/ml PTT-119 (from 39.6% ± 26.6 SD to 80.7% ± 10 SD and 91.5% ± 8 SD, respectively), while gamma IFN resulted in only a slight increase in colony growth inhibition when compared to the drug used alone. The association of alpha plus gamma IFN coupled with PTT-119 treatment did not significantly improve the results observed after exposure of leukemic progenitors to PTT-119 and alpha IFN alone. We conclude that a combined treatment with PTT-119 and IFN is probably worth testing both for purging methods before autologous bone marrow transplantation and for in vivo administration in chronic myeloid leukemia. [ABSTRACT FROM AUTHOR]

The in vitro effect of human recombinant interferon α (IFN) alone and in combination were studied on granulomonocytic colony forming units (CFU-GM) from the peripheral blood of 10 Ph1+ chronic myeloid leukemia (CML) patients and from the marrow of 5 normal or non-leukemic subjects. α- and γ-IFN alone determined a slight inhibition on colony growth with a preferential effect on 'pure' macrophagic colonies. At maximum concentration (10 U/ml) leukemic colony inhibition was 46±34% for αIFN and 43±19% for γIFN. Culture growth with α + γIFN in combination were significantly inhibited (up to 96±4%) with a concentration-related effect. Similar results were obtained with normal CFU-GM. The synergism that was found in vitro is probably relevant for the in vivo therapeutic effects of these compounds in CML and suggest that the combination is worth testing in vivo. [ABSTRACT FROM AUTHOR]

Lateral hypothalamus (LH) stimulation in cats which do not spontaneously attack rats, produces an attack pattern which may be divided into 3 main stages: the first, defined as exploratory time (ET), begins with an environmental search and culminates in orienting towards the prey; in the second, defined as attack time (AT), the cat stalks the rat; the last is the biting stage in which the cat seizes and kills the prey by biting its head and neck. The effects of ventral tegmental area (VTA) stimulation on the latency of the whole sequence and on the different stages of the attack pattern were studied. VTA activation resulted in a significant decrease of biting latency, due to the reduction of exploratory time. Moreover, a significant period of prey fixation, seldom present during LH stimulation alone, was observed after VTA-LH co-stimulation. Sulpiride injection caused the disappearance of VTA effects on the predatory pattern. The results indicate that VTA activation induces a decrease in behaviour related to exploration of the environment, and an increase in the focusing of attention on the prey, which seems an important component in the regulation of the predatory pattern. Pharmacological evidence indicates that the VTA effect is mediated by the mesolimbic-mesocortical dopaminergic (DA) system. [ABSTRACT FROM AUTHOR]

The efficacy of GM-CSF was investigated in 20 neutropenic patients (< 1500 neutrophils/µl) with acute visceral leishmaniasis due to Leishmania chagasi. Patients were randomized to receive either GM-CSF, 5 µg/kg daily (intravenously or subcutaneously), or placebo for ten days, in combination with pentavalent antimony, 10-20 mg/kg daily for 20 days. Neutrophil counts were significantly greater on days 5 and 10 of treatment in the GM-CSF group compared with the placebo group (p<0.02). Eosinophil and monocyte counts were also significantly increased in the GM-CSF group at day 10 (p≤0.03). Interestingly, at day 30, platelet counts were significantly higher in the GM-CSF treated group (p=0.007). Haemoglobin levels were significantly increased in the GM-CSF group on days 5 and 10 (p=0.04 and 0.02, respectively). Patients in the GM-CSF group experienced fewer secondary bacterial or viral infections than placebo patients. Infections occurred in only three patients given GM-CSF compared with eight patients given placebo (p<0.04). All patients had complete resolution of disease symptoms at three months. Few adverse events were recorded. GM-CSF given subcutaneously at a dose of 5 µg/kg daily for ten days was well tolerated, reversed neutropenia rapidly and reduced the number of secondary infections in patients with leishmaniasis. [ABSTRACT FROM AUTHOR]

The introduction of hematopoietic growth factors into the management of leukemia can influence the outcome of treatment in several ways, depending on the sensitivity and the response of normal and leukemic cells. In this paper we report on the effects of the administration of Escherichia coli-produced, human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) in 15 adult patients with acute nonlymphocytic leukemia (ANLL) resistant to first-line treatment or in relapse. GM-CSF was given at a dose of 5-10 micrograms/kg/day as a 6-h i.v. infusion, prior to chemotherapy (CHT) (for 7 days) and after CHT (until evidence of failure or of remission). In the pre-CHT period there was a clear trend towards an increase of circulating neutrophils (PMN) and/or blast cell count (median 0.3 vs. 1.0 x 10(9)/l for PMN, and 0.5 vs. 2.3 for blast cells). After chemotherapy, in the patients who achieved complete remission (CR), the median time to a PMN count greater than 0.5 x 10(9)/l and greater than 1 x 10(9)/l was 16 days (range 13-27) and 19 days (range 13-42) respectively. The outcome of treatment was CR for 8/15 (53%), death during induction for 3/15 (20%), and failure for 4/15 (27%). All failures occurred in patients with an increase of blast cell count during pre-CHT GM-CSF administration. Toxicity and side effects were minor, apart from an acute respiratory syndrome that developed twice in the same patient, at doses of 10 and 3 micrograms/kg/day. These data suggest that investigation of GM-CSF in the treatment of ANLL is worth pursuing, with special attention to GM-CSF effects prior to chemotherapy. [ABSTRACT FROM AUTHOR]

Live antibody-coated Trypanosoma brucei parasites remove variable surface glycoprotein (VSG)-antibody complexes from their surface upon warming to 37° C and evade antibody-activated complement lysis by both protein synthesis-dependent and protein synthesis-independent mechanisms. The protein synthesis-dependent process follows antibody-mediated trypanosome agglutination, whereas the protein synthesis-independent mechanism can occur in the absence of trypanosome agglutination. The latter process leads to a more rapid climination of complement-fixing VSG-antibody complexes. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined mutations in the TSH receptor (TSHR) extracellular region in thyroid functioning nodules. The researchers discovered the occurrence of two unusual heterozygous mutations in two of seven thyroid functioning nodules detected as single nodules or in a multinodular goiter. The implications of the discovery regarding the structure-function relationship of the TSHR is explained.

This article presents a study which examined the presence and distribution of the chemoreceptive molecule αtransducin in the pig gastrointestinal (GI) tract. Researchers harvested segments of the entire GI tract from 45 day-old piglets. The results also determined the characterization of cells expressing αtransducin, as well as the relationship between αtransducin cells and nerve fibers supplying the GI Tract mucosa.

A field experiment was designed to provide data on the effect of soil heterogeneity on the distribution of herbicides following leaching by irrigation and rain water. Terbuthylazine and bromacil, two nonconservative herbicides, together with CaBr2, a conservative chemical, were used in the reported experiment. The experimental field consisted of a noncultivated 175-m-2 plot in which 20 observation points were randomly selected. A hundred and ten centimeters of irrigation and rainwater were applied and the field was periodically sampled for chemical distributions. The spatial variability of the field was determined by measuring the Ks (saturated conductivity) and alpha (Gardner parameter). Auxiliary laboratory experiments were performed to define the adsorption-desorption of the chemicals studied in these field soils. Results on the adsorption-desorption of terbuthylazine and bromacil and on the redistribution of these chemicals in the field to a depth of 120 cm during leaching are shown. Bromacil leached to a greater extent than terbuthylazine. The differences among the concentrations of herbicides in the various cores studied may be explained in terms of properties of the chemicals and soil spatial variability. The residual concentrations of terbuthylazineand bromacil were also determined to a depth of 400 cm after the leaching of 110 cm of water. In some of the cores, two zones showing a relatively high concentration of terbuthylazine and bromacil were observed at depths of 40-60 and 200-300 cm, respectively. This redistribution pattern of the herbicides could be explained by the preferentialflow of the solute in the cores studied. [ABSTRACT FROM AUTHOR]