Effects of a remotely supervised resistance training program on muscle strength and body composition in adults with cystic fibrosis: Randomized controlled trial.

INTRODUCTION: Among the limited studies on physical exercise interventions in adults with cystic fibrosis (CF), few have specifically addressed the improvement of peripheral muscle strength and body fat-free mass. The aim of this study was to examine the impacts of a remotely supervised, individualized 8-week resistance training program of moderate to high intensity on strength and body composition in these subjects. METHODS: This was a randomized controlled trial performed in adults with CF. The exercise group (EX) performed three 1-h resistance training sessions per week over 8 weeks. The control group (CON) followed the physical activity recommendations of their physician. The main outcomes were muscle strength and body composition, with secondary measures including pulmonary function and quality of life. Two-way repeated measures analysis was used. RESULTS: In 23 participants (age 32.13 ± 7.72 years), the intervention showed a significant beneficial effect on leg press strength, with a large effect size, both in absolute (p = 0.011; η p 2 $$ {\eta}_{\mathrm{p}}^2 $$ = 0.281) and relative (p = 0.007; η p 2 $$ {\eta}_{\mathrm{p}}^2 $$ = 0.310) terms. Large intervention effects were observed on total fat mass (p < 0.001; η p 2 $$ {\eta}_{\mathrm{p}}^2 $$ = 0.415), body adiposity index (p < 0.001; η p 2 $$ {\eta}_{\mathrm{p}}^2 $$ = 0.436), and fat mass index (p < 0.001; η p 2 $$ {\eta}_{\mathrm{p}}^2 $$ = 0.445), all showing reduction in the EX group. In addition, significant large size effects were detected on total fat-free mass (p = 0.046; η p 2 $$ {\eta}_{\mathrm{p}}^2 $$ = 0.177), trunk fat-free mass (p = 0.039; η p 2 $$ {\eta}_{\mathrm{p}}^2 $$ = 0.188), and fat-free mass index (p = 0.048; η p 2 $$ {\eta}_{\mathrm{p}}^2 $$ = 0.174), all favoring exercise. No significant effects were observed on pulmonary function and quality of life. CONCLUSIONS: An 8-week remotely supervised resistance training program, with moderate to high intensity, effectively improved lower limb muscle strength and body composition.

Modulation of Synaptic Plasticity Genes Associated to DNA Damage in a Model of Huntington's Disease.

Huntington's disease (HD) is a disease characterized by the progressive degeneration of nerve cells in the brain. DNA damage has been implicated in many neurological disorders; however, the association between this damage and the impaired signaling related to neurodegeneration is still unclear. The transcription factor c-AMP-responsive element binding protein (CREB) has a relevant role in the neuronal plasticity process regulating the expression of several genes, including brain-derived neurotrophic factor (BDNF). Here we analyzed the direct link between DNA damage and the expression of genes involved in neuronal plasticity. The study was performed in model cell lines STHdhQ7 (wild type) and STHdhQ111 (HD model). Treatment with Etoposide (Eto) was used to induce double-strand breaks (DSBs) to evaluate the DNA damage response (DDR) and the expression of synaptic plasticity genes. Eto treatment induced phosphorylation of ATM (p-ATM) and H2AX (γH2AX), markers of DDR, in both cell lines. Interestingly, upon DNA damage, STHdhQ7 cells showed increased expression of activity-regulated cytoskeleton associated protein (Arc) and BDNF when compared to the HD cell line model. Additionally, Eto induced CREB activation with a differential localization of its co-activators in the cell types analyzed. These results suggest that DSBs impact differentially the gene expression patterns of plasticity genes in the normal cell line versus the HD model. This effect is mediated by the impaired localization of CREB-binding protein (CBP) and histone acetylation in the HD model. Our results highlight the role of epigenetics and DNA repair on HD and therefore we suggest that future studies should explore in depth the epigenetic landscape on neuronal pathologies with the goal to further understand molecular mechanisms and pinpoint therapeutic targets.

Synthesis, antitumor activity, 3D-QSAR and molecular docking studies of new iodinated 4-(3H)-quinazolinones 3N-substituted.

A novel series of 6-iodo-2-methylquinazolin-4-(3H)-one derivatives, 3a-n, were synthesized and evaluated for their in vitro cytotoxic activity. Compounds 3a, 3b, 3d, 3e, and 3h showed remarkable cytotoxic activity on specific human cancer cell lines when compared to the anti-cancer drug, paclitaxel. Compound 3a was found to be particularly effective on promyelocytic leukaemia HL60 and non-Hodgkin lymphoma U937, with IC50 values of 21 and 30 µM, respectively. Compound 3d showed significant activity against cervical cancer HeLa (IC50 = 10 µM). The compounds 3e and 3h were strongly active against glioblastoma multiform tumour T98G, with IC50 values of 12 and 22 µM, respectively. These five compounds showed an interesting cytotoxic activity on four human cancer cell types of high incidence. The molecular docking results reveal a good correlation between experimental activity and calculated binding affinity on dihydrofolate reductase (DHFR). Docking studies proved 3d as the most potent compound. In addition, the three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis exhibited activities that may indicate the existence of electron-withdrawing and lipophilic groups at the para-position of the phenyl ring and hydrophobic interactions of the quinazolinic ring in the DHFR active site.

An integer programming model to assign patients based on mental health impact for tele-psychotherapy intervention during the Covid-19 emergency.

The Covid-19 pandemic challenges healthcare systems worldwide while severely impacting mental health. As a result, the rising demand for psychological assistance during crisis times requires early and effective intervention. This contributes to the well-being of the public and front-line workers and prevents mental health disorders. Many countries are offering diverse and accessible services of tele-psychological intervention; Ecuador is not the exception. The present study combines statistical analyses and discrete optimization techniques to solve the problem of assigning patients to therapists for crisis intervention with a single tele-psychotherapy session. The statistical analyses showed that professionals and healthcare workers in contact with Covid-19 patients or with a confirmed diagnosis had a significant relationship with suicide risk, sadness, experiential avoidance, and perception of severity. Moreover, some Covid-19-related variables were found to be predictors of sadness and suicide risk as unveiled via path analysis. This allowed categorizing patients according to their screening and grouping therapists according to their qualifications. With this stratification, a multi-periodic optimization model and a heuristic are proposed to find an adequate assignment of patients to therapists over time. The integer programming model was validated with real-world data, and its results were applied in a volunteer program in Ecuador.

Ascaris lumbricoides, causa de la colecistitis aguda en el servicio de emergencia del Hospital "Alfredo Noboa Montenegro", 2018 / Ascaris lumbricoides, cause of acute cholecystitis in the emergency service of the "Alfredo Noboa Montenegro" Hospital, 2018

Ascaris lumbricoides provoca una de las helmintiasis más frecuentes en los países tropicales, pudiendo producir efectos patológicos en cualquier parte del organismo, siendo los conductos biliales uno de los sitios recurrentes provocando una colecistitis aguda. La CA es una de las principales causas de ingreso al servicio de Emergencia, es una inflamación de la vesícula cuyo diagnóstico oportuno es de vital importancia para la prevención de complicaciones. Por tal razón, determinar la frecuencia de las variables clínicas, de laboratorio y ecográficas, su relación con las comorbilidades asociadas a las características demográficas de los pacientes y el nivel de severidad de la colecistitis aguda causada por la A. lumbricoides de las Guías de Tokio 2018 del Servicio de Emergencia del Hospital Alfredo Noboa Montenegro durante el periodo junio - diciembre 2018, para la elaboración de un esquema diagnóstico. La metodología de investigación fue cuantitativa descriptiva de corte transversal. Dentro de los principales hallazgos, el CA aparece con prevalencia en el género femenino en un 69,41%, promedio de edad de 32 a 45 años, el 10% de 170 pacientes presentaron en su ecografía una forma parasitaria compatible con A. Lumbricoides, los resultados clínicos arrojaron presencia de dolor (67,34%), fiebre (68,65%), náuseas (45,93%); en los laboratorio la Proteína C Reactiva estuvo aumenta en el 94,18% de los casos, en imagenología se refleja presencia de líquido pericolecistico en un 78,82% y un engrosamiento de pared vesicular en un 34,12%. El nivel de severidad registrado según los criterios de las guías de Tokio 2018 fue grado I 35,3%, grado II 47,1% y grado III 17,6%. Se recomienda la estructuración de un esquema diagnóstico oportuno de colecistitis aguda causada por A. Lumbricoides(AU)

Ascaris lumbricoides causes one of the most frequent helminthiases in tropical countries, being able to produce pathological effects in any part of the body, being the bile ducts one of the recurrent sites causing acute cholecystitis. AC is one of the main causes of admission to the Emergency service, it is an inflammation of the gallbladder whose timely diagnosis is of vital importance for the prevention of complications. signs and symptoms, the timely diagnosis is of vital importance for the prevention of complications. For this reason, determine the frequency of clinical, laboratory and ultrasound variables, their relationship with the comorbidities associated with the demographic characteristics of the patients and the level of severity of acute cholecystitis cause of A. lumbricoides of the Tokyo Guidelines 2018 of the Hospital Emergency Service Alfredo Noboa Montenegro during the period June - December 2018, for the elaboration of a diagnostic scheme. The research methodology was quantitative cross-sectional descriptive. Among the main findings that were prevailed in the female gender in 69,41%, average age from 32 to 45 years, 10% of 170 patients presented in their ultrasound a parasitic form compatible with A. lumbricoides, clinical results that prevailed was presence of pain (67.34%), fever (68.65%), nausea (45.93%); in the laboratory findings the C Reactive Protein was increased in 94,18% of cases, in imaging the presence of pericolecist fluid is reflected in 78,82% and a thickening of the vesicular wall in 34,12%. The severity level recorded according to the criteria of the Tokyo 2018 guidelines was grade I 43,53%, grade II 48,24% and grade III 8,24%. The structuring of a timely diagnostic scheme for acute cholecystitis cause of A. lumbricoides is recommended(AU)

Influencia de la etnia mapuche sobre la indicación de terapia hormonal de la menopausia según aplicación escala de calidad de vida (mrs), en población rural de la araucanía / Influence of the Mapuche ethnic group on the indication of hormonal therapy for menopause according to the application of the quality of life scale (mrs), in a rural population of Araucanía

RESUMEN Objetivo: Relacionar la pertenencia a la etnia Mapuche y los síntomas climatéricos de indicación de Terapia Hormonal de la Menopausia (THM), en una población del sector rural de Boyeco, región de La Araucanía. Materiales y métodos: Estudio observacional realizado en mujeres rurales en control de salud en CESFAM Boyeco entre octubre de 2016 y enero de 2017. Ninguna de las participantes evaluadas recibía THM. Para el estudio, se consideró el número de apellidos mapuches. Se utilizó el instrumento validado para población chilena, "Escala MRS" (Menopause Rating Scale), el cual permite discriminar los diferentes dominios sintomáticos del climaterio. Resultados: El grupo en estudio lo componen 36 mujeres de 41 a 78 años de edad, promedio (DE) 52,8(8,6) años, un 52,8% tiene dos apellidos mapuches y 25% uno. Un 92,8% de las mujeres mapuche tiene indicación de terapia, versus todas las no mapuche. En las menores de 50 años, todas tiene indicación de terapia, frente a un 71,4% en las mayores de 50 años. Conclusiones: Las pacientes mapuches tienen mayor sintomatología en los dominios somáticos y psicológicos, especialmente aquellas bajo 50 años. Todas las mujeres estudiadas bajo 50 años requieren terapia, sin variación estadísticamente significativa x etnicidad.

SUMMARY Objective: To stablish the relationship between belonging to Mapuche ethnic group on the climacteric symptoms for indication of menopause hormone therapy (HTM), in the rural population of Boyeco, inside of Araucania's region, Chile. Materials and methods: An observational and descriptive study, in a sample in time of 36 women belonging to the sector who attended CESFAM Boyeco, between October 2016 and January 2017. None of the evaluated participants received THM. As exposure variable, it was considered the number the mapuche surnames. We used the Menopause Rating Scale (MRS), an international instrument validated for Chilean population, to discriminate the different symptomatic domains of the climacteric period. Results: 94.7% of mapuche women and all non-mapuche population had prescribed hormonal therapy. Independent of ethnicity, those under 50 years of age, 100% have an indication for therapy compared to 71.4% in those over 50 years of age. Conclusions: Mapuche patients have greater symptomatology in the somatic-psychological domains, especially in those under 50 years of age. The totality of women under 50 requires therapy, however, variation according to ethnicity.

Development and validation of a bioanalytical method for five antidepressants in human milk by LC-MS.

The use of medications during lactation is a common practice; however, pharmacological treatments impose serious doubts to both professionals and nursing mothers regarding the safety of drugs used during this period. Most of drugs are excreted in breast milk and there is great variability in the amount of analytes that can be received by the infant. Dilemmas about breastfeeding arise most commonly in relation to postpartum depression. Depression is a major clinical problem during the postpartum period and the vulnerability to onset or recurrence of depressive symptoms increases the possibility of psychotropic drug use during lactation. Selective inhibitors of serotonin reuptake are commonly prescribed for the treatment of depressive disorders, including fluoxetine, sertraline, citalopram, and paroxetine. A validated bioanalytical method using liquid chromatography coupled to mass spectrometry was developed and validated for determination of antidepressants in human milk following protein precipation. The bioanalytical method was successfully applied to assess milk samples from nursing mothers. From found concentrations, infant absolute (4.36-12.26µg/kg/day) and relative dose (0.60-2.90%,) were estimated and low values were obtained indicating safe use during laction. However, other factors such as complemantary feeding and hepatic or renal disorders in the infant should be considered.

Pharmacokinetics study of mazindol in plasma, oral fluid, and urine of volunteers.

PURPOSE: There are no pharmacokinetics studies in oral fluid reported in the literature, as well as there are no data on correlation of drug levels in plasma, urine, and oral fluid in order to propose alternative matrices to monitor the use of mazindol by drivers. The present work aimed to study, preliminarily, mazindol's pharmacokinetics in plasma and oral fluid, as well as investigate the correlation of drug levels in urine, plasma, and oral fluid. METHOD: Blood, urine, and oral fluid samples from seven healthy male volunteers were collected at 0, 1, 2, 4, 5, 6, 8, 10, and 24 h after administration of tablets of 2 mg mazindol and analyzed by a previously validated method by LC-MS with liquid-liquid extraction. Levels of the drug found were higher in plasma when compared with oral fluid and higher in urine in relation to plasma. The study of the mazindol's pharmacokinetics showed that the most suitable model to describe the variation of the concentration over time is the compartment open model with absorption and elimination following the first-order kinetics, and confirming literature data, drug is metabolized, being the major metabolite detected, but not quantified. CONCLUSION: It was not found a good correlation between the concentrations of mazindol in urine and plasma, but between plasma and oral fluid, there was a good correlation, suggesting this as an alternative matrix to plasma. However, studies involving more subjects are needed.

Analysis of cocaine/crack biomarkers in meconium by LC-MS.

Fetal exposure to illicit drugs is a worldwide problem, since many addicted women do not stop using it during pregnancy. Cocaine consumed in powdered (snorted or injected) or smoked (crack cocaine) form are harmful for the baby and its side effects are not completely known. Meconium, the first stool of a newborn, is a precious matrix usually discarded, that may contain amounts of substances consumed in the last two trimesters of pregnancy. Analyzing this biological matrix it is possible to detect the unaltered molecule of cocaine (COC) or its metabolite benzoylecgonine (BZE) and pyrolytic products anhydroecgonine methyl ester (AEME) and anhydroecgonine (AEC). A liquid chromatography mass spectrometry (LC-MS) method was validated for meconium samples after solvent extraction, followed by direct injection of 10µL. Linearity covered a concentration range of 15 to 500ng/mg with a lower limit of quantification (LLOQ) of 15ng/mg for all analytes. Matrix effect was evaluated and showed adequate results. Detection of illicit substances usage can be crucial for the baby, since knowing that can help provide medical care as fast as possible. The method proved to be simple and fast, and was applied to 17 real meconium samples.

Validation and application of a liquid chromatography-electrospray ionization mass spectrometric method for determination of mazindol in human plasma and urine.

INTRODUCTION: Even after removal of some stimulants, like fenproporex, amfepramone and mazindol, from Brazilian market, the use of these substances is still high, especially by drivers. Mazindol is the second most used anorectic agent in the world acting as an indirect sympathomimetic agonist, having stimulatory action on central nervous system. Plasma is a good matrix to monitor since it reflects the psychomotor effects of these drugs, but unlike urine has an invasive collection; drug levels and detection time are quite low. METHOD: The method involved a liquid-liquid extraction of the samples and a LC-MS analysis was fully validated. Method was used to analyze samples of urine and plasma collected from health volunteers in a period of 24h. Metabolite of mazindol was synthesized using alkaline conditions. RESULTS: After validation the method proved to be adequate to analyze samples collected from health volunteers. Method was linear in the concentration range of 0.1-10ng/mL (r=0.9982) for plasma and 5-50ng/mL (r=0.9973) for urine. DISCUSSION: Analysis of the samples showed that mazindol can be detected after 1h of administration and that concentration levels in urine were always higher than in plasma. Mazindol metabolite was detected only in urine.

Development of alternative methods for the determination of raloxifene hydrochloride in tablet dosage form / O desenvolvimento de métodos alternativos para a determinação do cloridrato de raloxifeno na forma de dosagem em comprimidos

Three methods are proposed for the quantitative determination of raloxifene hydrochloride in pharmaceutical dosage form: ultraviolet method (UV) high performance liquid chromatography (HPLC) and micellar capillary electrophoresis (MEKC). These methods were developed and validated and showed good linearity, precision and accuracy. Also they demonstrated to be specific and robust. The HPLC and MEKC methods were tested in regards to be stability indicating methods and they showed to have this attribute. The UV method used methanol as solvent and optimal wavelength at 284 nm, obeying Lambert-Beer law in these conditions. The chromatographic conditions for the HPLC method included: NST column C18 (250 x 4.6 mm x 5 µm), mobile phase water:acetonitrile:triethylamine (67:33:0,3 v/v), pH 3.5, flow rate 1.0 mL min^-1, injection volume 20.0 µl, UV detection 287 nm and analysis temperature 30 °C. The MEKC method was performed on a fused-silica capillary (40 cm effective length x 50 µm i.d.) using as background electrolyte 35.0 mmol L^-1 borate buffer and 50.0 mmol L^-1 anionic detergent sodium dodecyl sulfate (SDS) at pH 8.8. The capillary temperature was 32°C, applied voltage 25 kV, UV detection at 280 nm and injection was perfomed at 45 mBar for 4 s, hydrodimanic mode. In this MEKC method, potassium diclofenac (200.0 µg mL^-1) was used as internal standard. All these methods were statistically analyzed and demonstrated to be equivalent for quantitative analysis of RLX in tablets and were successfully applied for the determination of the drug...

Três métodos são propostos para a quantificação de cloridrato de raloxifeno em sua forma farmacêutica de comprimidos: espectrofotometria no ultravioleta (UV), cromatografia líquida de alta eficiência (HPLC) e eletroforese capilar micelar (MEKC). Estes métodos desenvolvidos e validados demonstraram linearidade, precisão e exatidão. Também foram específicos e robustos. Os métodos HPLC e MEKC foram desenvolvidos para indicar a estabilidade do fármaco e demonstraram ter este atributo. O método UV usou metanol como solvente e comprimento de onda de 284nm, obedecendo a Lei de Lambert-Beer nestas condições. Os parâmetros cromatográficos para o método HPLC foram: coluna NST C18 (250 x 4,6 mm x 5 µm), fase móvel composta de água:acetonitrila:trietilamina (67:33:0,3 v/v), pH 3,5, vazão da fase móvel de 1,0 mL min^-1, volume de injeção de 20 µl, detecção no comprimento de onda de 287 nm e temperatura de análise de 30°C. O método MEKC foi realizado utilizando capilar de sílica fundida (40 cm de comprimento efetivo x 50 µm de diâmetro interno) usando como fase móvel solução tampão borato 35.0 mmol L^-1 e solução de dodecil sulfato de sódio (SDS) 50.0 mmol L^-1 pH 8,8. A temperatura de análise foi de 32 °C, com voltagem aplicada de 25 kV, detecção no comprimento de onda de 280 nm e injeção da amostra realizada a 45 mBar por 4 s em modo hidrodinâmico. Para este método MEKC, foi utilizado diclofenaco de potássio (200.0 µg mL^-1) como padrão interno. Todos os métodos foram analisados estatisticamente e demostraram ser equivalentes para a análise quantitativa de raloxifeno em comprimidos e foram aplicados com sucesso na determinação do fármaco...

Stereospecific hydrolysis of a phosphoramidate used as an OPIDP model by human sera with PON1 192 alloforms.

O-hexyl 2,5-dichlorophenyl phosphoramidate (HDCP) is a racemic organophosphate compound (OP) that induces delayed neuropathy in vivo. The O-hexyl 2,5-dichlorophenyl phosphoramidate R (R-HDCP) isomer inhibits and ages neuropathic target esterase (NTE) in hen brain. Moreover, human serum paraoxonase-1 (PON1) is a Ca(2+)-dependent enzyme capable of hydrolyzing OPs. The enzymatic activity of PON1 against OPs depends on the genetic polymorphisms present at position 192 (glutamine or arginine). The catalytic efficiency of PON1 is an important factor that determines neurotoxic susceptibility to some OPs. In the present study, we characterized the stereospecific hydrolysis of HDCP by alloforms PON1 Q192R human serum by chiral chromatography. Forty-seven human samples were characterized for the PON1 192 polymorphism. The hydrolysis data demonstrate that the three alloforms of PON1 show an exclusive and significant stereospecific Ca(2+)-dependent hydrolysis of O-hexyl 2,5-dichlorophenyl phosphoramidate S isomer (S-HDCP) at 19-127 µM at the concentrations that remain in all the samples. This stereoselective Ca(2+)-dependent hydrolysis of S-HDCP is inhibited by EDTA and is independent of the PON1 Q192R alloform. The present research reinforces the hypothesis that R-HDCP (an isomer that inhibits and causes NTE aging) is the enantiomer that induces delayed neuropathy by this chiral phosphoramidate due to the low hydrolysis level of the R-HDCP observed in this study.

Determination of cocaine/crack biomarkers in colostrum by LC-MS following protein precipitation.

Drug abuse by nursing mothers is an ongoing concern because it may cause many adverse effects to the newborns. The development of analytical methods to analyze drugs of abuse in colostrum (first milk produced after birth) has a huge importance, because it enables the monitoring and the correct follow-up to users and newborns. A liquid chromatography mass spectrometry (LC-MS) method was developed and validated for the determination of cocaine and smoked cocaine (crack) biomarkers in colostrum. Cocaine (COC) and its major metabolite benzoylecgonine (BZE), the pyrolytic products anhydroecgonine methyl ester (AEME) and anhydroecgonine (AEC) were analyzed after a simple protein precipitation procedure using atropine (ATP) as internal standard (IS). Applying a chemometric approach study, all peaks were chromatographically separated at isocratic condition with a Kinetex HILIC column for polar compounds, at 30°C in 12min. One ion was detected for the quantification and three ions for confirmation of each analyte. The method was linear for all analytes in the concentration range of 5-300ng/mL with correlation coefficients (r) between 0.9983 and 0.9996. The lower limit of quantification (LLOQ) was 5ng/mL with acceptable validation parameters. Matrix effect was assessed by post-extraction addition approach and showed good results, demonstrating that protein precipitation cleaning procedure is fast, reliable and demand small quantities of organic solvent. The LC-MS method is fast and cheap compared to other equipments and was also successfully applied to assess real samples of colostrum from nursing mothers who were suspect of cocaine/crack abuse.

First-line therapy and methylation status of CHFR in serum influence outcome to chemotherapy versus EGFR tyrosine kinase inhibitors as second-line therapy in stage IV non-small-cell lung cancer patients.

The potential differential effect of first-line treatment and molecular mechanisms on survival to second-line chemotherapy or EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) has not been fully investigated. In particular, CHFR is frequently methylated in NSCLC and may influence outcome. We analyzed the outcome of second-line chemotherapy or EGFR TKIs in 179 of 366 patients who had been treated in an ERCC1 mRNA-based customized cisplatin trial and correlated the results with CHFR methylation status. CHFR methylation in circulating DNA was examined by methylation-specific assay. A panel of seven human EGFR wild-type NSCLC cell lines was characterized for their sensitivity to sequential treatment with cisplatin and erlotinib, and the results were correlated with CHFR. Patients who had received first-line docetaxel/cisplatin attained an overall survival of 19.2 months when treated with second-line EGFR TKIs, in comparison with 10.7 months when treated with second-line chemotherapy (P = 0.0002). However, for patients who had received first-line docetaxel/gemcitabine, overall survival was 14.8 months with EGFR TKIs and 10.8 months with chemotherapy (P = 0.29). For patients with unmethylated CHFR overall survival to EGFR TKIs was 21.4 months, and 11.2 months for those with treated with chemotherapy (P = 0.0001). In the only lung tumor cell line not expressing CHFR, pretreatment with cisplatin was antagonistic to erlotinib, while it was synergistic in the other six lines. Second-line EGFR TKIs improved survival in patients receiving first-line cisplatin-based treatment. Unmethylated CHFR predicts increased survival to EGFR TKIs.

Translational research in glioblastoma multiforme: molecular criteria for patient selection.

In spite of the dismal outcome of glioblastoma multiforme (GBM), we are in a position to provide a ray of hope to patients and families. Methylation of MGMT in tumor occurs in approximately a third of patients and predicts meaningful response and survival to adjuvant radiotherapy plus temozolomide. Limited access to tumor tissue in some patients could be circumvented by examining MGMT methylation in circulating serum DNA, although this approach needs to be validated. Molecular signatures are also promising prognostic and predictive markers, and clinical trials should be carried out to validate their use in the selection of patients for specific targeted therapies. Gene expression by quantitative PCR of key components of these molecular signatures could pave the way for easy identification of different subgroups of patients. Translational clinical trials are warranted in order to detect the subgroups of patients resistant to radiotherapy who may derive benefit from novel therapies, including antiangiogenic drugs.

From the bench to the bed: individualizing treatment in non-small-cell lung cancer.

At the time of diagnosis, half of lung cancer patients have advanced incurable disease. Different chemotherapy combinations--with or without targeted therapies--yield similar results in spite of the continuous efforts of clinicians. However, molecular biological studies have already shed a great deal of light on the existence of multiple genetic aberrations that can be useful for customizing treatment. mRNA transcripts involved in DNA repair pathways, such as ERCC1 and BRCA1, confer selective resistance to cisplatin or taxanes. Polymorphisms in DNA repair genes and methylation of checkpoint genes in circulating serum DNA could become important predictive markers of survival to certain cisplatin-based regimens. EGFR tyrosine kinase mutations are the crux of targeted therapies.

From the bench to the bed: individualizing treatment in non-small-cell lung cancer

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At the time of diagnosis, half of lung cancer patientshave advanced incurable disease. Different chemotherapycombinations −with or without targeted therapies−yield similar results in spite of the continuousefforts of clinicians. However, molecular biologicalstudies have already shed a great deal of light on theexistence of multiple genetic aberrations that can beuseful for customizing treatment. mRNA transcriptsinvolved in DNA repair pathways, such as ERCC1and BRCA1, confer selective resistance to cisplatin ortaxanes. Polymorphisms in DNA repair genes andmethylation of checkpoint genes in circulating serumDNA could become important predictive markers ofsurvival to certain cisplatin-based regimens. EGFRtyrosine kinase mutations are the crux of targetedtherapies

14-3-3sigma methylation in pretreatment serum circulating DNA of cisplatin-plus-gemcitabine-treated advanced non-small-cell lung cancer patients predicts survival: The Spanish Lung Cancer Group.

PURPOSE: Survival in patients with advanced non-small-cell lung cancer (NSCLC) who are treated with platinum-based chemotherapy is rather variable. Methylation-dependent transcriptional silencing of 14-3-3sigma, a major G2-M checkpoint control gene, could be a predictor of longer survival. PATIENTS AND METHODS: A sensitive methylation-specific polymerase chain reaction assay was used to evaluate 14-3-3sigma methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine-treated advanced NSCLC patients. RESULTS: 14-3-3sigma methylation was observed in all histologic types of 39 patients (34%). After a median follow-up of 9.8 months, median survival was significantly longer in the methylation-positive group (15.1 v 9.8 months; P = .004). Median time to progression was 8 months in the methylation-positive group and 6.3 months in the methylation-negative group (log-rank test, P = .027). A multivariate Cox regression model identified only 14-3-3sigma methylation status and Eastern Cooperative Oncology Group performance status as independent prognostic factors for survival. In an exploratory analysis, median survival for 22 methylation-positive responders has not been reached, whereas survival was 11.3 months for 29 methylation-negative responders (P = .001). CONCLUSION Methylation of 14-3-3sigma is a new independent prognostic factor for survival in NSCLC patients receiving platinum-based chemotherapy. It can be reliably and conveniently detected in the serum, thus obviating the need for tumor tissue analysis.