Abstract Cognitive deficits are considered a key feature of schizophrenia, and they usually precede the onset of the illness and continue after psychotic symptoms appear. Current antipsychotic drugs ...have little or no effect on the cognitive deficits of this disorder. Prolyl oligopeptidase (POP) is an 81-kDa monomeric serine protease that is expressed in brain and other tissues. POP inhibitors have shown neuroprotective, anti-amnesic and cognition-enhancing properties. Here we studied the potential of IPR19, a new POP inhibitor, for the treatment of the cognitive symptoms related to schizophrenia. The efficacy of the inhibitor was evaluated in mouse models based on subchronic phencyclidine and acute dizocilpine administration, and in adult offspring from mothers with immune reaction induced by polyinosinic:polycytidylic acid administration during pregnancy. Acute IPR19 administration (5 mg/kg, i.p.) reversed the cognitive performance deficits of the three mouse models in the novel object recognition test, T-maze, and eight-arm radial maze. The compound also ameliorates deficits of the prepulse inhibition response. The in vitro inhibitory efficacy and selectivity, brain penetration and exposure time after injection of IPR19 were also addressed. Our results indicate that the inhibition of POP using IPR19 may offer a promising strategy to develop drugs to ameliorate the cognitive deficits of schizophrenia.
Alterations of dopamine D
(D1R) and D
receptor (D2R) are proposed in schizophrenia but brain neuroimaging and postmortem studies have shown controversial results in relation to D1R and D2R density. ...Besides, scarce information on the functionality of brain D1R and D2R is available. The present study characterized G-protein activation by D1R and D2R agonists in postmortem human brain. Furthermore, D2R functional status was compared between schizophrenia and control subjects.
G-protein receptor coupling was assessed in control caudate nucleus and frontal cortex by
SGTPγS-binding stimulation induced by increasing concentrations (10
-10
M) of dopamine, and the selective dopaminergic agonists SKF38393 (D1R) and NPA (D2R). Concentration-response curves to NPA stimulation of
SGTPγS binding were analyzed in antipsychotic-free (n = 10) and antipsychotic-treated (n = 7) schizophrenia subjects and matched controls (n = 17).
In caudate,
SGTPγS-binding responses to agonists were compatible with the existence of functional D2R. In contrast, stimulations in cortex showed responses that did not correspond to D1R or D2R.
SGTPγS-binding activation by NPA in caudate displayed biphasic curves with similar profile in schizophrenia (EC
= 7.94 nM; EC
= 7.08 μM) and control (EC
= 7.24 nM; EC
= 15.14 μM) subjects. The presence or absence of antipsychotic medication did not influence the pharmacological parameters.
Feasibility of functional evaluation of dopamine receptors in postmortem human brain by conventional
SGTPγS-binding assays appears to be restricted to signalling through inhibitory G
proteins. These findings provide functional information about brain D2R status in subjects with schizophrenia and do not support the existence of D2R supersensitive in this mental disorder.
Background
Alterations of dopamine D
1
(D1R) and D
2
receptor (D2R) are proposed in schizophrenia but brain neuroimaging and
postmortem
studies have shown controversial results in relation to D1R and ...D2R density. Besides, scarce information on the functionality of brain D1R and D2R is available. The present study characterized G-protein activation by D1R and D2R agonists in
postmortem
human brain. Furthermore, D2R functional status was compared between schizophrenia and control subjects.
Methods
G-protein receptor coupling was assessed in control caudate nucleus and frontal cortex by
35
SGTPγS-binding stimulation induced by increasing concentrations (10
–10
–10
–3
M) of dopamine, and the selective dopaminergic agonists SKF38393 (D1R) and NPA (D2R). Concentration–response curves to NPA stimulation of
35
SGTPγS binding were analyzed in antipsychotic-free (
n
= 10) and antipsychotic-treated (
n
= 7) schizophrenia subjects and matched controls (
n
= 17).
Results
In caudate,
35
SGTPγS-binding responses to agonists were compatible with the existence of functional D2R. In contrast, stimulations in cortex showed responses that did not correspond to D1R or D2R.
35
SGTPγS-binding activation by NPA in caudate displayed biphasic curves with similar profile in schizophrenia (EC
50H
= 7.94 nM; EC
50L
= 7.08 μM) and control (EC
50H
= 7.24 nM; EC
50L
= 15.14 μM) subjects. The presence or absence of antipsychotic medication did not influence the pharmacological parameters.
Conclusions
Feasibility of functional evaluation of dopamine receptors in
postmortem
human brain by conventional
35
SGTPγS-binding assays appears to be restricted to signalling through inhibitory G
i/o
proteins. These findings provide functional information about brain D2R status in subjects with schizophrenia and do not support the existence of D2R supersensitive in this mental disorder.
The incidence of lung cancer during pregnancy is rising due to the high rate of smokers in young women and the late mean age of pregnancy; in addition, considering that the patients are young women ...with a higher incidence of molecular alterations, molecular testing in lung adenocarcinoma should always be performed, even in pregnancy. Here, we report the case of a lung adenocarcinoma diagnosed during pregnancy with a long survival who benefitted from brain radiotherapy, conventional chemotherapy, and ALK TKI-targeted treatment. It reveals the safety of whole brain radiotherapy during pregnancy and consideration of other brain radiation techniques even in palliative cases, which should be personalized and managed by a multidisciplinary team. However, upfront management of brain metastasis in ALK-positive patients remains unresolved.
The 'cancer cell fusion' theory is controversial due to the lack of methods available to identify hybrid cells and to follow the phenomenon in patients. However, it seems to be one of the best ...explanations for both the origin and metastasis of primary tumors. Herein, we co-cultured lung cancer stem cells with human monocytes and analyzed the dynamics and properties of tumor-hybrid cells (THC), as well as the molecular mechanisms beneath this fusion process by several techniques: electron-microscopy, karyotyping, CRISPR-Cas9, RNA-seq, immunostaining, signaling blockage, among others. Moreover, mice models were assessed for in vivo characterization of hybrids colonization and invasiveness. Then, the presence of THCs in bloodstream and samples from primary and metastatic lesions were detected by FACS and immunofluorescence protocols, and their correlations with TNM stages established. Our data indicate that the generation of THCs depends on the expression of CD36 on tumor stem cells and the oxidative state and polarization of monocytes, the latter being strongly influenced by microenvironmental fluctuations. Highly oxidized M2-like monocytes show the strongest affinity to fuse with tumor stem cells. THCs are able to proliferate, colonize and invade organs. THC-specific cell surface signature CD36
+
CD14
+
PANK
+
allows identifying them in matched primary tumor tissues and metastases as well as in bloodstream from patients with lung cancer, thus functioning as a biomarker. THCs levels in circulation correlate with TNM classification. Our results suggest that THCs are involved in both origin and spread of metastatic cells. Furthermore, they might set the bases for future therapies to avoid or eradicate lung cancer metastasis.
To present a descriptive analysis of pediatric craniopharyngiomas (PedCPG) treated in various Spanish hospitals, defining factors related to recurrence and performing a critical analysis of the ...results.
We undertook a multicenter retrospective review of PedCPG treated between 2000 and 2017. Data collected included epidemiological variables, clinical and radiological characteristics, goal of first surgery, rate of recurrence and its approach, adjuvant treatment, complications and permanent morbidity. Associations were studied between progression and number of progressions and independent variables.
The study involved 69 children from 8 Spanish hospitals. Most of the tumors invaded several intracranial compartments at diagnosis, with the hypothalamus involved in 41.3% of cases. The first treatment strategy was usually gross total resection (GTR) (71%), with some patients treated with radiotherapy or intracystic chemotherapy. The progression rate after first surgery was 53% in a mean follow-up of 88.2 months (range 7–357). In the GTR group 38.8% of tumors recurred, 40% in the group of subtotal resection or biopsy and 93.3% in the cyst fenestration±Ommaya reservoir group. Mortality was 7.2%. Follow-up period, size of the tumor and goal of first surgery were significantly related with progression.
Our results in terms of disease control, hormonal or visual impairment and mortality were acceptable, but there are several areas for improvement. Our short-term goals should be to create a national register of PedCPG, reach a consensus about a treatment algorithm, and improve diagnosis of hypothalamic dysfunction to avoid preventable morbidity.
Presentar un análisis descriptivo de los craneofaringiomas pediátricos tratados en varios hospitales españoles, definiendo los factores relacionados con la recurrencia y realizando un análisis crítico de los resultados.
Estudio retrospectivo multicéntrico de los craneofaringiomas pediátricos tratados entre 2000-2017. Se recogieron variables epidemiológicas, clínicas y radiológicas, el objetivo de la primera cirugía, la tasa de recurrencia y su abordaje, los tratamientos adyuvantes, así como las complicaciones y la morbilidad permanente. Se estudió la relación estadística entre la progresión y el número de progresiones con las variables independientes.
Se incluyeron 69 niños tratados en 8 hospitales españoles. La mayoría de los tumores se extendían por varios compartimentos intracraneales al diagnóstico, con invasión hipotalámica en el 41,3%. Habitualmente, la primera estrategia de tratamiento fue la resección radical (71%), con algunos pacientes tratados con radioterapia o quimioterapia intraquística. La tasa de progresión tras la primera cirugía fue del 53% en un seguimiento medio de 88,2 meses (rango 7-357). En el grupo de resección radical recurrieron un 38,8% de los tumores, un 40% en el de resección subtotal o biopsia y un 93,3% en el de fenestración quística±reservorio Ommaya. La mortalidad fue de un 7,2%. Las variables relacionadas de forma significativa con progresión fueron el tiempo de seguimiento, el tamaño del tumor y el objetivo de la primera cirugía.
Los resultados obtenidos fueron aceptables en control de la enfermedad, secuelas hormonales o visuales y mortalidad, aunque hay varias áreas susceptibles de mejora. Nuestros objetivos a corto plazo deberían estar orientados a crear un registro nacional de craneofaringiomas pediátricos, alcanzar un consenso respecto al algoritmo de tratamiento y mejorar el diagnóstico de la disfunción hipotalámica para evitar morbilidad.
PDF
