KRAS p.G12C mutation occurs in 1% of EGFR-mutated advanced non-small-cell lung cancer patients progressing on a first-line treatment with a tyrosine kinase inhibitor.

BACKGROUND: KRAS is mutated in ∼30% of non-small-cell lung cancer (NSCLC) but it has also been identified as one of the mechanisms underlying resistance to tyrosine kinase inhibitors (TKIs) in EGFR-positive NSCLC patients. Novel KRAS inhibitors targeting KRAS p.G12C mutation have been developed recently with promising results. The proportion of EGFR-positive NSCLC tumours harbouring the KRAS p.G12C mutation upon disease progression is completely unexplored. MATERIALS AND METHODS: Plasma samples from 512 EGFR-positive advanced NSCLC patients progressing on a first first-line treatment with a TKI were collected. The presence of KRAS p.G12C mutation was assessed by digital PCR. RESULTS: Overall, KRAS p.G12C mutation was detected in 1.17% of the samples (n = 6). In two of these cases, we could confirm that the KRAS p.G12C mutation was not present in the pre-treatment plasma samples, supporting its role as an acquired resistance mutation. According to our data, KRASG12C patients showed similar clinicopathological characteristics to those of the rest of the study cohort and no statistically significant associations between any clinical features and the presence of the mutation were found. However, two out of six KRASG12C tumours harboured less common EGFR driver mutations (p.G719X/p.L861Q). All KRASG12C patients tested negative for the presence of p.T790M resistance mutation. CONCLUSIONS: The KRAS p.G12C mutation is detected in 1% of EGFR-positive NSCLC patients who progress on a first line with a TKI. All KRASG12C patients were negative for the presence of the p.T790M mutation and they did not show any distinctive clinical feature.

Dynamical Solitons and Boson Fractionalization in Cold-Atom Topological Insulators.

We study the Z_{2} Bose-Hubbard model, a chain of interacting bosons the tunneling of which is dressed by a dynamical Z_{2} field. The interplay between spontaneous symmetry breaking (SSB) and topological symmetry protection gives rise to interesting fractional topological phenomena when the system is doped to certain incommensurate fillings. In particular, we hereby show how topological defects in the Z_{2} field can appear in the ground state, connecting different SSB sectors. These defects are dynamical and can travel through the lattice carrying both a topological charge and a fractional particle number. In the hardcore limit, this phenomenon can be understood through a bulk-defect correspondence. Using a pumping argument, we show that it survives also for finite interactions, demonstrating how boson fractionalization induced by topological defects can occur in strongly correlated bosonic systems. Our results indicate the possibility of observing this phenomenon, which appears for fermionic matter in solid-state and high-energy physics, using ultracold atomic systems.

Anti-Inflammatory Local Effect of Hydroxytyrosol Combined with Pectin-Alginate and Olive Oil on Trinitrobenzene Sulfonic Acid-Induced Colitis in Wistar Rats.

Purpose: Evaluate the efficacy of hydroxytyrosol in the local treatment of inflammatory colitis. Currently, the existing treatments for inflammatory bowel diseases does not cure the disease and it is associated with high rates of side effects and complications. Hydroxytyrosol is a phenyl-ethyl-alcohol derived from the hydrolysis of oleuropein and present in olive oil, previous studies have demonstrated the anti-inflammatory effect of dietary hydroxytyrosol supplement, with no toxicity. Materials & Methods: Colitis has been induced by using Trinitrobenzene Sulfonic Acid at 40 rats. They were divided into four groups randomly: 10 rats without treatment; 10 rats with pectin/alginate mixture; 10 rats treated with pectin/alginate + olive oil; 10 rats treated with pectin/alginate + olive oil + hydroxytyrosol. Animals were sacrificed 10 days after induction of trinitrobenzene sulfonic acid, receiving 5 days of continuous treatment. Samples of the rectal area were studied and observed under a microscope to determine the damage by Hunter scoring modified, assessing inflammatory infiltration, number of intestinal walls involved, damage to the mucosal architecture, and edema. Results: When the rectum was analyzed in a global way, nonsignificant differences were observed; however, when performing an individualized analysis, statistically significant differences in the inflammatory infiltrate are present in the samples, which were evaluated using the ANOVA and Student-T statistics. Conclusions: Local treatment with the natural antioxidant hydroxytyrosol combined with pectin/alginate and olive oil of inflammatory bowel disease has been shown to be effective against inflammatory infiltration of TNBS-induced colitis.

Objectively and subjectively measured physical activity and its relation to cardiovascular risk factors in older people-Which is most appropriate?

OBJECTIVES: To determine the strength of the association between objectively and subjectively measured physical activity (PA) and cardiovascular risk factors (CVRF) in a sample of older adults to assess which measure of PA is most appropriate for use in this population. STUDY DESIGN AND OUTCOME MEASURES: The study was a cross-sectional analysis of a community-dwelling sample aged 60 years or more (61 women and 34 men). Data collection included anthropometric measurements, blood analytics, and objective and subjective measurements of PA from accelerometers and Yale PA Survey questionnaires, respectively. RESULTS: Although the questionnaire indicated a higher summary index (total units) of PA in men than in women, objective measurements of total PA (mean counts per minute and steps per day) did not differ by sex. However, we obtained different results between women and men when we analyzed the relation between objective and subjective PA parameters and CVRF. In women, parameters that indicate cardiovascular risk, such as body mass index (BMI), waist circumference (WC), glucose, and total cholesterol, negatively correlated with objective PA parameters, while HDLc positively correlated with objective PA parameters and negatively with subjective PA parameters. In men, BMI and WC were negatively correlated with objective PA parameters, while blood cholesterol, LDLc, and triglycerides negatively correlated with subjective PA parameters. CONCLUSIONS: In women, it seems more appropriate to use objective methods to measure PA, while in men, objective and subjective methods seem to be complementary. Both methods of measurement, accelerometers and questionnaires, should be used simultaneously in research studies in older populations to establish precise relationships between PA and cardiovascular risk.

Obesity parameters, physical activity, and physical fitness are correlated with serum dipeptidyl peptidase IV activity in a healthy population.

OBJECTIVE: To determine whether obesity, physical fitness, and physical activity parameters are associated with the enzymatic activity of serum dipeptidyl peptidase IV (sDPPIV) in a sample of healthy women and men. DESIGN AND METHODS: We have correlated parameters of obesity, physical fitness, and physical activity with sDPPIV activity in 374 healthy subjects (age: 60.7 ± 6.9 years, body mass index: 26.1 ± 4.1 kg/m2). Enzymatic activity was analyzed using spectrofluorimetry, body composition was assessed by impedanciometry, physical fitness data were obtained using the Senior Fitness Test, and physical activity data were collected by accelerometer. Pearson's partial correlation analysis was applied to determine the relationship between DPPIV activity and the rest of parameters and significantly correlated variables were introduced into linear regression models to predict DPPIV. RESULTS: Serum DPPIV activity was negatively associated with obesity parameters such as body mass (r = -0.112), body mass index (BMI) (r = -0.147), waist circumference (r = -0.164), waist-to-hip ratio (-0.104), and percentage of fat mass (r = -0.185). Serum DPPIV activity was positively associated with cardiovascular fitness (r = 0.138), total amount of physical activity (r = 0.153), and time spent doing light exercise (r = 0.184). Regression models revealed sex differences in enzyme activity with overall activity higher in women than in men (ß = 0.437, p < 0.001). Further, percent fat mass was an independent negative predictor of DPPIV activity (ß = -0.184, p = 0.001). Serum DPPIV activity was positively predicted based on the amount of time spent doing light physical activity (ß = 0.167, p = 0.001). CONCLUSION: Our results demonstrate that sDPPIV activity is positively associated with healthier parameters regarding fatness, fitness and physical activity.

Síndrome de Erasmus / Erasmus syndrome

La neumoconiosis constituye un grupo de enfermedades asociadas con la exposición e inhalación de polvo mineral, de partículas inorgánicas, sílice, berilio, carbón, cobalto, talco, etc. La exposición al polvo de sílice se asocia no sólo con silicosis, sino también con enfermedad pulmonar obstructiva crónica, cáncer de pulmón, insuficiencia renal y riesgo aumentado de tuberculosis pulmonar y enfermedades autoinmunes. Está bien establecida la asociación entre el contacto con el sílice por vía inhalatoria y enfermedades autoinmunes, particularmente en el contexto de una exposición intensa. La exposición al sílice se ha vinculado con un incremento de la síntesis de anticuerpos y complejos inmunes, aún sin la presencia de características clínicas de enfermedad autoinmune. El riesgo de desarrollar esclerosis sistémica, artritis reumatoidea, lupus eritematoso sistémico, dermatomiositis / polimiositis y anticuerpos anticitoplasmáticos del neutrófilo (ANCA) positivos (vasculitis) esta descripto en varios estudios. En paciente que trabajan en canteras con escasas medidas de prevención el desarrollo de silicosis ha llegado ser tan severo que ha requerido trasplante pulmonar; sobre esta base se recomienda seguirlos con un perfil inmunológico como control o estar atentos a otras manifestaciones de autoinmunidad. La esclerosis sistémica es una enfermedad autoinmune definida como un desorden generalizado de la microvasculatura y del tejido conectivo, con engrosamiento y obliteración de los vasos arteriales de piel, pulmón, tracto gastrointestinal, corazón y riñones. Su etiología es desconocida pero probablemente concurren factores endógenos y exógenos. Entre los factores exógenos, la exposición ocupacional juega un rol importante como causa potencial, incluyendo el polvo de sílice, cloruro de vinilo, resina epoxi, bleomicina, hidrocarburos aromáticos, aceites. Excepto el s-lice todos los otros agentes producen cambios reversibles una vez suspendido el contacto con el agente. El polvo de sílice y su inhalación es un factor de riesgo bien reconocido de esclerosis sistémica. Las partículas de cristal de sílice (cuarzo) que miden menos de un micrometro son las más patogénicas ya que al ser inertes pueden permanecer por tiempo indeterminado en el tejido. El antecedente de exposición al polvo de sílice y esclerosis sistémica se conoce como Síndrome de Erasmus.

Susceptibility of Diaphorina citri (Hemiptera: Liviidae) and Its Parasitoid Tamarixia radiata (Hymenoptera: Eulophidae) to Entomopathogenic Fungi under Laboratory Conditions.

Diaphorina citri (Kuwayama) is a global pest of citrus that transmits the bacteria associated with the disease, Huanglongbing. Entomopathogenic fungi and the parasitoid Tamarixia radiata (Waterston) are important biological control agents of this pest and likely to interact in D. citri populations. As a basis for interaction studies, we determined the susceptibility of nymphs and adults of D. citri and adults of the parasitoid T. radiata to six fungal isolates from the species Beauveria bassiana s.l. (Bals.-Criv.) Vuill. (isolates B1 and B3), Metarhizium anisopliae s.s. (Metsch.) (Ma129 and Ma65) and Isaria fumosorosea Wize (I2 and Pae). We conducted experiments evaluating infection levels in all three insect groups following inoculation with a series of conidial concentrations (1 × 104-1 × 108 conidia mL-1). Results showed that D. citri nymphs and T. radiata were more susceptible to fungal isolates than D. citri adults. Overall, B. bassiana and M. anisopliae isolates caused the greatest infection compared with I. fumosorosea isolates in all three groups of insects. Isolates B1 (B. bassiana) and Ma129 (M. anisopliae) infected a greater proportion of adults and nymphs of D. citri, respectively. Both isolates of B. bassiana caused greater infection in T. radiata compared with isolates of the other fungal species. We propose that isolates B1 and Ma129 are the strongest candidates for control of D. citri. Our results represent the first report of entomopathogenic fungi infecting T. radiata, and the basis for future studies to design a biological control programme that uses both agents more efficiently against D. citri populations.

Spotlight on the relevance of mtDNA in cancer

The potential role of the mitochondrial genome has recently attracted interest because of its high mutation frequency in tumors. Different aspects of mtDNA make it relevant for cancer‘s biology, such as it encodes a limited but essential number of genes for OXPHOS biogenesis, it is particularly susceptible to mutations, and its copy number can vary. Moreover, most ROS in mitochondria are produced by the electron transport chain. These characteristics place the mtDNA in the center of multiple signaling pathways, known as mitochondrial retrograde signaling, which modifies numerous key processes in cancer. Cybrid studies support that mtDNA mutations are relevant and exert their effect through a modification of OXPHOS function and ROS production. However, there is still much controversy regarding the clinical relevance of mtDNA mutations. New studies should focus more on OXPHOS dysfunction associated with a specific mutational signature rather than the presence of mutations in the mtDNA (AU)

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Physical activity and dietary habits related to cardiovascular risk in independent community-living older women.

A side effect of increased life expectancy is a surge in sequelae of diseases and injuries, which in turn increase the duration of life with disability among the elderly. The aim of this study was to ascertain the physical activity and nutritional parameters that better predict cardiovascular risk in a cohort of older women. A cross-sectional study was designed including 65 women able to independently perform basic activities of daily life. Data collection included anthropometric measurement, blood pressure measurement, blood analytics, objectively measurement of physical activity, and dietary assessment. We were able to generate models that explain the relationship between physical activity, diet, and these health measurement parameters. We observed that the combination of moderate physical activity and a diet including protein-rich foods as nuts, dairy, and eggs were better predictors associated with favorable changes in risk factors for cardiovascular disease than age.

Haplo-Cord transplantation compared to haploidentical transplantation with post-transplant cyclophosphamide in patients with AML.

For patients with AML, the best alternative donor remains to be defined. We analyze outcomes of patients who underwent myeloablative umbilical cord blood or haploidentical hemopoietic stem cell transplantation (HSCT) in Spain. Fifty-one patients underwent single umbilical cord blood transplantation supported by a third party donor (Haplo-Cord) between 1999 and 2012, and 36 patients received an haploidentical HSCT with post-transplant cyclophosphamide (PTCY-haplo) between 2012 and 2014 in GETH centers. The Haplo-Cord cohort included a higher proportion of patients with high disease risk index and use of TBI in the conditioning regimen, and hematopoietic cell transplantation-age Comorbidity Age Index was higher in PTCY-haplo patients. Cumulative incidence of neutrophil engraftment was 97% in the Haplo-Cord and 100% in the PTCY-haplo group, achieved in a median of 12 and 17 days, respectively (P=0.01). Grade II-IV acute GvHD rate was significantly higher in the PTCY-haplo group (9.8% vs 29%, P=0.02) as well as chronic GvHD rates (20% vs 38%, P=0.03). With a median follow-up of 61 months for the Haplo-Cord group and 26 months for the PTCY-haplo cohort, overall survival at 2 years was 55% and 59% (P=0.66), event-free survival was 45% vs 56% (P=0.46), relapse rate was 27% vs 21% (P=0.79), and non-relapse mortality was 17% vs 23% (P=0.54), respectively. In this multicenter experience, Haplo-Cord and PTCY-haplo HSCT offer valid alternatives for patients with AML. Neutrophil engraftment was faster in the Haplo-Cord cohort, with similar survival rates, with higher GvHD rates after haploidentical HSCT.

Sex differences in the aging pattern of renin-angiotensin system serum peptidases.

BACKGROUND: Serum peptidases, such as angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (ACE2), neutral endopeptidase (NEP), aminopeptidase N (APN), and aminopeptidase A (APA), are important elements of the renin-angiotensin system (RAS). Dysregulation of these enzymes has been associated with hypertension and cardiovascular risk. In the present study, serum activities of RAS peptidases were analyzed to evaluate the existence of sexual differences, with a possible different pattern in pre- and post-andropausal/post-menopausal participants. METHODS: One hundred and eighteen healthy men and women between 41 and 70 years of age (58 women and 60 men) were recruited to participate in the study. Serum RAS-regulating enzymes were measured by spectrofluorimetry. Enzymatic activity was recorded as units of enzyme per milliliter of serum (U/mL). RESULTS: Significantly lower serum APA activity was observed in men with respect to women; no sex differences were detected for ACE, ACE2, NEP, or APN. Significantly lower APA and ACE serum activity were observed in older men compared to older women. In contrast, younger (<55 years) men had significantly higher values of NEP serum activity than younger women. Significantly lower ACE serum activity was detected in older men compared to younger men. In women, significantly higher ACE2 serum activity was observed in older women compared to younger women. CONCLUSIONS: These results suggest a differential effect of aging on the activity of RAS enzymes in men and women, especially with respect to the breakpoint of andropausia/menopausia, on the critical serum enzymatic activities of the RAS, which could correlate with sexual differences in cardiovascular risk.

Spotlight on the relevance of mtDNA in cancer.

The potential role of the mitochondrial genome has recently attracted interest because of its high mutation frequency in tumors. Different aspects of mtDNA make it relevant for cancer's biology, such as it encodes a limited but essential number of genes for OXPHOS biogenesis, it is particularly susceptible to mutations, and its copy number can vary. Moreover, most ROS in mitochondria are produced by the electron transport chain. These characteristics place the mtDNA in the center of multiple signaling pathways, known as mitochondrial retrograde signaling, which modifies numerous key processes in cancer. Cybrid studies support that mtDNA mutations are relevant and exert their effect through a modification of OXPHOS function and ROS production. However, there is still much controversy regarding the clinical relevance of mtDNA mutations. New studies should focus more on OXPHOS dysfunction associated with a specific mutational signature rather than the presence of mutations in the mtDNA.

Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS.

The safety and efficacy of a 4-day myeloablative conditioning (MAC) regimen consisting of Bu 3.2 mg/kg and fludarabine 40 mg/m(2)/day for HLA-identical sibling allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies was investigated in 133 patients (median age, 47 years; range 19-74 years) with de novo AML (60%), secondary AML (20%) or myelodysplastic syndrome (20%). All patients engrafted. Hepatic veno-occlusive disease occurred in five patients (4%), and severe toxicities, mostly mucositis, occurred in twenty-three (17%) patients. The non-relapse mortality (NRM) at 100 days was 1.5%. The incidences of acute GVHD grade 2-4 and grade 3-4 were 32 and 13%, respectively. At a median follow-up of 38 months, the cumulative incidence of chronic GVHD was 67%. The relapse incidence was 30% (27 and 31%, respectively, in patients with early- and late-stage disease), and the overall NRM was 15%. The actuarial 4-year disease-free survival (DFS) and overall survival (OS) were 54 and 62%, respectively. Patients aged <50 years had better outcomes compared with older patients (DFS 64 vs 42%, P=0.006; OS 73 vs 47%, P<0.001, respectively).

Experience with anidulafungin in patients with allogeneic hematopoietic stem cell transplantation and graft-versus-host disease.

BACKGROUND: It is well known that both acute and chronic graft-versus-host disease (GVHD) are associated with invasive fungal disease (IFD). Because the galactomannan antigen diagnostic test has low specificity and sensitivity outside of the neutropenic period, many institutions use posaconazole or voriconazole for IFD prophylaxis during GVHD treatment. Moreover, several factors, mainly hepatic impairment, can limit the use of extended spectrum azoles, both in prophylaxis or treatment. METHODS: We retrospectively analyzed 25 patients with allogeneic hematopoietic stem cell transplantation (HSCT) and GVHD - grade III-IV acute GHVD (n = 15), progressive chronic GVHD (n = 7), and "overlap" GVHD (n = 3) - who received intravenous anidulafungin (200 mg on day 1, followed by 100 mg once daily). If necessary, anidulafungin treatment was followed by oral administration of 200 mg voriconazole twice a day or 200 mg posaconazole 3 times daily until patients were considered not at risk for IFD. RESULTS: Twenty-one patients (85%) received anidulafungin as prophylaxis and 5 patients (15%) received it as treatment. Median duration of intravenous anidulafungin administration was 8 days (range 6-17). Seven patients (28%) presented mild adverse effects, with no significant interactions with calcineurin inhibitors. Sequentially, 4 patients received voriconazole and 6 posaconazole. Two patients (8%) developed IFD after anidulafungin withdrawal: 1 with Candida albicans and the other with Mucor, 8 and 5 days after withdrawal, respectively. CONCLUSIONS: Our results are of interest owing to the absence of data in the literature on anidulafungin use in HSCT patients with GVHD, and suggest that anidulafungin, because of its spectrum, pharmacological profile, low toxicity, and absence of interactions with immunosuppressants, could be a drug of choice in this setting.

Case Series: Fetal Pulmonary Vein A-Wave Reversal: An Early Marker of Left-Sided Cardiac Anomalies?

Background Improvements in congenital heart disease (CHD) screening are needed based on the lack of sensitivity of current screening methods and the understanding that the early detection of certain CHDs may improve outcomes. Fetal venous circulation has caught medical attention, and two studies demonstrated that it is feasible to register pulmonary vein flow velocity waveforms (FVWs) during early gestation. Meanwhile, the latter study proposed pulmonary vein A-wave reversal as a marker of cardiac anomaly. Methods We report a series of six consecutive fetuses with confirmed cardiac anomalies that underwent first-trimester screening, including pulmonary vein FVWs, at our center during 2013. CHD was confirmed by late pregnancy echocardiography, and in three cases fetal autopsies were performed. Result/Discussion The ductus venosus (DV) and nuchal translucency (NT) predicted 50% of CHD cases, whereas the combination of markers identified 66.6% of CHD cases. When adding pulmonary vein assessment, the rate of detection rose to 83.3%. Total five of six cases of CHD had reversal of pulmonary vein A-wave during early pregnancy. The sixth case with CHD and nonreversal of A-wave was described as right ventricle hypoplasia with type 1 tricuspid atresia and persistent ductus arteriosus. Conclusion This is the first series reporting pulmonary vein end-diastolic reversal as a CHD screening add-on during early pregnancy. The addition of pulmonary vein FVW assessment to the current CHD screening bundle could increase the rate detection of cardiac anomalies. This pilot study suggests that pulmonary vein end-diastolic flow reversal favors detection of left-sided CHD over the right-sided ones.

Relationship between physical activity and markers of oxidative stress in independent community-living elderly individuals.

The aim of the present study was to examine the relationship between objective data of physical activity and markers of oxidative stress in older men and women. Participants were old adults, aged≥60years (61 women and 34 men) who were all capable of performing basic daily activities by themselves and lived on their own. To describe physical activity we used objective data measured by accelerometers which record active and sedentary periods during everyday life for five days. Determination of oxidative stress was conducted from three perspectives: determination plasma total antioxidant status (TAS), plasma antioxidant enzyme activities, i.e., glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD), and membrane lipid peroxidation (TBARS). In the group of women, those who met physical activity recommendations (WR) had lower level of TAS. In addition, the moderate to vigorous physical activity (MVPA) was negatively correlated with TAS. Simultaneously, MVPA was correlated with increase in the GPx antioxidant enzyme activity, and the counts per minute were positively correlated with CAT activity. In the group of men, the cpm and the MVPA were negatively correlated with lipid peroxidation while lifestyle physical activity was positively correlated with CAT activity. These findings suggest that MVPA in the elderly although it is related to a decrease in the TAS in women, induces adaptive increase in antioxidant enzyme activity and decreases lipid peroxidation in both women and men. These results suggest that at this time of life, it is not only the amount of physical activity performed that is important but also its intensity.