Frontal aslant tract: Anatomy and tractography description in the Mexican population.

Background: The aim of the study was to describe the origin, course, and termination of frontal aslant tract (FAT) in the Mexican population of neurosurgical referral centers. Methods: From January 2018 to May 2019, we analyzed 50 magnetic resonance imaging (MRI) studies in diffusion tensor imaging sequences of patients of the National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez." Five brains were fixed by the Klingler method and dissected in the neurosurgery laboratory of the Hospital Civil de Guadalajara to identify the origin, trajectory, and ending of the FAT. Results: FAT was identified in 100% of the MRI and brain dissections. The origin of the FAT was observed in 63% from the supplementary premotor area, 24% from the supplementary motor area, and 13% in both areas. Its ending was observed in the pars opercularis in 81%, pars triangularis in 9%, and in both pars opercularis and ventral premotor area in 10% in the magnetic resonance images, with a left side predominance. In the hemispheres dissections, the origin of FAT was identified in 60% from the supplementary premotor area, 20% from the supplementary motor area, and 20% in both areas. Its ending was observed in the pars opercularis in 80% and the pars triangularis in 20%. It was not identified as an individual fascicle connected with the contralateral FAT. Conclusion: In the Mexican population, FAT has a left predominance; it is originated more frequently in the supplementary premotor area, passes dorsal to the superior longitudinal fascicle II and the superior periinsular sulcus, and ends more commonly in the pars opercularis.

ASTEMIZOLE, AN INHIBITOR OF ETHER-À-GO-GO-1 POTASSIUM CHANNEL, INCREASES THE ACTIVITY OF THE TYROSINE KINASE INHIBITOR GEFITINIB IN BREAST CANCER CELLS.

BACKGROUND: Expression and activity of the potassium channel ether-à-go-go-1 (EAG1) are strongly related to carcinogenesis and tumor progression, which can be exploited for therapeutic purposes. EAG1 activity may be reduced by preventing its phosphorylation with epidermal growth factor receptor (EGFR) kinase inhibitors and by astemizole, which blocks the channel pore and downregulates its gene expression. OBJECTIVE: We aimed to study the potential cooperative antiproliferative effect of the EGFR inhibitor gefitinib and the EAG1-blocker astemizole, in breast cancer cells. MATERIALS AND METHODS: The cells were characterized by immunocytochemistry. Inhibitory concentrations were determined by non-linear regression analysis using dose-response curves. The nature of the pharmacological effect was evaluated by the combination index equation while cell cycle analysis was studied by flow cy-tometry. RESULTS: Astemizole and gefitinib inhibited cell proliferation in a concentration-dependent manner, with inhibitory concentrations (IC 50) values of 1.72 µM and 0.51 µM, respectively. All combinations resulted in a synergistic antiproliferative effect. The combination of astemizole and gefitinib diminished the percentage of cells in G2/M and S phases, while increased accumulation in G0/G1 of the cell cycle. CONCLUSIONS: Astemizole and gefitinib synergistically inhibited proliferation in breast cancer cells expressing both EGFR and EAG1. Our results suggest that the combined treatment increased cell death by targeting the oncogenic activity of EAG1.

Astemizole, an inhibitor of ether-à-go-go-1 potassium channel, increases the activity of the tyrosine kinase inhibitor gefitinib in breast cancer cells

Abstract Background Expression and activity of the potassium channel ether-à-go-go-1 (EAG1) are strongly related to carcinogenesis and tumor progression, which can be exploited for therapeutic purposes. EAG1 activity may be reduced by preventing its phosphorylation with epidermal growth factor receptor (EGFR) kinase inhibitors and by astemizole, which blocks the channel pore and downregulates its gene expression. Objective We aimed to study the potential cooperative antiproliferative effect of the EGFR inhibitor gefitinib and the EAG1-blocker astemizole, in breast cancer cells. Materials and Methods The cells were characterized by immunocytochemistry. Inhibitory concentrations were determined by non-linear regression analysis using dose-response curves. The nature of the pharmacological effect was evaluated by the combination index equation while cell cycle analysis was studied by flow cytometry. Results Astemizole and gefitinib inhibited cell proliferation in a concentration-dependent manner, with inhibitory concentrations (IC 50) values of 1.72 µM and 0.51 µM, respectively. All combinations resulted in a synergistic antiproliferative effect. The combination of astemizole and gefitinib diminished the percentage of cells in G2/M and S phases, while increased accumulation in G0/G1 of the cell cycle. Conclusions Astemizole and gefitinib synergistically inhibited proliferation in breast cancer cells expressing both EGFR and EAG1. Our results suggest that the combined treatment increased cell death by targeting the oncogenic activity of EAG1.

The Celiac Trunk and Its Anatomical Variations: A Cadaveric Study.

BACKGROUND: The celiac artery, celiac axis or celiac trunk is the first major abdominal branch of the aorta. Anatomic variations and accessory vessels have been reported with variable percentages. The purpose of this study was to report the pattern of the celiac trunk and its anatomic variations in a sample of Mexican population. METHODS: Celiac trunk dissection was performed in 140 fresh cadavers. Cadavers of Mexican subjects aged 18 years and older were included. Cadavers with previous upper abdominal surgery, abdominal trauma, disease process that distorted the arterial anatomy or signs of putrefaction were excluded. Celiac trunk variations and external diameter, accessory vessels, and vertebral level of origin were described. Celiac trunk patterns were reported according to the Panagouli classification. This study was reviewed and approved by the Ethics Committee of our Hospital. RESULTS: The celiac trunk derived in a common hepatic artery, a left gastric artery and a splenic artery (type I) in 43.6% of dissections. A true tripod was found in 7.1% and a false tripod in 36.4%. Celiac trunk bifurcation (type II) was found in 7.1%. Additional branches (type III) were observed in 47.9%. One or both phrenic arteries originated from the celiac trunk in 41.4% of dissections. Celiac trunk tetrafurcation was observed in 12.9%, pentafurcation in 12.9%, hexafurcation in 1.4%, and heptafurcation in 0.7%. The mean diameter of the celiac trunk ranged from 6 to 12 mm, with a mean diameter of 7.2 mm (SD = 1.39 mm). No significant difference was found between the diameters of the different types of celiac trunk (P > 0.05). The celiac trunk originated between the 12th thoracic and first lumbar vertebral bodies in 90% of dissections. CONCLUSIONS: Trifurcation of the celiac trunk was lower than previously reported. A high proportion of cases with additional vessels were found.

Luteinizing hormone modulates intracellular calcium, protein tyrosine phosphorylation and motility during human sperm capacitation.

In order to fertilize, spermatozoa must undergo physiological and biochemical changes during their transit along the female reproductive tract before reaching and fusing with the oocyte, process known as capacitation. Sperm modifications associated with capacitation are modulated by their interaction with molecules present in the female reproductive tract. During the woman fertile window, some reproductive hormones reach their maximum concentrations in serum, such as the luteinizing hormone (LH). Since spermatozoa preparing to fertilize may be exposed to LH, the purpose of this work was to study the effects of this hormone on intracellular Ca2+ concentrations ([Ca2+]i), protein tyrosine phosphorylation, sperm motility and acrosome reaction under capacitating conditions. The results showed that LH increases the duration and amplitude of Ca2+ oscillations. Furthermore, motility analysis indicated that LH decreases rapid progressive motility and that sperm hyperactivation as well as several kinetic parameters augment in the presence of 0.5 and 1 µg/ml of the hormone. In addition, these two hormone concentrations also consistently promoted protein tyrosine phosphorylation. However, no effects on acrosome reaction were observed. In conclusion, the evidence indicates that LH modulates several sperm function variables involved in capacitation, suggesting that may have an important and unexplored role during human fertilization.

Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence.

An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents.

Human sperm degradation of zona pellucida proteins contributes to fertilization.

BACKGROUND: The mammalian oocyte extracellular matrix known as the zona pellucida (ZP) acts as a barrier to accomplish sperm fusion with the female gamete. Although penetration of the ZP is a limiting event to achieve fertilization, this is one of the least comprehended stages of gamete interaction. Even though previous studies suggest that proteases of sperm origin contribute to facilitate the passage of sperm through the ZP, in human this process is not yet fully understood. The aim of this study was to determine the ability of human sperm to degrade recombinant human ZP (rhZPs) proteins and to characterize the proteases involved in this process. METHODS: Purified rhZP2, rhZP3 and rhZP4 proteins were incubated with capacitated sperm and the proteolytic activity was determined by Western blot analysis. To further characterize the proteases involved, parallel incubations were performed in the presence of the protease inhibitors o-phenanthroline, benzamidine and MG-132 meant to block the activity of metalloproteases, serine proteases and the proteasome, respectively. Additionally, protease inhibitors effect on sperm-ZP binding was evaluated by hemizona assay. RESULTS: The results showed that rhZPs were hydrolyzed in the presence of capacitated sperm. O-phenanthroline inhibited the degradation of rhZP3, MG-132 inhibited the degradation of rhZP4 and benzamidine inhibited the degradation of the three proteins under investigation. Moreover, hemizona assays demonstrated that sperm proteasome inhibition impairs sperm interaction with human native ZP. CONCLUSIONS: This study suggests that sperm proteasomes could participate in the degradation of ZP, particularly of the ZP4 protein. Besides, metalloproteases may be involved in specific degradation of ZP3 while serine proteases may contribute to unspecific degradation of the ZP. These findings suggest that localized degradation of ZP proteins by sperm is probably involved in ZP penetration and may be of help in understanding the mechanisms of fertilization in humans.

Biological effects of recombinant human zona pellucida proteins on sperm function.

The initial interaction between gametes takes place at the level of the sperm surface and the zona pellucida (ZP), the extracellular matrix of the egg in mammals. Successful fertilization requires the proper molecular recognition of the ZP by the sperm. Recently, human ZP was demonstrated to be composed of four proteins: ZP1, ZP2, ZP3, and ZP4. The goals of this study were to determine the effects of recombinant human ZP2, ZP3, and ZP4 on human sperm acrosomal exocytosis and sperm motility. Exposure of sperm to ZP proteins, alone or in combination, promoted acrosomal exocytosis in a time-dependent manner. This effect occurred in parallel with a considerable decrease in progressive motility, coincident with an increase in nonprogressive sperm motility. An analysis of kinetic parameters of ZP-treated sperm demonstrated that a characteristic motility pattern could be defined by values of curvilinear velocity > 63.9 mum/s and linearity