RESUMEN
Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane receptor tyrosine kinases, have recently become an attractive method for precision anticancer therapies since the approval of Larotrectinib and Entrectinib by FDA. Herein, we reported the discovery of a series of novel indazolylaminoquinazoline and indazolylaminoindazole as TRK inhibitors. The representative compound 30f exhibited good inhibitory activity against TRKWT, TRKG595R and TRKG667C with IC50 values of 0.55 nM, 25.1 nM and 5.4 nM, respectively. The compound also demonstrated potent superior to Larotrectinib antiproliferative activity against a panel of Ba/F3 cell lines transformed with both NTRK wild type and mutant fusions (IC50 = 10-200 nM). In addition, compound 30f exhibited good in vitro metabolic stability (T1/2 = 73.0 min), indicating that the quinazoline derivatives may have better metabolic stability. Finally, the binding mode of compound 30f predicted by molecular docking well explained the good enzyme inhibitory activity of indazolylaminoquinazoline compounds as TRK inhibitor. Thus, compound 30f can be used as a promising lead molecule for further structural optimization.
Asunto(s)
Neoplasias , Humanos , Tropomiosina , Simulación del Acoplamiento Molecular , Proteínas Tirosina Quinasas Receptoras , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) often loses effectiveness against non-small cell lung malignancies (NSCLCs) with ALK gene rearrangements (ALK+). 19 novel imidazo[1,2-b]pyridazine macrocyclic derivatives were designed, synthesized, and tested for their biological activities in an effort to develop ALK inhibitors that would overcome second-generation ALK-TKIs, particularly the G1202R mutation and the lorlatinib-resistant L1196M/G1202R double mutations. Of all the target substances, O-10 had the most effective enzymatic inhibitory activity, with IC50 values for ALKWT, ALKG1202R, and ALKL1196M/G1202R of 2.6, 6.4, and 23 nM, respectively. O-10, on the other hand, reduced the growth of ALK-positive Karpas299, BaF3-EML4-ALKG1202R, and BaF3-EML4-ALKL1196M/G1202R cells with IC50 values of 38, 52, and 64 nM, respectively. This was equally effective to the reference drug Repotrectinib (IC50 = 40, 164, and 208 nM). The kinase selectivity profile, liver microsome stability test and in vivo pharmacokinetic properties in SD rats of compound O-10 were further evaluated. O-10 was regarded as an effective ALK inhibitor for the treatment of mutations overall.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Ratas , Animales , Quinasa de Linfoma Anaplásico , Resistencia a Antineoplásicos , Ratas Sprague-Dawley , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Mutación , Lactamas Macrocíclicas/farmacología , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Based on EGFR-TKI Osimertinib as lead compound, a series of novel macrocyclic derivatives bearing aniline pyrimidine scaffolds were designed and synthesized by macrocyclization. Their structures were identified by 1H NMR, 13C NMR, 19F NMR and HRMS. The pharmacological activities of the target compounds were tested and the preliminary structure-activity relationship was discussed. Among them, 17-membered ring compound H1 displayed the best inhibitory activities against EGFRL858R/T790M and EGFRd746-750/T790M with IC50 value of 2.92 nM and 0.34 nM, respectively. Exhilaratingly, 17-membered ring compound H7 possessed the most potent antiproliferative activity against BaF3-EGFRdel19/T790M cell lines (IC50 = 0.035 µm), which rivaled that of Osimertinib (IC50 = 0.033 µm).
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Antineoplásicos , Neoplasias Pulmonares , Acrilamidas , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Antineoplásicos/química , Proliferación Celular , Receptores ErbB , Humanos , Indoles , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
A kind of hydroxylated polymethoxyflavone (PMFs) existing in the citrus genus, 5-Demethyltangeretin (5-DTAN), has been reported to possess several bioactivities in vitro and in vivo. The aim of this study was to investigate whether acetylation could enhance the anticancer activity and oral bioavailability of 5-DTAN. PC-3 human prostate cancer cells were treated with tangeretin (TAN), 5-DTAN, and 5-acetylated TAN (5-ATAN), and the results showed that the cytotoxic effect 5-ATAN (IC50 value of 5.1 µM) on the cell viability of PC-3 cells was stronger than that of TAN (IC50 value of 17.2 µM) and 5-DTAN (IC50 value of 11.8 µM). Compared to 5-DTAN, 5-ATAN treatment caused a more pronounced DNA ladder, increased the sub-G1 phase population, and induced G2/M phase arrest in the cell cycle of PC-3 cells. We also found that 5-ATAN triggered the activation of caspase-3 and the progression of the intrinsic mitochondrial pathway in PC-3 cells, suggesting the induction of apoptosis. In a cell wound healing test, 5-ATAN dose-dependently reduced the cell migration, and the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) was decreased after 48 h of 5-ATAN treatment. Moreover, oral administration of 5-ATAN showed a significantly stronger inhibitory effect on tumor size and tumor weight in tumor-bearing nude mice than those of vehicle or the 5-DTAN group (p < 0.05). Furthermore, pharmacokinetic results showed that single-dose oral administration of 5-ATAN exhibited a higher maximum concentration (Cmax) and area under the curve (AUC) of 5-DTAN in plasma than that of 5-DTAN. More extensive distribution of 5-DTAN to most tissues of mice was also observed in mice treated with 5-ATAN for 7 days. In conclusion, acetylation strongly enhances the anticancer activity and oral bioavailability of 5-DTAN and could be a promising strategy to promote the potential bioactivities of natural products.
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Antineoplásicos , Flavonas , Animales , Humanos , Masculino , Ratones , Acetilación , Apoptosis , Disponibilidad Biológica , Línea Celular Tumoral , Metaloproteinasa 2 de la Matriz , Ratones Desnudos , Flavonas/química , Flavonas/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacocinéticaRESUMEN
We examine closed-form approximations for the equilibrium Ca2+ and buffer concentrations near a point Ca2+ source representing a Ca2+ channel, in the presence of a mobile buffer with two Ca2+ binding sites activated sequentially and possessing distinct binding affinities and kinetics. This allows us to model the impact on Ca2+ nanodomains of realistic endogenous Ca2+ buffers characterized by cooperative Ca2+ binding, such as calretinin. The approximations we present involve a combination or rational and exponential functions, whose parameters are constrained using the series interpolation method that we recently introduced for the case of simpler Ca2+ buffers with a single Ca2+ binding site. We conduct extensive parameter sensitivity analysis and show that the obtained closed-form approximations achieve reasonable qualitative accuracy for a wide range of buffer's Ca2+ binding properties and other relevant model parameters. In particular, the accuracy of the derived approximants exceeds that of the rapid buffering approximation in large portions of the relevant parameter space.
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Calcio , Sitios de Unión , Tampones (Química) , CinéticaRESUMEN
This study aims to investigate the potential mechanism of curcumin in mediating interleukin-6(IL-6)/signal transducer and activator of transcription 3(STAT3) signaling pathway to repair intestinal mucosal injury induced by 5-fluorouracil(5-FU) chemotherapy for colon cancer. SD rats were intraperitoneally injected with 60 mg·kg~(-1)·d~(-1) 5-FU for 4 days to establish a model of intestinal mucosal injury. Then the rats were randomly divided into model group(equal volume of normal saline), curcumin low, medium and high dose groups(50, 100, 200 mg·kg~(-1)), and normal SD rats were used as control group(equal volume of normal saline). Each group received gavage administration for 4 consecutive days, and the changes of body weight and feces were recorded every day. After administration, blood was collected from the heart, and jejunum tissues were collected. The levels of serum interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) were detected by ELISA, and at the same time, the concentration of Evans blue(EB) in jejunum was measured. Hematoxylin-eosin(HE) staining was used to observe the pathological state of jejunum, and the length of jejunum villi and the depth of crypt were measured. The positive expression levels of claudin, occludin and ZO-1 were detected by immunohistochemistry. Western blot was used to detect the protein expression of IL-6, p-STAT3, E-cadherin, vimentin and N-cadherin in jejunum tissues. The results showed that, curcumin significantly increased body weight and fecal weight(P<0.05 or P<0.01), decreased fecal score, EB concentration, IL-1ß and TNF-α levels(P<0.05 or P<0.01) in rats. In addition, curcumin maintained the integrity of mucosal surface and villi structure of jejunum to a large extent, and reduced pathological changes in a dose-dependent manner. Meanwhile, curcumin could increase the positive expression of occludin, claudin and ZO-1(P<0.05 or P<0.01), repair intestinal barrier function, downregulate the protein expression of IL-6, p-STAT3, vimentin and N-cadherin in jejunum tissues(P<0.05 or P<0.01), and upregulate the protein expression of E-cadherin(P<0.05). Therefore, curcumin could repair the intestinal mucosal injury induced by 5-FU chemotherapy for colon cancer, and the mechanism may be related to the inhibition of IL-6/STAT3 signal and the inhibition of epithelial-mesenchymal transition(EMT) process.
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Neoplasias del Colon , Curcumina , Animales , Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/toxicidad , Interleucina-6/genética , Mucosa Intestinal/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de SeñalRESUMEN
We consider the stationary solution for the Ca2+ concentration near a point Ca2+ source describing a single-channel Ca2+ nanodomain in the presence of a single mobile Ca2+ buffer with 1:1 Ca2+ binding. We present computationally efficient approximants that estimate stationary single-channel Ca2+ nanodomains with great accuracy in broad regions of parameter space. The presented approximants have a functional form that combines rational and exponential functions, which is similar to that of the well-known excess buffer approximation and the linear approximation but with parameters estimated using two novel, to our knowledge, methods. One of the methods involves interpolation between the short-range Taylor series of the free buffer concentration and its long-range asymptotic series in inverse powers of distance from the channel. Although this method has already been used to find Padé (rational-function) approximants to single-channel Ca2+ and buffer concentrations, extending this method to interpolants combining exponential and rational functions improves accuracy in a significant fraction of the relevant parameter space. A second method is based on the variational approach and involves a global minimization of an appropriate functional with respect to parameters of the chosen approximations. An extensive parameter-sensitivity analysis is presented, comparing these two methods with previously developed approximants. Apart from increased accuracy, the strength of these approximants is that they can be extended to more realistic buffers with multiple binding sites characterized by cooperative Ca2+ binding, such as calmodulin and calretinin.
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Calcio , Calmodulina , Sitios de Unión , Calcio/metabolismo , Calmodulina/metabolismoRESUMEN
With the semiclassical ensemble model, we systematically investigate the correlated electron dynamics in strong-field nonsequential double ionization (NSDI) by the counter-rotating circularly polarized two-color (CPTC) laser pulses. Our results show that the angular distributions of the electrons in NSDI sensitively depend on the intensity ratio of the CPTC laser fields. At the small ratio, the electron pairs emit with a relative angle of about 120°, and this angle shifts to 40° as the ratio increases and finally it exhibits a wide range distribution as the intensity ratio further increases. Back analysis of the NSDI trajectories shows that this behavior results from the relative-intensity-dependence of the release time of the electron pairs in the CPTC laser fields. The release times of the electron pairs are directly mapped to the angular distribution. Our results indicate that the emission times of the correlated electrons in NSDI can be controlled with the CPTC laser fields.
RESUMEN
Laser-induced electron tunneling ionization from atoms and molecules plays as the trigger for a broad class of interesting strong-field phenomena in attosecond community. Understanding the time of electron tunneling ionization is vital to achieving the ultimate accuracy in attosecond metrology. We propose a novel attosecond photoelectron interferometer, which is based on the interference of the direct and near-forward rescattering electron wave packets, to determine the time information characterizing the tunneling process. Adding a weak perturbation in orthogonal to the strong fundamental field, the phases of the direct and the near-forward rescattering electron wave packets are modified, leading to the shift of the interferogram in the photoelectron momentum distributions. By analyzing the response of the interferogram to the perturbation, the real part of the ionization time, which denotes the instant when the electron exits the potential barrier, and the associated rescattering time are precisely retrieved. Moreover, the imaginary part of the ionization time, which has been interpreted as a quantity related to electron motion under the potential barrier, is also unambiguously determined.
RESUMEN
Oscillatory networks often include neurons with membrane potential resonance, exhibiting a peak in the voltage amplitude as a function of current input at a nonzero (resonance) frequency (fres). Although fres has been correlated to the network frequency (fnet) in a variety of systems, a causal relationship between the two has not been established. We examine the hypothesis that combinations of biophysical parameters that shift fres, without changing other attributes of the impedance profile, also shift fnet in the same direction. We test this hypothesis, computationally and experimentally, in an electrically coupled network consisting of intrinsic oscillator (O) and resonator (R) neurons. We use a two-cell model of such a network to show that increasing fres of R directly increases fnet and that this effect becomes more prominent if the amplitude of resonance is increased. Notably, the effect of fres on fnet is independent of the parameters that define the oscillator or the combination of parameters in R that produce the shift in fres, as long as this combination produces the same impedance vs. frequency relationship. We use the dynamic clamp technique to experimentally verify the model predictions by connecting a model resonator to the pacemaker pyloric dilator neurons of the crab Cancer borealis pyloric network using electrical synapses and show that the pyloric network frequency can be shifted by changing fres in the resonator. Our results provide compelling evidence that fres and resonance amplitude strongly influence fnet, and therefore, modulators may target these attributes to modify rhythmic activity.
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Sinapsis Eléctricas/fisiología , Potenciales de la Membrana/fisiología , Modelos Neurológicos , Neuronas/fisiología , Animales , Braquiuros , Impedancia Eléctrica , Ganglios de Invertebrados/fisiología , Masculino , Vías Nerviosas/fisiología , Técnicas de Placa-Clamp , PeriodicidadRESUMEN
With the classical ensemble model, we have investigated the pulse-duration dependence of nonsequential double ionization (NSDI) over a wide range of laser intensity. The correlated electron momentum distributions are distinctly different for the few-cycle and multiple cycle pulses, which agree well with the previous experiments. Based on this agreement, we analyzed the underlying process for the pulse-duration dependence of the electron correlation by tracing the classical trajectories. Counterintuitively, our analysis shows that the recollision-induced excited states of NSDI could resist ionization in the strong laser field for a time much longer than one optical cycle even at very high intensities. For the multiple-cycle pulses, NSDI events with such a long time delay have significant contribution to the total NSDI yields, which is responsible for the pulse-duration dependence of the observed correlated patterns in the electron momentum distributions.
RESUMEN
BACKGROUND: Pulmonary metastases occur in up to 25% of colorectal cancer (CRC) patients. Many studies have reported that pulmonary metastasectomy might increase 5-year survival of these patients. The aim of this study was to describe our experience with pulmonary metastasectomy for metastatic colorectal cancer and to explore the prognostic value of p53 overexpression and other factors. METHODS: Between July 2002 and December 2013, the clinicopathological data of 88 patients with colorectal carcinoma who underwent pulmonary metastases resection were retrospectively reviewed and analyzed. Clinical, biochemical and imaging, and operative data, and expression of p53 were retrospectively collected. Immunohistochemical staining for p53 was performed on paraffin-embedded 5-µm sections using mouse anti-human tumor protein p53 monoclonal antibody (DO-7, Dako, Denmark). Overall survival (OS) was calculated from resection of pulmonary metastases to death. The prognostic effect of each variable on survival was evaluated using the Kaplan-Meier method and log-rank test. For the multivariate analysis of prognostic factors, the Cox regression model was used. RESULTS: There were 58 men and 30 women in this study, and their median age was 55 (range 31 to 85). Video-assisted thoracoscopic surgery (VATS) was performed in 59 cases (78%), and 29 patients (19%) underwent thoracotomy. Lung wedge resection and pulmonary lobectomy were performed in 52 (59.1%) and 36 (40.9%) patients, respectively. After a median follow-up duration of 44 months, the cumulative 5-year survival was 45.4%, and the median overall survival was 57.8 months. The expression of p53 significantly influenced survival. In patients with p53 protein overexpression, we observed a median OS of 46.1 months, whereas the median OS of patients with negative protein expression of p53 was 62.6 months (p = 0.047). However, in multivariate analysis, p53 overexpression was failed to be an independently significant prognostic factor for survival. CONCLUSIONS: Pulmonary resection of metastatic colorectal cancer might offer a chance to prolong survival including those patients with extrapulmonary metastases. p53 protein expression was identified as a prognosis-related factor for surgery.
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Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/cirugía , Proteína p53 Supresora de Tumor/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/patología , Masculino , Metastasectomía , Persona de Mediana Edad , Análisis Multivariante , Neumonectomía , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Cirugía Torácica Asistida por Video , ToracotomíaRESUMEN
To evaluate the efficacy and safety of Choudongning (CDN)capsule in children with Tourette's syndrome of spleen deficiency and phlegm accumulation through a randomized double-blind three-arm controlled phase â ¢ study in 588 patients from 8 hospitals. The included patients were randomly divided into test group, positive control group and placebo group at the ratio of 3â¶1â¶1. Patients in the test group orally took CDN capsules and simulated Tiapridal tablets; the patients in positive control group took Tiapridal tablets and simulated CDN capsules; whereas the patients in placebo group orally took the simulated agents of the above two drugs. The treatment course was 6 weeks for three groups. The global grading rates, YGTSS scores and its factor scores, the degree of social function damage, as well as traditional Chinese medicine syndrome efficacy were evaluated as the outcome measures on efficacy. The AEs/ADRs, vital signs and laboratory testing were observed as outcome measures on safety. The total effective rate of YGTSS was 75.92% in the test group, 72.65% in the positive control group, and 37.29% in the placebo group. Non inferiority test stands between the test group and the positive control group, and they were superior to placebo group in efficacy with statistical difference. Significant difference had also been found among the 3 groups in YGTSS tics score, motor tics score, vocal tics, degree of social function damage and traditional Chinese medicine syndrome efficacy. During the study, there were 5 (1.42%)ADRs in the test group, 10 (8.55%)in the positive control group and 3 (2.54%)in the placebo group. The incidence of ADRs in the test group was lower than that in the positive control group, with statistical difference. It is clear to say that CDN capsule can effectively treat the Tourette's syndrome of spleen deficiency and phlegm accumulation. Its efficacy is not inferior to the commonly used Tiapridal tablets, with even less adverse reactions, so it has clinical application value.
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Medicamentos Herbarios Chinos/uso terapéutico , Síndrome de Tourette/tratamiento farmacológico , Cápsulas , Niño , Método Doble Ciego , Humanos , Medicina Tradicional China , Bazo/fisiopatología , Resultado del TratamientoRESUMEN
A series of novel 1,5-benzodiazepine-2,4-dione derivatives with C-6 amide substituents were designed and synthesized using three-component reactions. The preliminary assays showed that most of them displayed moderate to good antitumor activities against human lung carcinoma (A549), human breast epithelial carcinoma (MCF-7), human colon carcinoma (HCT116), human cervical carcinoma (Hela) and Lewis lung carcinoma (2LL). Exhilaratingly, the activity level of 6m rivaled that of 5-Fluorouracil (5-Fu) against MCF-7 cell lines, which might be used as novel lead scaffold for potential anticancer development.
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Antineoplásicos/farmacología , Benzodiazepinas/farmacología , Descubrimiento de Drogas , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Benzodiazepinas/síntesis química , Benzodiazepinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células HeLa , Humanos , Células MCF-7 , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Sushi domain-containing protein 4 (SUSD4) is a complement regulatory protein whose primary function is to inhibit the complement system, and it is involved in immune regulation. The role of SUSD4 in cancer progression has largely remained elusive. SUSD4 was studied across a variety of cancer types in this study. According to the results, there is an association between the expression level of SUSD4 and prognosis in multiple types of cancer. Further analysis demonstrated that SUSD4 expression level was related to immune cell infiltration, immune-related genes, tumor heterogeneity, and multiple cancer pathways. Additionally, we validated the function of SUSD4 in colorectal cancer cell lines and found that knockdown of SUSD4 inhibited cell growth and impacted the JAK/STAT pathway. By characterizing drug sensitivity in organoids, we found that the expression of SUSD4 showed a positive correlation trend with IC50 of Selumetinib, YK-4-279, and Piperlongumine. In conclusion, SUSD4 is a valuable prognostic indicator for diverse types of cancer, and it has the potential to be a target for cancer therapy.
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Neoplasias Colorrectales , Piperidonas , Humanos , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Pronóstico , Transducción de SeñalRESUMEN
OBJECTIVE: To investigate the clinical efficacy and safety of oxcarbazepine (OXC) suspension in children with focal epilepsy. METHODS: A total of 118 children aged 2-14 years, who were newly diagnosed with focal epilepsy between October 2009 and December 2011, were randomly divided into experimental group (n=60) and control group (n=58). The experimental group was treated with an orally suspension of OXC and the control group was orally administered with carbamazepine (CBZ) tablets. The two treatment regimens were compared in terms of clinical efficacy and safety. RESULTS: After 13 and 26 weeks of treatment, the experimental group had response rates of 75% and 72% respectively and seizure-free rates of 53% and 50%, and the control group had response rates of 71% and 66% and seizure-free rates of 50% and 43% respectively. There were no significant differences in the clinical efficacy between the two groups (P>0.05). After 26 weeks of treatment, the adverse event rates of the experimental and control groups were 18% and 40% respectively, with a significant difference between the two groups (P<0.05). CONCLUSIONS: OXC suspension has a comparable clinical efficacy to that of CBZ tablets in children aged 2-14 years who are newly diagnosed with focal epilepsy, but OXC suspension causes fewer adverse events and has higher safety.
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Anticonvulsivantes/uso terapéutico , Carbamazepina/análogos & derivados , Epilepsias Parciales/tratamiento farmacológico , Adolescente , Carbamazepina/efectos adversos , Carbamazepina/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Masculino , Oxcarbazepina , SuspensionesRESUMEN
Background: Experimental complex febrile seizures induce a persistent hippocampal hyperexcitability and an enhanced seizure susceptibility in adulthood. The rearrangement of filamentous actin (F-actin) enhances the excitability of hippocampus and contributes to epileptogenesis in epileptic models. However, the remodeling of F-actin after prolonged febrile seizures is to be determined. Methods: Prolonged experimental febrile seizures were induced by hyperthermia on P10 and P14 rat pups. Changes of actin cytoskeleton in hippocampal subregions were examined at P60 and the neuronal cells and pre- /postsynaptic components were labeled. Results: F-actin was increased significantly in the stratum lucidum of CA3 region in both HT + 10D and HT + 14D groups and further comparison between the two groups showed no significant difference. The abundance of ZNT3, the presynaptic marker of mossy fiber (MF)-CA3 synapses, increased significantly whereas the postsynaptic marker PSD95 did not change significantly. Overlapping area of F-actin and ZNT3 showed a significant increase in both HT+ groups. The results of cell counts showed no significant increase or decrease in the number of neurons in each area of hippocampus. Conclusion: F-actin was significantly up-regulated in the stratum lucidum of CA3, corresponding to the increase of the presynaptic marker of MF-CA3 synapses after prolonged febrile seizures, which may enhance the excitatory output from the dentate gyrus to CA3 and contribute to the hippocampal hyperexcitability.
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ADN Polimerasa Dirigida por ADN/genética , Esclerosis Cerebral Difusa de Schilder/genética , Mutación , ADN Polimerasa gamma , Esclerosis Cerebral Difusa de Schilder/diagnóstico , Esclerosis Cerebral Difusa de Schilder/tratamiento farmacológico , Esclerosis Cerebral Difusa de Schilder/etiología , Heterocigoto , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Blood supply, which is crucial for nutrition and drug delivery, was determined by microvessel density as well as the diffusion distance between vessels and cancer cells. Therefore, we evaluated the distance from microvessels to cancer cells (Dmvcc) and its role in the prognosis of non-small cell lung cancer (NSCLC) patients. METHODS: Patients with primary NSCLC were retrospectively analyzed. The tumor samples were immunochemically stained with CD31 to visualize the microvessels. The Dmvcc was defined as the mean distance from each microvessel to its nearest cancer cell in the "hot-spot" of an individual patient. The patients were stratified into short- and long-distance groups using five strategies, including dichotomy by the median value, optimal cutoff, trichotomy, quartation and per-10 µm increase. The correlation between the Dmvcc and survival was evaluated by using univariate and multivariate analyses with various Dmvcc strategies. RESULTS: In total, 100 patients were analyzed. The median value of Dmvcc was 13.1 µm (ranged, 1.6 to 269.7 µm; mean value, 24.4 ± 33.5 µm). The optimal cutoff value of Dmvcc for predicting survival outcome was 20 µm. Dmvcc was significantly related to overall survival (OS) with all the five categories (p = 0.001-0.000004) and progression-free survival (PFS) categorized by optimal cutoff value (p = 0.024), trichotomy (p = 0.041) and per-10 µm increase (p = 0.040) after adjusting for other factors. Patients with longer Dmvcc (≥20 µm) were observed to have poor survival outcomes (OS: HR = 13.5, 95CI: 4.42-41.18, p = 0.000005; PFS: 3.26, 95CI: 1.56-6.81, p = 0.002). A high Dmvcc per-10 µm was associated with a significantly increased risk of cancer-related death and progression by 98% (p = 0.0001) and 30% (p = 0.044), respectively. CONCLUSION: The NSCLC tissues had varying distances from microvessels to cancer cells, and long distances were strongly associated with poor survival.