Therapeutic potential of ERK5 targeting in triple negative breast cancer

Triple negative breast cancers (TNBCs) account for 15% of all breast cancers, and represent one of the most aggressive forms of the disease, exhibiting short relapse-free survival. In contrast to other breast cancer subtypes, the absence of knowledge about the etiopathogenic alterations that cause TNBCs force the use of chemotherapeutics to treat these tumors. Because of this, efforts have been devoted with the aim of incorporating novel therapies into the clinical setting. Kinases play important roles in the pathophysiology of several tumors, including TNBC. Since expression of the MAP kinase ERK5 has been linked to patient outcome in breast cancer, we analyzed the potential value of its targeting in TNBC. ERK5 was frequently overexpressed and active in samples from patients with TNBC, as well as in explants from mice carrying genetically-defined TNBC tumors. Moreover, expression of ERK5 was linked to a worse prognosis in TNBC patients. Knockdown experiments demonstrated that ERK5 supported proliferation of TNBC cells. Pharmacological inhibition of ERK5 with TG02, a clinical stage inhibitor which targets ERK5 and other kinases, inhibited cell proliferation by blocking passage of cells through G₁ and G₂, and also triggered apoptosis in certain TNBC cell lines. TG02 had significant antitumor activity in a TNBC xenograft model in vivo, and also augmented the activity of chemotherapeutic agents commonly used to treat TNBC. Together, these data indicate that ERK5 targeting may represent a valid strategy against TNBC, and support the development of trials aimed at evaluating the clinical effectiveness of drugs that block this kinase.     

Repeated administration of an aqueous spray-dried extract of the leaves of Passiflora alata Curtis (Passifloraceae) inhibits body weight gain without altering mice behavior

Ethnopharmacological relevance

Passiflora alata is a Southern American species that constitutes many traditional remedies as well as phytomedicines used for sedative and anxiolytic purposes in Brazil. However studies on repeated treatment effects are scarce.

Aim of the study

To evaluate behavioral, physiological and biochemical effects of the repeated treatment with an aqueous spray-dried extract of Passiflora alata leaves containing 2.5% (w/v) of flavonoids (PA) in mice.

Material and methods

Male adult CF1 mice were treated (p.o.) for 14 days with PA (2.5; 25 or 250 mg/kg). The feeding behavior was evaluated at the beginning (1 h after the first administration) and at the end of the treatment (15th day). The body weight gain and food consumption were monitored along the days. On day 15 mice were evaluated on plus maze, spontaneous locomotor activity, catalepsy and barbiturate sleeping time tests. Serum glucose, lipids, ALT and AST enzymes were determined. Liver, kidney, perirenal fat, epididymal and peritoneal fat were analyzed.

Results

The repeated treatment with the highest dose tested (250 mg/kg) did not alter the mice behavior on open field, elevated plus maze, catalepsy and barbiturate sleeping time tests. Repeated administration of PA 250 decreased mice feeding behavior and weight gain. PA 25 and PA 250 reduced mice relative liver weight and caused mild hepatic hydropic degeneration as well as a decrease in alanine aminotransferase (ALT) serum level.

Conclusions

These results indicate that Passiflora alata does not present central cumulative effects and point to the needs of further studies searching for its hepatotoxicity as well as potential anorexigenic.     

Porous Semi‐Interpenetrating Hydrogel Networks Based on Dextran and Polyacrylamide With Superfast Responsiveness

AAm was free‐radical polymerized at various temperatures in the presence of N,N'‐methylenebisacrylamide as a cross‐linker and dextran resulting in novel Dx/PAAm semi‐IPNs. The structure and morphology of networks were investigated by means of FTIR, DSC, and ESEM. In comparison to the PAAm network, the interior network structures of the novel semi‐IPNs prepared at ?18 °C exhibit a heterogeneous morphology consisting of pores of sizes about 80 µm, while those formed at +5 and +25 °C have pores with sizes about 3 µm. The Dx/PAAm semi‐IPNs exhibited higher swelling ratios, than those without Dx, irrespective of the gel preparation temperature. Moreover, Dx/PAAm semi‐IPN hydrogels formed at ?18 °C attain the equilibrium state in water within 15 s.

     

Diagnosis of Regional Cerebral Blood Flow Abnormalities Using Spect: Agreement between Individualized Statistical Parametric Maps and Visual Inspection by Nuclear Medicine Physicians with Different Levels of Expertise in Nuclear Neurology

INTRODUCTION:

Visual analysis is widely used to interpret regional cerebral blood flow (rCBF) SPECT images in clinical practice despite its limitations. Automated methods are employed to investigate between-group rCBF differences in research studies but have rarely been explored in individual analyses.

OBJECTIVES:

To compare visual inspection by nuclear physicians with the automated statistical parametric mapping program using a SPECT dataset of patients with neurological disorders and normal control images.

METHODS:

Using statistical parametric mapping, 14 SPECT images from patients with various neurological disorders were compared individually with a databank of 32 normal images using a statistical threshold of p<0.05 (corrected for multiple comparisons at the level of individual voxels or clusters). Statistical parametric mapping results were compared with visual analyses by a nuclear physician highly experienced in neurology (A) as well as a nuclear physician with a general background of experience (B) who independently classified images as normal or altered, and determined the location of changes and the severity.

RESULTS:

Of the 32 images of the normal databank, 4 generated maps showing rCBF abnormalities (p<0.05, corrected). Among the 14 images from patients with neurological disorders, 13 showed rCBF alterations. Statistical parametric mapping and physician A completely agreed on 84.37% and 64.28% of cases from the normal databank and neurological disorders, respectively. The agreement between statistical parametric mapping and ratings of physician B were lower (71.18% and 35.71%, respectively).

CONCLUSION:

Statistical parametric mapping replicated the findings described by the more experienced nuclear physician. This finding suggests that automated methods for individually analyzing rCBF SPECT images may be a valuable resource to complement visual inspection in clinical practice.     

Multidetector-row computed tomography in evaluation of atherosclerotic carotid plaques complicated with intraplaque hemorrhage

Our aim was to determine the sensitivity and specificity of multidetector-row computed tomography (CT) in detecting atherosclerotic carotid plaques complicated with intraplaque hemorrhage. We examined carotid plaques from 31 patients operated for carotid artery stenosis. Results of preoperative multidetector-row CT analysis of carotid plaques were compared with results of histological analysis of the same plaque areas. Carotid endarterectomy was performed within 1 week of multidetector-row CT. American Heart Association classification of atherosclerotic plaques was applied for histological classification. Median tissue density of carotid plaques complicated with intraplaque hemorrhage was 22 Hounsfield units (HU). Median tissue density of noncalcified segments of uncomplicated plaques was 59 HU (p=0.0062). The highest tissue density observed for complicated plaques was 31 HU. Multidetector-row CT detected plaques complicated with hemorrhage with sensitivity of 100% and specificity of 64.7%, with tissue density of 31 HU as a threshold value. Multidetector-row CT showed a high level of sensitivity and a moderate level of specificity in detecting atherosclerotic carotid plaques complicated with hemorrhage.     

Xanthogranulomatous epididymitis: clinical report and immunohistochemical analysis

Xanthogranulomatous epididymitis is an uncommon non-neoplastic process with destruction of tissue and replacement by striking cellular infiltration of foamy macrophages, dense lymphocytes and plasma cells. We report on a 72-year-old man with a clinical history of inadequately treated arterial hypertension, who presented with a right scrotal mass associated with right scrotal pain for 10 days. Physical examination revealed pyogenic discharge from the hyperemic and edematous scrotum, with normal body temperature. Testicular tumor markers were normal. Ultrasonography (US) of the right testis showed edematous scrotal layers and a heterogeneous area of poorly defined margins within the testis and epididymis. There was minimal hydrocele, and the right funiculus was of normal diameter with no edema or pathologic formation. The progression of clinical findings, inflammatory parameters, US and color Doppler US findings with negative testicular tumor markers indicated surgical treatment. After preoperative treatment, right orchiepididymectomy was performed. Histology confirmed the diagnosis of xanthogranulomatous epididymitis.     

Progression of articular cartilage degeneration after application of muscle stretch

The aim of study was to evaluate the progression of the ankle articular cartilage alterations after a post-immobilization muscle stretching. Twenty-nine Wistar rats were separated into five groups: C--control, S--stretched, SR--stretch recovery, IS--immobilized and stretched, and ISR--immobilized stretched recovery. The immobilization was maintained for 4 weeks and the left ankle was then stretched manually through a full dorsal flexion for 10 times for 60 s with a 30 s interval between each 60 s period, 7 days/week for 3 weeks. The recovery period was of 7 weeks. At the end of the experiment, the left ankles were removed, processed in paraffin, and stained in hematoxylin-eosin and safranin O. Two blinded observers evaluated the articular cartilage using the Mankin grading system (cellularity, chondrocyte cloning, and proteoglycan content) through light microscopy, and performed the morphometry (cellularity, total thickness, non-calcified thickness, and calcified thickness measures). Both the Mankin grading system and the morphometric analysis showed that the ISR group presented the most increased cellularity among the groups. The IS and SR groups showed the highest proteoglycan loss, and the ISR group showed the same content of proteoglycan observed in the C group. No significant differences were found in the chondrocyte cloning, the total cartilage thickness, the non-calcified cartilage thickness, and the calcified cartilage thickness among the groups. The results suggest that the cartilage can recover the proteoglycan loss caused by immobilization and stretching, probably because of the increased chondrocyte density. Therefore, the ankle articular cartilage responded as to repair the metabolic deficits.