Pharmacokinetics and antineoplastic activity of galectin-1-targeting OTX008 in combination with sunitinib

Purpose

OTX008 is a galectin-1-targeting compound, currently undergoing a phase I clinical trial. This study aimed at investigating OTX008 pharmacokinetics (PK) and antineoplastic activity.

Methods

Pharmacokinetics and activity of OTX008 were analyzed in the human ovarian carcinoma A2780-1A9 and glioblastoma U87MG xenografted in nude mice. In vitro, OTX008 was tested on tumor and endothelial cells.

Results

After 5 mg/kg i.v., OTX008 achieved plasma Cmax of 14.39 μg/mL, distributed rapidly, and was eliminated with a half-life of 31.4 h. Tumor OTX008 Cmax (1.65 μg/g, 1.76 μM), achieved at 0.5 h, remained high at 24 h (0.516 μg/g, 0.55 μM) with AUC of 15.76 μg/g*h. OTX008 accumulated in the tumor after repeated administrations achieving a concentration of 2.3 μM, compatible with the concentrations active in vitro. OTX008 (5 mg/kg i.v., every other day for 3 weeks) inhibited the in vivo growth of A2780-1A9, whereas U87MG was not sensitive. In vitro, OTX008 affected endothelial cell proliferation, motility, invasiveness, and cord formation. Tumor cell proliferation was also inhibited, with differences in sensitivity among cell lines (IC50 from 1 to 190 μM). OTX008 potentiated the activity of the tyrosine kinase inhibitor sunitinib on A2780-1A9 in vivo and in vitro, where the combination showed synergistic (endothelial cells) and additive (A2780-1A9) antiproliferative activity, indicating that the combination targets both the tumor and vascular compartments.

Conclusions

OTX008—alone or in combination with sunitinib—has a favorable PK and antineoplastic activity on selected tumor models through the effects on both endothelial and tumor cells.     

Meta-analytic clustering of the insular cortex: characterizing the meta-analytic connectivity of the insula when involved in active tasks

The human insula has been parcellated on the basis of resting state functional connectivity and diffusion tensor imaging. Little is known about the organization of the insula when involved in active tasks. We explored this issue using a novel meta-analytic clustering approach. We queried the BrainMap database asking for papers involving normal subjects that recorded activations in the insular cortex, retrieving 1305 papers, involving 22,872 subjects and a total of 2957 foci. Data were analyzed with several different methodologies, some of which expressly designed for this work. We used meta-analytic connectivity modeling and meta-analytic clustering of data obtained from the BrainMap database. We performed cluster analysis to subdivide the insula in areas with homogeneous connectivity, and density analysis of the activated foci using Voronoi tessellation. Our results confirm and extend previous findings obtained investigating the resting state connectivity of the anterior-posterior and left-right insulae. They indicate, for the first time, that some blocks of the anterior insula play the role of hubs between the anterior and the posterior insulae, as confirmed by their activation in several different paradigms. This finding supports the view that the network to which the anterior insula belongs is related to saliency detection. The insulae of both sides can be parcellated in two clusters, the anterior and the posterior: the anterior is characterized by an attentional pattern of connectivity with frontal, cingulate, parietal, cerebellar and anterior insular highly connected areas, whereas the posterior is characterized by a more local connectivity pattern with connections to sensorimotor, temporal and posterior cingulate areas. This antero-posterior subdivision, better characterized on the right side, results sharper with the connectivity based clusterization than with the behavioral based clusterization. The circuits belonging to the anterior insula are very homogeneous and their blocks in multidimensional scaling of MACM-based profiles are in central position, whereas those belonging to the posterior insula, especially on the left, are located at the periphery and sparse, thus suggesting that the posterior circuits bear a more heterogeneous connectivity. The anterior cluster is mostly activated by cognition, whereas the posterior is mostly activated by interoception, perception and emotion.     

Endogenous survivin modulates survival and proliferation in UVB-treated human keratinocytes

Abstract:  Survivin is a bi-functional member of inhibitor of apoptosis protein family, as it is able to both inhibit apoptosis and to regulate cell cycle. We investigated the role of survivin in human keratinocytes under normal conditions and during UVB irradiation. Survivin siRNA decreases proliferation and induces apoptosis in human keratinocytes, in a mode consistent with the mitotic catastrophe. Low doses UVB increase survivin expression at earlier times, while high doses down-regulate survivin level. Low doses UVB induce cell cycle arrest in G2/M, while high doses UVB cause apoptosis. Moreover, overexpression of survivin protects keratinocytes from UVB-induced apoptosis, and silencing of survivin renders keratinocytes more susceptible to UVB-induced cell death. Finally, survivin siRNA increases UVB-induced reduction of cell proliferation. Taken together, these results indicate that survivin plays a critical role in epidermal homeostasis in normal conditions and during UVB exposure, with possible implication in skin carcinogenesis.     

Enhancement of GABAA-current run-down in the hippocampus occurs at the first spontaneous seizure in a model of temporal lobe epilepsy

Refractory temporal lobe epilepsy (TLE) is associated with a dysfunction of inhibitory signaling mediated by GABA_A receptors. In particular, the use-dependent decrease (run-down) of the currents (I_GABA) evoked by the repetitive activation of GABA_A receptors is markedly enhanced in hippocampal and cortical neurons of TLE patients. Understanding the role of I_GABA run-down in the disease, and its mechanisms, may allow development of medical alternatives to surgical resection, but such mechanistic insights are difficult to pursue in surgical human tissue. Therefore, we have used an animal model (pilocarpine-treated rats) to identify when and where the increase in I_GABA run-down occurs in the natural history of epilepsy. We found: (i) that the increased run-down occurs in the hippocampus at the time of the first spontaneous seizure (i.e., when the diagnosis of epilepsy is made), and then extends to the neocortex and remains constant in the course of the disease; (ii) that the phenomenon is strictly correlated with the occurrence of spontaneous seizures, because it is not observed in animals that do not become epileptic. Furthermore, initial exploration of the molecular mechanism disclosed a relative increase in α4-, relative to α1-containing GABA_A receptors, occurring at the same time when the increased run-down appears, suggesting that alterations in the molecular composition of the GABA receptors may be responsible for the occurrence of the increased run-down. These observations disclose research opportunities in the field of epileptogenesis that may lead to a better understanding of the mechanism whereby a previously normal tissue becomes epileptic.     

Assessment of the potential toxicity of a linear alkylbenzene sulfonate (LAS) to freshwater animal life by means of cladoceran bioassays

The acute and chronic toxic effects of LAS on the cladocerans Daphnia similis, Ceriodaphnia dubia and Ceriodaphnia silvestrii were tested. Both types of toxicity bioassays and the methods of culture and stock maintenance of the test organisms conformed to the recommendations of ABNT (Brazilian Society of Technical Standards), which closely follow the standard methods of USEPA. The results obtained for EC₅₀ (48 h) were: 14.17 mg L⁻¹ for D. similis, 11.84 mg L⁻¹ for C. dubia and 13.52 mg L⁻¹ for C. silvestrii. In the chronic toxicity tests performed on C. dubia and C. silvestrii, there was a significant decrease in the fecundity of the exposed animals; the value of NOEC for C. dubia and C. silvestrii were 1.00 mg L⁻¹ and 2.50 mg L⁻¹, respectively. Cladoceran bioassays provided evidence that LAS concentration as low as 1.00 mg L⁻¹ can damage invertebrate animal life in freshwaters, concentrations that can be found in many eutrophic rivers and reservoirs.     

First-ever stroke and outcome in patients admitted to Perugia Stroke Unit: predictors for death, dependency, and recurrence of stroke within the first three months

Predictors of poor outcome after first-ever stroke within 3 months in consecutive patients admitted to our Stroke Unit were defined. Factors included age, sex, risk factors, occurrence of transient ischemic attacks, extension of cerebral infarction, presumed cause of stroke, clinical findings, and demographic characteristics. Multiple regression models were used to analyze predictors of mortality, dependency and stroke recurrence. A total of 435 patients with first-ever stroke were included. Of these, 358 patients had ischemic stroke and 77 hemorrhagic stroke. Three-month mortality rate was 20.5%. After the same period, 24.6% of survivors were dependent (mRS > or = 3) and 5.0% of patients had recurrent stroke. Age, the presence of atrial fibrillation, impaired consciousness on admission, and stroke severity were related to mortality. The presence of stroke due to an undetermined cause or small vessel disease was associated with lower mortality. Partial anterior circulation syndrome or lacunar syndrome were both related to better outcome. The best predictors for dependency after 3 months were age and stroke severity. The only variable identified as the best predictor for recurrence was the presence of diabetes mellitus.     

Quality of life and depression in a cohort of female patients with chronic disease

Background

Differences in health-related quality of life perception in patients with chronic disease may depend on pre-existing differences in personality profile. The purpose of the study was to investigate in a cohort of female patients with chronic diseases the relationship between the Quality of Life perception and the potential presence of depressive symptoms.

Patients and methods

Female patients with chronic diseases were enrolled in the study. Exclusion criteria were diagnosis of psychopathological condition, treatment with psychoactive substances.Methodological approach was based on administration of the following test. Short Form health survey SF-36, Symptom Check List SCL-90-R, Satisfaction Profile test (SAT-P) and Beck Depression Inventory-II (BDI-II). The Pearson correlation coefficient was used to evaluate the relationship between depressive symptoms and Quality of life as assessed by psychometric test.

Results

57 patients, aged 52(±3,4), responded to inclusion criteria. 57% of patients had a diagnosis of functional dyspepsia or gastro-oesophageal reflux not complicated, and the remaining 43% musculoskeletal diseases. The statistical analysis showed an inverse correlation between the variable Bodily Pain of the SF-36 and the variable Depression scales of the SCL-90-R.In a second phase another sample of female patients was enrolled in the study. 64 patients, aged 49(±3,2), responded to inclusion criteria.Another significant negative correlation was found between the Somatic-Affective factor of the BDI-II and the scale Physical Functioning of the SAT-P.

Discussions

In female patients with chronic disease depressive symptoms resulted influenced by pain and vice versa. The treatment of depressive symptoms could improve the quality of life of patients.