La inmunoterapia una alternativa terapéutica en ancianos con cáncer de pulmón de células no pequeñas / Immunotherapy, a therapeutic option in elder people with non small cells lung cancer

RESUMEN El cáncer es un problema prioritario de salud pública en el mundo. En Cuba constituye la segunda causa de muerte en la mayoría de grupos de edades y fundamentalmente en la población mayor de 60 años. El objetivo fue evaluar el impacto de la inmunoterapia como una alternativa terapéutica que mejora las funciones de supervivencia en pacientes ancianos con cáncer de pulmón de células no pequeñas. Se realizó un estudio analítico experimental donde el universo estuvo integrado por 123 ancianos con diagnóstico de cáncer de pulmón los cuales fueron tratados con inmunoterapia en Matanzas. Fueron utilizadas variables de control a las cuales se les aplicaron las medidas de resumen correspondientes utilizando las pruebas de hipótesis de chi cuadrado y las razones de verosimilitud para su análisis y estadístico y fueron evaluadas las funciones de supervivencia usando las curvas de Kaplan Meier. Se demostró la eficacia y seguridad de la inmunoterapia en el tratamiento de los pacientes estudiados. Por ello consideramos que el impacto secuencial de la combinación de la cirugía, la quimioterapia, la radioterapia y las terapias biológicas, tiende a prolongar la supervivencia de los pacientes que sufren cáncer de pulmón de células no pequeñas con una calidad de vida éticamente aceptable. Las nuevas terapias inmunológicas que consisten en devolver al sistema inmunológico de los pacientes, la capacidad de reconocer al tumor como extraño, y por tanto luchar contra él; han producido respuestas y beneficios muy importantes (AU).

SUMMARY Cancer is a priority public health problem in the world. In Cuba, it is the second cause of death in most age groups and mainly in the population aged over 60 years. To evaluate the impact of immunotherapy as a therapeutic alternative that improves survival functions in elder patients with non-small cell lung cancer. An experimental analytical study was carried out; the universe was composed by 123 elder people diagnosed with lung cancer who were treated with immunotherapy in Matanzas. Control variables were used to which the corresponding summary measures were applied using chi-square hypothesis tests and likelihood ratios for their analysis and statistics; survival functions were evaluated using Kaplan Meier curves. The efficacy and safety of immunotherapy in the treatment of the studied patients was demonstrated. Therefore, the authors believe that the sequential impact of the combination of surgery, chemotherapy, radiotherapy and biological therapies tends to extend the survival of patients suffering from non-small cell lung cancer with an ethically acceptable life quality. The new immunological therapy, consisting in returning to the patients´ immunologic system the capacity of recognizing a tumor as foreign, and therefore, fighting against it, have yielded very important answers and benefits (AU).

Medical nutrition therapy for gestational diabetes mellitus based on Mediterranean Diet principles: a subanalysis of the St Carlos GDM Prevention Study.

OBJECTIVES: To assess whether Mediterranean Diet (MedDiet)-based medical nutrition therapy facilitates near-normoglycemia in women with gestational diabetes mellitus (GDMw) and observe the effects on adverse pregnancy outcomes. RESEARCH DESIGN AND METHODS: This is a secondary analysis of the St Carlos GDM Prevention Study, conducted between January and December 2015 in Hospital Clínico San Carlos (Madrid, Spain). One thousand consecutive women with normoglycemia were included before 12 gestational weeks (GWs), with 874 included in the final analysis. Of these, 177 women were diagnosed with gestational diabetes mellitus (GDM) and 697 had normal glucose tolerance. All GDMw received MedDiet-based medical nutrition therapy with a recommended daily extra virgin olive oil intake ≥40 mL and a daily handful of nuts. The primary goal was comparison of hemoglobin A1c (HbA1c) levels at 36-38 GWs in GDMw and women with normal glucose tolerance (NGTw). RESULTS: GDMw as compared with NGTw had higher HbA1c levels at 24-28 GWs (5.1%±0.3% (32±0.9 mmol/mol) vs 4.9%±0.3% (30±0.9 mmol/mol), p=0.001). At 36-38 GWs values were similar between the groups. Similarly, fasting serum insulin and homeostatic model assessment insulin resitance (HOMA-IR) were higher in GDMw at 24-28 GWs (p=0.001) but became similar at 36-38 GWs. 26.6% of GDMw required insulin for glycemic control. GDMw compared with NGTw had higher rates of insufficient weight gain (39.5% vs 22.0%, p=0.001), small for gestational age (6.8% vs 2.6%, p=0.009), and neonatal intensive care unit admission (5.6% vs 1.7%, p=0.006). The rates of macrosomia, large for gestational age, pregnancy-induced hypertensive disorders, prematurity and cesarean sections were comparable with NGTw. CONCLUSIONS: Using a MedDiet-based medical nutrition therapy as part of GDM management is associated with achievement of near-normoglycemia, subsequently making most pregnancy outcomes similar to those of NGTw.

Buddleja globosa (matico) prevents collagen-induced platelet activation by decreasing phospholipase C-gamma 2 and protein kinase C phosphorylation signaling.

Platelets play a key role in thrombosis and cardiovascular diseases. Medicinal plants could be one of the most important factors that influence risks for platelet activation. Buddleja globosa (known as "matico") is a medicinal plant with many biological activities. The high content of polyphenols suggest that matico could have antiplatelet activity. The present study was aimed at evaluating mechanisms of antiplatelet action of an extract of matico. We demonstrated that matico extract at low concentrations and in a concentration dependent manner (0.05-1 mg/mL) was a potent inhibitor of platelet aggregation in response to collagen, convulsion and ADP (IC50 values was 61 µg/mL, 72 µg/mL and 290 µg/mL, respectively). In this sense matico extract exerted the greatest antiaggregant activity induced by collagen. Similarly, matico showed a decrease in % of positive platelet for P-selectina (vehicle, 0.01, 0.05, 0.1, 0.5 and 1 mg/mL were 32 ± 2%, 29 ± 2 (p < 0.05), 19 ± 1 (p < 0.01), 15 ± 2 (p < 0.01), 10 ± 1% (p < 0.01) and 7 ± 2% (p < 0.01), respectively) and PAC-1 binding (vehicle, 0.01, 0.05, 0.1, 0.5 and 1 mg/mL were 59 ± 1, 58 ± 3 (n.s), 55 ± 2 (p < 0.05), 50 ± 2 (p < 0.01), 38 ± 1 (p < 0.01), 36 ± 2 (p < 0.01). The cellular mechanism for the antiplatelet activity of matico might be mediated by the inhibition of phospholipase C-gamma 2 and protein kinase C phosphorylation. This beneficial property of matico may be of importance in thrombosis, in which platelet activation and aggregation are important determinants of thrombus initiation and development, and may contribute to the beneficial effects of matico intake in the prevention of cardiovascular diseases.

Relationship between serum selenium, sociodemographic variables, other trace elements and lipid profile in an adult Spanish population.

INTRODUCTION: Several studies have shown an inverse relationship between selenium status and cardiovascular health, although epidemiologic evidence yielded by the randomized trials did not find a beneficial effect of selenium administration. The aim of this study was to analyze the association between serum selenium levels and lipid profile adjusted by age, sex and other associated factors among a general adult population in Spain. MATERIALS AND METHODS: We recruited 372 hospital employee volunteers (60 men and 312 women) with a mean age of 47 (SD: 10.9), whom were given a standardized questionnaire. Serum selenium concentration was measured by electrothermal atomization atomic absorption spectrometry. Serum copper and zinc concentrations were measured using flame atomic absorption spectrometry. RESULTS: The mean of serum selenium was 79.5µg/L (SD: 11.7) with no sex-dependent differences. In the multivariate linear regression analysis, the associated factors with the mean levels of selenium were: age (ß=0.223; CI 95%: 0.101-0.345), p<0.001; widowhood (ß=-9.668; CI 95%: -17.234 to -2.102), p=0.012; calcium supplements (ß=3.949; CI 95%: 0.059-7.838), p=0.047; zinc (ß=0.126; CI 95%: 0.013-0.238), p=0.028 and glucose (ß=0.172; CI 95%: 0.062- 0.281), p=0.002; Participants with serum selenium≥79.5µg/L were 1.98 (OR=1.98; CI 95% 1.17-3.35; p=0.011) and 2.04 times (OR=2.04; CI 95% 1.06-3.97; p=0.034) more likely to have cholesterol ≥200mg/dL and LDL-c ≥100mg/dL respectively than those with serum selenium <79.5µg/L. CONCLUSIONS: Higher selenium was positively associated with increased total and LDL cholesterol but not with HDL-c and triglycerides. More studies are needed in order to confirm the lower serum selenium findings in widows.

Association between the cytogenetic profile of tumor cells and response to preoperative radiochemotherapy in locally advanced rectal cancer.

Neoadjuvant radiochemotherapy to locally advanced rectal carcinoma patients has proven efficient in a high percentage of cases. Despite this, some patients show nonresponse or even disease progression. Recent studies suggest that different genetic alterations may be associated with sensitivity versus resistance of rectal cancer tumor cells to neoadjuvant therapy. We investigated the relationship between intratumoral pathways of clonal evolution as assessed by interphase fluorescence in situ hybridization (51 different probes) and response to neoadjuvant radiochemotherapy, evaluated by Dworak criteria in 45 rectal cancer tumors before (n = 45) and after (n = 31) treatment. Losses of chromosomes 1p (44%), 8p (53%), 17p (47%), and 18q (38%) and gains of 1q (49%) and 13q (75%) as well as amplification of 8q (38%) and 20q (47%) chromosomal regions were those specific alterations found at higher frequencies. Significant association (P < 0.05) was found between alteration of 1p, 1q, 11p, 12p, and 17p chromosomal regions and degree of response to neoadjuvant therapy. A clear association was observed between cytogenetic profile of the ancestral tumor cell clone and response to radiochemotherapy; cases presenting with del(17p) showed a poor response to neoadjuvant treatment (P = 0.03), whereas presence of del(1p) was more frequently observed in responder patients (P = 0.0002). Moreover, a significantly higher number of copies of chromosomes 8q (P = 0.004), 13q (P = 0.003), and 20q (P = 0.002) were found after therapy versus paired pretreatment rectal cancer samples. Our results point out the existence of an association between tumor cytogenetics and response to neoadjuvant therapy in locally advanced rectal cancer. Further studies in larger series of patients are necessary to confirm our results.

A novel role of Eruca sativa Mill. (rocket) extract: antiplatelet (NF-κB inhibition) and antithrombotic activities.

BACKGROUND: Epidemiological studies have shown the prevention of cardiovascular diseases through the regular consumption of vegetables. Eruca sativa Mill., commonly known as rocket, is a leafy vegetable that has anti-inflammatory activity. However, its antiplatelet and antithrombotic activities have not been described. METHODS: Eruca sativa Mill. aqueous extract (0.1 to 1 mg/mL), was evaluated on human platelets: (i) P-selectin expression by flow cytometry; (ii) platelet aggregation induced by ADP, collagen and arachidonic acid; (iii) IL-1ß, TGF-ß1, CCL5 and thromboxane B2 release; and (iv) activation of NF-κB and PKA by western blot. Furthermore, (v) antithrombotic activity (200 mg/kg) and (vi) bleeding time in murine models were evaluated. RESULTS: Eruca sativa Mill. aqueous extract (0.1 to 1 mg/mL) inhibited P-selectin expression and platelet aggregation induced by ADP. The release of platelet inflammatory mediators (IL-1ß, TGF-ß1, CCL5 and thromboxane B2) induced by ADP was inhibited by Eruca sativa Mill. aqueous extract. Furthermore, Eruca sativa Mill. aqueous extract inhibited NF-κB activation. Finally, in murine models, Eruca sativa Mill. aqueous extract showed significant antithrombotic activity and a slight effect on bleeding time. CONCLUSION: Eruca sativa Mill. presents antiplatelet and antithrombotic activity.

Optimization of the modification of carrier proteins with aminated haptens.

In this report we show that succinic groups are far more reactive to amino compounds than the carboxylic groups derived from Asp and Glu on the protein when using coupling via 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (even by an 8 fold factor). Accordingly, a new carrier-protein was designed where both natural amino and carboxylic moieties were transformed into succinic residues. To prepare this hypersuccinylated carrier, all exposed carboxylic acids were first transformed into amino groups by reaction with ethylendiamine after activation with EDCI. Secondly, all these residues together with the ones from Lys were succinylated to prepare a fully succinylated protein. This was even more relevant considering that the amount of Lysine was 2-4 fold lower than Asp and Glu in most of the proteins. These "hyper-succinylated" proteins (KLH or BSA) offer significant improvements in protein reactivity compared to the native proteins (by a factor of 8-10). The optimization of the reaction, in which the presence of dioxane was found to be influential, permitted further improvements in the modification of the protein. Finally, this new strategy was successfully used to develop antibodies against the commercial anti-tumor molecule, ET-637-NH2. Using native KLH no response was found, whereas 1/64,000 serum dilutions gave very high values in ELISA procedures when immunization was performed using the hyper-succinylated KLH.

Directed covalent immobilization of aminated DNA probes on aminated plates.

A new protocol that enables the immobilization of DNA probes on aminated micro-titer plates activated with aldehyde-dextran via an amino group artificially introduced in the 3' end of the oligonucleotide probe is reported in this work. The method is based on the use of hetero-functional-dextran as a long and multifunctional spacer arm covalently attached to an aminated surface capable of immobilizing DNA oligonucleotides. The immobilization occurred only via the amino introduced in the 3' end of the probe, with no implication of the DNA bases in the immobilization, ensuring that the full length of the probe is available for hybridization. These plates having immobilized oligonucleotide probes are able to hybridize complementary DNA target molecules. The tailor-made hetero-functional aldehyde-aspartic-dextran together with the chemical blocking of the remaining primary amino groups on the support using acetic anhydride avoid the nonspecific adsorption of DNA on the surface of the plates. Using these activated plates, (studying the effect of the probe concentration, temperature, and time of the plate activation on the achieved signal), thus, the covalent immobilization of the aminated DNA probe was optimized, and the sensitivity obtained was similar to that achieved using commercial biotin-streptavidin systems. The new DNA plates are stable under very drastic experimental conditions (90% formamide, at 100 degrees C for 30 min or in 100 mM NaOH).