Efectos de la estimulación transcraneal con corriente directa (tDCS) sobre el consumo de tabaco, la motivación y la autoeficacia para dejar de fumar / Effects of transcranial direct current stimulation (tDCS) on tobacco use, motivation and self-efficacy to quit smoking

Estudios recientes de estimulación transcraneal con corriente directa (tDCS), aplicada sobre la corteza prefrontal dorsolateral (CPFDL), han demostrado que pueden reducir el craving y el consumo de tabaco. Sin embargo, existen pocas investigaciones que hayan evaluado los efectos del tDCS sobre la motivación y la autoeficacia para dejar de fumar. El objetivo de este estudio fue evaluar los efectos de la tDCS sobre el patrón de consumo, la motivación y la autoeficacia percibida para dejar de fumar en 16 personas con Trastorno por Consumo de Tabaco (TCT). Se utilizó un diseño de series temporales con replicación intrasujeto ABAB. El tratamiento consistió en la aplicación de 10 sesiones repetidas de tDCS a 1.5 mA durante 20 minutos sobre la CPFDL (cátodo F3 y ánodo F4), una sesión diaria durante dos semanas (lunes a viernes). Tras una fase de descanso de un mes, se replicó el tratamiento intrasujeto en idénticas condiciones. La intervención completa duró nueve semanas y fue completada por 10 participantes. Los resultados mostraron una reducción significativa en la dependencia a la nicotina, el número de cigarrillos fumados y los niveles de monóxido de carbono (CO) en el aire espirado. Además, observamos una mejora significativa en la motivación y la autoeficacia percibida para dejar de fumar. Estos hallazgos sugieren que el tDCS, aplicado sobre la CPFDL, puede ser una técnica efectiva para usar como terapia coadyuvante a otras estrategias farmacológicas y/o psicológicas empleadas en las Unidades de Conductas Adictivas (UCAs), u otros centros de atención a las drogodependencias. Sin embargo, se necesitan más estudios que investiguen la interacción entre los efectos de la nicotina y el tDCS para encontrar la estrategia óptima de tratamiento. (AU)

Recent studies of transcranial direct current stimulation (tDCS), applied to the dorsolateral prefrontal cortex (CPFDL), have shown that they can reduce craving and smoking. However, there is little research that has evaluated the effects of tDCS on motivation and self-efficacy to quit smoking. The objective of this study was to evaluate the effects of tDCS on the pattern of consumption, motivation and perceived self-efficacy to quit smoking in 16 people with Tobacco Use Disorder (TUD). A time series design with intrasubject ABAB replication was used. The treatment consisted of applying 10 repeated sessions of tDCS at 1.5 mA for 20 minutes on the CPFDL (cathode F3 and anode F4), one daily session for two weeks (Monday to Friday). After a one-month rest phase, the intra-subject treatment was replicated under identical conditions. The entire intervention lasted nine weeks and was completed by 10 participants. The results showed a significant reduction in nicotine dependence, the number of cigarettes smoked and the levels of carbon monoxide (CO) in the exhaled air. Furthermore, we observed a significant improvement in motivation and perceived self-efficacy to quit smoking. These findings suggest that the tDCS, applied on the CPFDL, may be an effective technique to use as adjunctive therapy to other pharmacological and / or psychological strategies used in the Addictive Behavior Units, or other drug addiction care centers. However, more studies are needed to investigate the interaction between the effects of nicotine and tDCS to find the optimal treatment strategy. (AU)

Intraoperative brain mapping during awake surgery in symptomatic supratentorial cavernomas / Mapeo cerebral intraoperatorio con paciente despierto en la cirugía de cavernomas supratentoriales sintomáticos

Background Complete resection of symptomatic supratentorial cavernoma (SCA) and removal of the surrounding gliotic area is recommended to minimize the risk of persistent seizures or (re)bleeding. Surgery of SCA located in an eloquent area, can carry out severe postoperative neurological morbidity. We report a study aimed to assess feasibility, extent of resection and outcome after surgical removal of CA by cortico-subcortical intraoperative brain stimulation (ioBS) in the awake patient. Methods Six patients diagnosed of symptomatic SCA located on an eloquent area and operated on while awake under local anaesthesia ioBS, were included. Preoperative planning included neuropsychologic assessment of language-related functions, sociocognitive functions and executive functions. Intraoperatively, we recorded the results achieved in the planned neuropsychological tasks when stimulation was applied (cortical and subcortical). Postoperative control 3D MRI was scheduled at 1 month after surgery to calculate extent of resection. Neuropsychological assessment at 6 months after surgery was performed in all cases. Results Six patients (5 females, 1 male) aged 24–48 years were included in our study. Locations of the lesions were right insular (n=1), left insular (n=1), left temporo-insular (n=1), left temporal (n=2) and left frontal (n=1). In all patients, positive findings were obtained during ioBS. In 5 patients, complete surgical resection was achieved. Two patients had postoperative transient neurological deficits, one case of hemiparesis, one case of dysnomia, both cleared over a 6-month period. Clinical follow-up revealed that all patients experienced complete recovery from preoperative symptoms within a year and five patients with seizures showed marked improvement and eventually quit antiepileptic drugs. Neuropsychological assessment at 6 months provided normal results compared to preoperative baseline in all domains (AU)

Antecedentes y objetivo La resección completa de los cavernomas supratentoriales (SCA) sintomáticos, incluyendo el área gliótica perilesional, es el tratamiento de elección para evitar la persistencia de crisis y el resangrado. La cirugía de los SCA localizados en áreas elocuentes puede asociar graves complicaciones neurológicas. Presentamos un estudio cuyo objetivo es documentar la viabilidad de la estimulación corticosubcortical intraoperatoria (ioBS) en el paciente despierto y su impacto en el grado de exéresis y el resultado clínico final. Materiales y métodos Incluimos 6 pacientes diagnosticados de SCA sintomático localizado en área elocuente, que fueron intervenidos mediante ioBS en el paciente despierto. El estudio preoperatorio incluyó una valoración neuropsicológica de funciones lingüísticas, sociocognitivas y ejecutivas. Durante la realización de la ioBS en el paciente despierto registramos los resultados obtenidos por los pacientes en las tareas neuropsicológicas planificadas. El grado de exéresis se estimó en una RM realizada un mes tras la cirugía. A los 6 meses de la cirugía se realizó una evaluación neuropsicológica de control. Resultados Cinco mujeres y un hombre con edades comprendidas entre los 24 y 48 años fueron incluidos en el estudio. Las localizaciones de los cavernomas fueron insular derecha (n=1), insular izquierda (n=1), temporo-insular izquierda (n=1), temporal izquierda (n=2) y frontal izquierda (n=1). En todos los pacientes se encontraron hallazgos tras la ioBS. Se obtuvo una exéresis completa en 5 casos. Dos pacientes presentaron déficit neurológico transitorio, un caso de hemiparesia y un caso de disnomia, que mejoró a los 6 meses (AU)

Intraoperative brain mapping during awake surgery in symptomatic supratentorial cavernomas.

BACKGROUND: Complete resection of symptomatic supratentorial cavernoma (SCA) and removal of the surrounding gliotic area is recommended to minimize the risk of persistent seizures or (re)bleeding. Surgery of SCA located in an eloquent area, can carry out severe postoperative neurological morbidity. We report a study aimed to assess feasibility, extent of resection and outcome after surgical removal of CA by cortico-subcortical intraoperative brain stimulation (ioBS) in the awake patient. METHODS: Six patients diagnosed of symptomatic SCA located on an eloquent area and operated on while awake under local anaesthesia ioBS, were included. Preoperative planning included neuropsychologic assessment of language-related functions, sociocognitive functions and executive functions. Intraoperatively, we recorded the results achieved in the planned neuropsychological tasks when stimulation was applied (cortical and subcortical). Postoperative control 3D MRI was scheduled at 1 month after surgery to calculate extent of resection. Neuropsychological assessment at 6 months after surgery was performed in all cases. RESULTS: Six patients (5 females, 1 male) aged 24-48 years were included in our study. Locations of the lesions were right insular (n=1), left insular (n=1), left temporo-insular (n=1), left temporal (n=2) and left frontal (n=1). In all patients, positive findings were obtained during ioBS. In 5 patients, complete surgical resection was achieved. Two patients had postoperative transient neurological deficits, one case of hemiparesis, one case of dysnomia, both cleared over a 6-month period. Clinical follow-up revealed that all patients experienced complete recovery from preoperative symptoms within a year and five patients with seizures showed marked improvement and eventually quit antiepileptic drugs. Neuropsychological assessment at 6 months provided normal results compared to preoperative baseline in all domains. CONCLUSIONS: Our study suggests that ioBS in the awake surgery of symptomatic SCA located in eloquent areas, allows to increase the rate of complete resection, minimizing postoperative neurological and neuropsychological deficit, and improving postoperative seizures control.

Intraoperative brain mapping of language, cognitive functions, and social cognition in awake surgery of low-grade gliomas located in the right non-dominant hemisphere.

OBJECTIVE: The aim of our study was to evaluate the usefulness of cortical-subcortical intraoperative brain mapping (ioBM) in resective awake surgery of low-grade gliomas (LGG) of the right non-dominant hemisphere (RndH). It was estimated how ioBM may affect both the extent of resection and postoperative outcome of language, spatial cognition, social cognition, and executive functions including attention and working memory. PATIENTS AND METHODS: Fifteen patients that underwent ioBM in resective awake surgery of LGG located on the RndH, were included. A cohort of 15 patients with the same tumour location operated under general anaesthesia without brain mapping was used as control. Specific intraoperative tasks for each location were carried out and results registered. Neuropsychological assessment was performed preoperatively and at 6 months after surgery. RESULTS: In the group of patients operated by using ioBM in awake surgery, an 86.66 % mean of resection was obtained compared to 60.33 % in the control group. Speech arrest and incorrect naming responses were elicited in higher proportion in frontal and insular locations. Parietal stimulation associated higher number of incorrect responses in social cognition task. Parietal and temporal stimulation were more frequently associated with incorrect performance of spatial cognition task. Parietal stimulation associated with higher frequency incorrect execution of attention and working memory tasks. After comparing clinical and neuropsychological results in both cohorts, worst outcome at 6 months was observed in the group of patients operated under general anaesthesia without brain mapping, especially in parietal and insular locations. CONCLUSIONS: Intraoperative identification of language, cognitive functions, and social cognition of RndH by means of ioBM, can be of paramount importance in improving the extent of resection of low-grade gliomas and positively affects clinical and neuropsychological outcome at six months.

Intraoperative brain mapping during awake surgery in symptomatic supratentorial cavernomas.

BACKGROUND: Complete resection of symptomatic supratentorial cavernoma (SCA) and removal of the surrounding gliotic area is recommended to minimize the risk of persistent seizures or (re)bleeding. Surgery of SCA located in an eloquent area, can carry out severe postoperative neurological morbidity. We report a study aimed to assess feasibility, extent of resection and outcome after surgical removal of CA by cortico-subcortical intraoperative brain stimulation (ioBS) in the awake patient. METHODS: Six patients diagnosed of symptomatic SCA located on an eloquent area and operated on while awake under local anaesthesia ioBS, were included. Preoperative planning included neuropsychologic assessment of language-related functions, sociocognitive functions and executive functions. Intraoperatively, we recorded the results achieved in the planned neuropsychological tasks when stimulation was applied (cortical and subcortical). Postoperative control 3D MRI was scheduled at 1 month after surgery to calculate extent of resection. Neuropsychological assessment at 6 months after surgery was performed in all cases. RESULTS: Six patients (5 females, 1 male) aged 24-48 years were included in our study. Locations of the lesions were right insular (n=1), left insular (n=1), left temporo-insular (n=1), left temporal (n=2) and left frontal (n=1). In all patients, positive findings were obtained during ioBS. In 5 patients, complete surgical resection was achieved. Two patients had postoperative transient neurological deficits, one case of hemiparesis, one case of dysnomia, both cleared over a 6-month period. Clinical follow-up revealed that all patients experienced complete recovery from preoperative symptoms within a year and five patients with seizures showed marked improvement and eventually quit antiepileptic drugs. Neuropsychological assessment at 6 months provided normal results compared to preoperative baseline in all domains. CONCLUSIONS: Our study suggests that ioBS in the awake surgery of symptomatic SCA located in eloquent areas, allows to increase the rate of complete resection, minimizing postoperative neurological and neuropsychological deficit, and improving postoperative seizures control.

A tetradecapeptide somatostatin dicarba-analog: Synthesis, structural impact and biological activity.

We described here the first tetradecapeptide somatostatin-analogue where the disulfide bridge has been replaced by a carbon-carbon double bond. This analogue was prepared using microwave assisted ring closing metathesis (RCM) using the 2nd generation Grubbs as catalyst. Under our optimized conditions the cyclization between allylGly 3 and 14 proceeded in moderate yield, excellent cyclic/linear ratio and very high Z-double bond selectivity. NMR studies also demonstrated that the conformational flexibility of this peptide is increased in comparison to that of the natural hormone. Remarkably, this alkene-bridged somatostatin analog is highly selective against somatostatin receptors 1 and 5, suggesting that conformational rigidity is not required for the efficient interaction of somatostatin analogues with these two receptors.

Insights into structure-activity relationships of somatostatin analogs containing mesitylalanine.

The non-natural amino acid mesitylalanine (2,4,6-trimethyl-L-phenylalanine; Msa) has an electron-richer and a more conformationally restricted side-chain than that of its natural phenylalanine counterpart. Taking these properties into account, we have synthesized ten somatostatin analogs containing Msa residues in different key positions to modify the intrinsic conformational flexibility of the natural hormone. We have measured the binding affinity of these analogs and correlated it with the main conformations they populate in solution. NMR and computational analysis revealed that analogs containing one Msa residue were conformationally more restricted than somatostatin under similar experimental conditions. Furthermore, we were able to characterize the presence of a hairpin at the pharmacophore region and a non-covalent interaction between aromatic residues 6 and 11. In all cases, the inclusion of a D-Trp in the eighth position further stabilized the main conformation. Some of these peptides bound selectively to one or two somatostatin receptors with similar or even higher affinity than the natural hormone. However, we also found that multiple incorporations of Msa residues increased the life span of the peptides in serum but with a loss of conformational rigidity and binding affinity.

Distinct and specific roles of AKT1 and AKT2 in androgen-sensitive and androgen-independent prostate cancer cells.

AKT isoforms are expressed in prostate cancer and their expression and localization have different associations with clinical characteristics. However, the distinct roles of the AKT isoforms in prostate cancer cells are largely unknown. In the present study, we demonstrate distinct roles for AKT1 and AKT2 in cell growth and migration. Ablation of AKT1 and AKT2 decreased the proliferation of the androgen-independent cell line PC-3, although by different mechanisms. AKT1 ablation induced loss of cell adhesion and subsequent apoptosis. AKT2 (but not AKT1) ablation promoted cell cycle arrest at G0/G1, associated with downregulation of cyclin D, CDK6 and CDK2, and upregulation and cytoplasmic-to-nuclear redistribution of p27. The increase of p27 protein levels was due to more gene transcription and an increase in protein stability. The increased stability of p27 was induced by delocalisation of Skp2 and a lower level of p27 phosphorylation at Thr187. AKT1 and AKT2 ablation inhibited and stimulated PC-3 cell migration, respectively. An AKT isoform-specific function could be associated with its subcellular localization. We found that AKT1 and AKT2 were mainly localised in the cytoplasm and nucleus, respectively. In androgen-sensitive cell line LNCaP, the ablation of AKT1 or AKT2 caused apoptosis but in androgen-independent LNCaP sublines, the effect of AKT1 ablation was lower; whereas no changes were observed after AKT2 ablation. Taken together, our data show that AKT1 and AKT2 have non-redundant roles in the regulation of PC-3 cell proliferation and migration. These could be explained by their subcellular localization and/or the specific regulation of downstream effectors. Furthermore, contribution of AKT isoforms to the progression of prostate cancer may change from an androgen-sensitive to a hormone-refractory stage. These findings may help design new targeted strategies for inhibiting AKT isoforms in prostate cancer.

EGF promotes neuroendocrine-like differentiation of prostate cancer cells in the presence of LY294002 through increased ErbB2 expression independent of the phosphatidylinositol 3-kinase-AKT pathway.

An increased neuroendocrine (NE) cell population in prostate cancer is associated with more aggressive disease and recurrence after androgen-deprivation therapy, although the mechanism responsible is unknown. In this study, we report that the treatment of LNCaP cells with epidermal growth factor (EGF) in the presence of LY294002, an inhibitor of the phosphoinositol 3'-kinase (PI3K)-AKT pathway, induced an increase of levels and activity of ErbB2. Under these conditions, we also observed cell survival and NE differentiation. When we treated with wortmannin, another PI3K inhibitor, or we knocked down PI3K or AKT isoforms in the presence of EGF, ErbB2 up-regulation was not observed, suggesting that the increase of ErbB2 induced by EGF plus LY294002 is not mediated by the PI3K-Akt pathway. Other targets of LY294002 were also discounted. We also show that ErbB2 up-regulation is directly involved in neuroendocine differentiation but not in cell survival as ErbB2 levels increased in parallel with NE differentiation marker levels, whereas ErbB2 knockdown reduced them; other NE differentiation inducers also increased the ErbB2 levels and the immunohistochemical analysis of prostate cancer samples showed colocalization of ErbB2 and chromogranin A. We found that, in LNCaP cells, EGF in combination with LY294002 increased ErbB2 levels by a PI3K/AKT-independent mechanism and that this increase was associated with the acquisition of a NE phenotype. These results suggest that is worth reconsidering ErbB2 as a drug target in prostate cancer and this should be kept in mind when designing new clinical schedules for the treatment of this disease.

SHP-1 in cell-cycle regulation.

The reversible phosphorylation of tyrosine residues in proteins, which is governed by the balanced action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is a key element of the signaling pathways that are involved in the control of cell proliferation. Deregulation of either of these key regulators leads to abnormal cell signaling, which is largely associated with human pathologies including cancer. This review focuses on recent studies on the role of the protein tyrosine phosphatase SHP-1 on cell-cycle regulation and its possible roles in tumour onset and progression. SHP-1 is a PTP with two SH2 domains that is expressed in haematopoietic cells and, moderately, in many other cell types, especially malignant epithelial cells. SHP-1 regulates cell proliferation, whether it is by controlling mitogenic pathways activated by receptors with tyrosine kinase activity, or by regulating components of the cell-cycle machinery such as CDK2, p27 and cyclin D1. Since several inhibitors targeting SHP-1 have demonstrated their value in cancer treatment, this phosphatase has been proposed as a therapeutic target for this pathology.

SSTR1- and SSTR3-selective somatostatin analogues.

We prepared the two enantiomers of 3-(3'-quinolyl)-alanine (Qla, 1) in multigram scale by asymmetric hydrogenation. These amino acids, protected as Fmoc derivatives, were then used in the solid-phase synthesis of two new somatostatin 14 (SRIF-14) analogues 8 a and 8 b, tetradecapeptides in which the tryptophan residue (Trp8) is replaced by one of the two enantiomers of 3-(3'-quinolyl)-alanine (Qla8) and therefore lack the N--H bond in residue 8. The selectivity of these new analogues for the somatostatin receptors, SSTR1-5, was measured. Substitution with L-Qla8 yielded peptide 8 a, which was highly selective for SSTR1 and SSTR3, with an affinity similar to that of SRIF-14. Substitution by D-Qla gave the relatively selective analogue 8 b, which showed high affinity for SSTR3 and significant affinity for SSTR1, SSTR2 and SSTR5. The biological results demonstrate that bulky and electronically poor aromatic amino acids at position 8 are compatible with strong activity with SSTR1 and SSTR3. Remarkably, these high affinity levels were achieved with peptides in which the conformational mobility was increased with respect to that of SRIF-14. This observation suggests that conformational rigidity is not required, and might be detrimental to the interaction with receptors SSTR1 and SSTR3. The absence of an indole N proton in Qla8 might also contribute to the increased flexibility observed in these analogues.

EGF prevents the neuroendocrine differentiation of LNCaP cells induced by serum deprivation: the modulator role of PI3K/Akt.

The primary focus of this investigation was to study the relationship between neuroendocrine (NE) differentiation and epidermal growth factor (EGF) because both have been implicated in the progression of prostate cancer. For this purpose, we used gefitinib and trastuzumab, which are inhibitors of EGF receptor (EGFR) and ErbB2, respectively. EGF prevents NE differentiation induced by androgen depletion. This effect is prevented by gefitinib, which blocks the activation of EGFR and ErbB2, stimulation of mitogen-activated protein kinase (MAPK), and cell proliferation induced by EGF. Conversely, trastuzumab does not inhibit the effect of EGF on EGFR phosphorylation, MAPK activity, cell proliferation, and NE differentiation, although it reduces ErbB2 levels specifically, suggesting that ErbB2 is not necessary to inhibit NE differentiation. Prevention of NE differentiation by EGF is mediated by a MAPK-dependent mechanism and requires constitutive Akt activation. The abrogation of the PI3K/Akt pathway changes the role of EGF from inhibitor to inductor of NE differentiation. We show that EGFR tyrosine kinase, MAPK, and PI3K inhibitors inhibit the cell proliferation stimulated by EGF but induce the acquisition of NE phenotype. Altogether, the present data should be borne in mind when designing new clinical schedules for the treatment of prostate cancer, including the use of ErbB receptors and associated signaling pathway inhibitors.

Autocrine regulation of human prostate carcinoma cell proliferation by somatostatin through the modulation of the SH2 domain containing protein tyrosine phosphatase (SHP)-1.

The present study was intended to gain additional information on the growth regulation of prostate by somatostatin (SRIF) and the intracellular events involved. The human prostate adenocarcinoma cell lines PC-3 and LNCaP produce SRIF and express subtypes 2 and 5 of SRIF receptors. The secretion of SRIF is related to the proliferative status of these cells; an inverse relationship exists between cell proliferation and the amount of secreted SRIF. Moreover, the growth of PC-3 cells is inhibited by SRIF overexpression and increased by blockage of endogenous SRIF. Coincident with the increase in SRIF secretion, the activity and levels of the SH2 domain containing protein tyrosine phosphatase (SHP)-1, present in PC-3 cells are augmented, but the effect can be partially prevented by neutralization of secreted endogenously SRIF. The activity of SHP-1 is also stimulated by the SRIF analog RC160. Overexpression of SHP-1 induces inhibition of PC-3 cell growth. SHP-1 is also present in normal prostate, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and well differentiated adenocarcinoma. In contrast, no signal is detected in poorly differentiated prostate cancer. These findings demonstrate that SRIF inhibits PC-3 and LNCaP cell proliferation through an autocrine/paracrine SRIF loop. This effect could be mediated by activation of the tyrosine phosphatase SHP-1 detected in these cells as well as in human prostate and prostate cancer.