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BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
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Adenocarcinoma/tratamiento farmacológico , Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Administración Oral , Antagonistas de Receptores Androgénicos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Benzamidas , Progresión de la Enfermedad , Método Doble Ciego , Humanos , Masculino , Metástasis de la Neoplasia/diagnóstico por imagen , Nitrilos , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Radiografía , Receptores Androgénicos , Análisis de SupervivenciaRESUMEN
BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that has been shown to improve survival in two placebo-controlled phase 3 trials, and is approved for patients with metastatic castration-resistant prostate cancer. The objective of the TERRAIN study was to compare the efficacy and safety of enzalutamide with bicalutamide in patients with metastatic castration-resistant prostate cancer. METHODS: TERRAIN was a double-blind, randomised phase 2 study, that recruited asymptomatic or minimally symptomatic men with prostate cancer progression on androgen-deprivation therapy (ADT) from academic, community, and private health-care provision sites across North America and Europe. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive enzalutamide 160 mg/day or bicalutamide 50 mg/day, both taken orally, in addition to ADT, until disease progression. Patients were stratified by a permutated block method (block size of four), by whether bilateral orchiectomy or receipt of luteinising hormone-releasing hormone agonist or antagonist therapy started before or after the diagnosis of metastases, and by study site. Participants, investigators, and those assessing outcomes were masked to group assignment. The primary endpoint was progression-free survival, analysed in all randomised patients. Safety outcomes were analysed in all patients who received at least one dose of study drug. The open-label period of the trial is in progress, wherein patients still on treatment at the end of the double-blind treatment period were offered open-label enzalutamide at the discretion of the patient and study investigator. This trial is registered with ClinicalTrials.gov, number NCT01288911. FINDINGS: Between March 22, 2011, and July 11, 2013, 375 patients were randomly assigned, 184 to enzalutamide and 191 to bicalutamide. 126 (68%) and 168 (88%) patients, respectively, discontinued their assigned treatment before study end, mainly due to progressive disease. Median follow-up time was 20·0 months (IQR 15·0-25·6) in the enzalutamide group and 16·7 months (10·2-21·9) in the bicalutamide group. Patients in the enzalutamide group had significantly improved median progression-free survival (15·7 months [95% CI 11·5-19·4]) compared with patients in the bicalutamide group (5·8 months [4·8-8·1]; hazard ratio 0·44 [95% CI 0·34-0·57]; p<0·0001). Of the most common adverse events, those occurring more frequently with enzalutamide than with bicalutamide were fatigue (51 [28%] of 183 patients in the enzalutamide group vs 38 [20%] of 189 in the bicalutamide group), back pain (35 [19%] vs 34 [18%]), and hot flush (27 [15%] vs 21 [11%]); those occurring more frequently with bicalutamide were nausea (26 [14%] vs 33 [17%]), constipation (23 [13%] vs 25 [13%]), and arthralgia (18 [10%] vs 30 [16%]). The most common grade 3 or worse adverse events in the enzalutamide or bicalutamide treatment groups, respectively, were hypertension (13 [7%] vs eight [4%]), hydronephrosis (three [2%] vs seven [4%]), back pain (five [3%] vs three [2%]), pathological fracture (five [3%] vs two [1%]), dyspnoea (four [2%] vs one [1%]), bone pain (one [1%] vs four [2%]), congestive cardiac failure (four [2%] vs two [1%]), myocardial infarction (five [3%] vs none), and anaemia (four [2%] vs none]). Serious adverse events were reported by 57 (31%) of 183 patients and 44 (23%) of 189 patients in the enzalutamide and bicalutamide groups, respectively. One of the nine deaths in the enzalutamide group was thought to be possibly related to treatment (due to systemic inflammatory response syndrome) compared with none of the three deaths in the bicalutamide group. INTERPRETATION: The data from the TERRAIN trial support the use of enzalutamide rather than bicalutamide in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. FUNDING: Astellas Pharma, Inc and Medivation, Inc.
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Anilidas/uso terapéutico , Nitrilos/uso terapéutico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Compuestos de Tosilo/uso terapéutico , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Anilidas/efectos adversos , Artralgia/inducido químicamente , Dolor de Espalda/inducido químicamente , Benzamidas , Estreñimiento/inducido químicamente , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Método Doble Ciego , Disnea/inducido químicamente , Fatiga/inducido químicamente , Fracturas Espontáneas/inducido químicamente , Insuficiencia Cardíaca/inducido químicamente , Sofocos/inducido químicamente , Humanos , Hidronefrosis/inducido químicamente , Hipertensión/inducido químicamente , Masculino , Persona de Mediana Edad , Infarto del Miocardio/inducido químicamente , Náusea/inducido químicamente , Nitrilos/efectos adversos , Pacientes Desistentes del Tratamiento , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/uso terapéutico , Compuestos de Tosilo/efectos adversosRESUMEN
Both ischemic stroke (IS) and hemorrhagic stroke (HS) are reported to occur due to thrombosis on the arteries of the brain. As diabetes mellitus is a risk factor for strokes and insulin is reported to prevent thrombosis, the role of insulin in IS and HS was investigated. Forty eight stroke victims (IS = 22, HS = 26) and equal number of aged and sex matched normal volunteers participated in the study. Nitric oxide was determined by methemoglobin method. Insulin and Dermcidin isoform-2 (DCN2) level was determined by ELISA by using insulin and dermcidin antibody. Insulin binding to the platelet membrane was analyzed by scat chard plot. Treatment of normal platelet rich plasma (10(8)platelets/ml) with 15µUnits insulin/ml produced 1.41 nmol NO. The PRP from the IS and HS victims produced 0.38 nmol NO and 0.08 nmol NO respectively. Pretreatment of PRP from IS or HS subjects with 15 µM aspirin followed by 15µUnits of insulin/ml resensitized the platelets to the inhibitory effect of insulin. Mice hepatocytes treated with 0.14 µM DCN2 abolished the glucose induced insulin synthesis by NO that can be reversed by using 15 µM aspirin. It can be concluded that presence of DCN2 in stroke causes a condition similar to type I diabetes and nullified the effect of insulin in the inhibition of platelet aggregation in both IS and HS. The effect was reversed by 15 µM aspirin.
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Insulina/biosíntesis , Insulina/sangre , Agregación Plaquetaria/fisiología , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Hepatocitos/metabolismo , Humanos , Masculino , Ratones , Persona de Mediana EdadRESUMEN
BACKGROUND: High altitude illness (HAI) is a cluster of syndromes which develops due to the injury of the central nervous system produced by the reduction of the partial pressure of O2 in the atmosphere which disappears on decent. The HAI also results in a prothrombotic condition leading to acute coronary syndrome (ACS), which cannot be controlled on descent to the ground level. There is no diagnosis in HAI to forewarn of the impending ACS. A protein identified to be dermcidin isoform 2 (dermcidin), produced in the system due to environmental stresses, has been reported to be a potent diabetogenic agent. Investigation was carried out to determine the systemic stimulation of dermcidin synthesis at different levels of altitudes in normal adult male volunteers to assess the feasibility of developing a diagnosis for ACS in HAI due to dermcidin synthesis. METHODS: Normal, nondiabetic, normotensive male volunteers (25 - 35 years old, n = 16) participated in the study. The plasma dermcidin level was determined by enzyme linked immunosorbent assay (ELISA) and by in vitro translation of dermcidin mRNA. The plasma insulin level was determined by ELISA and blood glucose level was determined in a glucometer (Behringer). RESULTS: The plasma dermcidin level in the volunteers at ground level was 10 +/- 2.10 nM and increased to 80 +/- 4.62 nM at 15000 feet altitude. For each 1000 feet increase of altitude, the dermcidin level increased by 5.83 +/- 0.21 nM with a Coefficient of Correlation "r" = +0.9405. The increase of plasma dermcidin level was found to be inversely related to the decrease of plasma insulin level from 23 microunit/mL to 5 microunit/mL from sea level to 15000 feet height ("r" = -0.9951) with concomitant increase of blood sugar level from 80 +/- 3.6 mg/dL to 135 +/- 2.01 mg/dL. CONCLUSIONS: These results suggest the feasibility of a diagnosis of a prediabetic condition by determining the plasma dermcidin level in HAI by simple ELISA which may also be useful to forewarn of the possibility of developing an impending prothrombotic condition in HAI.
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Mal de Altura/diagnóstico , Dermcidinas/sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Isoformas de Proteínas/sangre , Glucemia/análisis , Dermcidinas/química , Humanos , Isoformas de Proteínas/clasificaciónRESUMEN
Machine learning (ML) has been used for classification of heart diseases for almost a decade, although understanding of the internal working of the black boxes, i.e., non-interpretable models, remain a demanding problem. Another major challenge in such ML models is the curse of dimensionality leading to resource intensive classification using the comprehensive set of feature vector (CFV). This study focuses on dimensionality reduction using explainable artificial intelligence, without negotiating on accuracy for heart disease classification. Four explainable ML models, using SHAP, were used for classification which reflected the feature contributions (FC) and feature weights (FW) for each feature in the CFV for generating the final results. FC and FW were taken into account in generating the reduced dimensional feature subset (FS). The findings of the study are as follows: (a) XGBoost classifies heart diseases best with explanations, with an increase in 2% in model accuracy over existing best proposals, (b) explainable classification using FS exhibits better accuracy than most of the literary proposals, and (c) with the increase in explainability, accuracy can be preserved using XGBoost classifier for classifying heart diseases, and (d) the top four features responsible for diagnosis of heart disease have been exhibited which have common occurrences in all the explanations reflected by the five explainable techniques used on XGBoost classifier based on feature contributions. To the best of our knowledge, this is first attempt to explain XGBoost classification for diagnosis of heart diseases using five explainable techniques.
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In the title compound, C(22)H(24)FN(3)O(4)S, the cyclo-hexane ring adopts a chair conformation and the five-membered ring is essentially planar, with a maximum deviation of 0.040â (2)â Å. The dihedral angles between the five-membered ring and the tolyl and fluoro-benzene rings are 56.74â (12) and 89.88â (12)°, respectively. The two terminal benzene rings make a dihedral angle of 63.53â (12)°. The crystal structure displays inter-molecular C-Hâ¯O and N-Hâ¯O hydrogen bonds. An intra-molecular C-Hâ¯O hydrogen bond also occurs.
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Great attempts have been done for the development of novel antiviral compounds against SAR-CoV-2 to end this pandemic situation and save human society. Herewith, we have synthesized 3-substituted indole/2-substituted pyrrole 1,2-dihydropyridine and azaxanthone scaffolds using simple, commercially available starting materials in a one-pot, green, and regioselective manner. Further, the regioselectivity of product formation was confirmed by various studies such as controlled experiments, density functional theory (DFT), Mulliken atomic charge, and electrostatic potential (ESP) surface. In addition, 3-substituted indole 1,2-dihydropyridine was successfully converted into a biologically enriched pharmacophore scaffold, viz., indolylimidazopyridinylbenzofuran scaffold, in excellent yield. Moreover, the synthesized 3-substituted indole 1,2-dihydropyridine/2-substituted pyrroles were analyzed in docking studies for anti-SARS-CoV-2 properties against their main protease (Mpro) and anti-Delta plus properties against their protein of the Delta plus K417N mutant. Further, the drug-likeness prediction was analyzed by the Lipinski rule and other pharmacokinetic properties like absorption, distribution, metabolism, excretion, and toxicity using preADMET prediction. Interestingly, the docking results show that out of 20 synthesized compounds, 5 of them for Mpro of SAR-CoV-2 and 9 of them for 7NX7 spike glycoprotein's A chain of Delta plus K417N show greater binding affinity when compared with remdesivir that is the first to receive FDA approval and is currently used as a potent drug for the treatment of COVID-19. These results suggest that indole/pyrrole substituted 1,2-dihydropyridine derivatives are capable of combating SARS-CoV-2 and its Delta plus mutant.
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Objectives: Because the damage of kidney tissue is associated with hypertension and impaired nitric oxide (NO) synthesis, and as aspirin is reported to stimulate the synthesis of renal r-cortexin, an anti-hypertensive protein, we investigated the role of aspirin as bolus dose on elevated blood pressure induced by deoxycorticosterone acetate (DOCA)-salt in animal model. Methods: The chronic antihypertensive effect of aspirin on DOCA treated with ASA group of rats (n = 6) was evaluated after ingestion of 0.35 µM aspirin as a bolus dose in every 24 h using tail cuff methods. The plasma aspirin, NO, and r-cortexin levels were determined by spectrophotometric, methemoglobin, and ELISA methods, respectively. Synthesis of r-cortexin mRNA was determined. Aspirin activated nitric oxide synthase (AANOS) was purified by chromatographic methods. Results: Our results showed after 3 h of administration of aspirin (0.35 µM) to the DOCA treated with ASA group of rats decreased the systolic blood pressure from 139.39 ± 7.36 mm of Hg to 116.57 ± 6.89 mm of Hg and diastolic blood pressure from 110.4 ± 7 mm of Hg to 86.4 ± 2.76 mm of Hg. The reduction of BPs was found to be related to the increased plasma aspirin from 0.00 µM to 0.042 µM, plasma NO from 0.4 ± 0.19 nM to 1.9 ± 0.5 nM, and cortexin levels from 64.36 ± 12.6 nM to 216.7 ± 21.3 nM. The molecular weight of purified AANOS is 18 kDa. Conclusion: It can be concluded that aspirin possesses antihypertensive effect on blood pressure in chronic administration. Aspirin can stimulate NO synthesis through the activation of AANOS, which stimulated the production of r-cortexin in kidney cortex cells and thereby reducing elevated BP in hypertensive rats.
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In randomized clinical trials, the use of potentially subjective endpoints has led to frequent use of blinded independent central review (BICR) and event adjudication committees to reduce possible bias in treatment effect estimators based on local evaluations (LE). In oncology trials, progression-free survival (PFS) is one such endpoint. PFS requires image interpretation to determine whether a patient's cancer has progressed, and BICR has been advocated to reduce the potential for endpoints to be biased by knowledge of treatment assignment. There is current debate, however, about the value of such reviews with time-to-event outcomes such as PFS. We propose a BICR audit strategy as an alternative to a complete-case BICR to provide assurance of the presence of a treatment effect. We develop an auxiliary-variable estimator of the log-hazard ratio that is more efficient than simply using the audited (i.e., sampled) BICR data for estimation. Our estimator incorporates information from the LE on all the cases and the audited BICR cases, and is an asymptotically unbiased estimator of the log-hazard ratio from BICR. The estimator offers considerable efficiency gains that improve as the correlation between LE and BICR increases. A two-stage auditing strategy is also proposed and evaluated through simulation studies. The method is applied retrospectively to a large oncology trial that had a complete-case BICR, showing the potential for efficiency improvements.
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Biometría/métodos , Bioestadística/métodos , Análisis de Supervivencia , Sesgo , Supervivencia sin Enfermedad , Humanos , Neoplasias/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/normasRESUMEN
In the title compound, C(23)H(19)Cl(2)N(5)OS, the triazole ring makes dihedral angles of 24.81â (18), 69.94â (19) and 35.68â (18)° with the dichloro-phenyl, benzene and meth-oxy-phenyl rings, respectively. An intra-molecular N-Hâ¯N hydrogen bond occurs. In the crystal, inversion dimers linked by pairs of N-Hâ¯S hydrogen bonds occur. In addition, there are weak C-Hâ¯π inter-actions involving the dichloro-phenyl and triazole rings.
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In the title compound, C(22)H(19)ClN(4)Se(2), the mean plane of the non-fused selenadiazole ring forms dihedral angles of 54.20â (16)° and 70.48â (11)°, respectively, with the essentially planar [maximum deviations of 0.025â (5) and 0.009â (2)â Å, respectively] methyl-phenyl and chloro-phenyl substituents. The tetra-hydro-1,2,3-benzoselenadiazole group is disordered over two sets of sites with a refined occupancy ratio of 0.802â (5):0.198â (5). In the crystal, weak inter-molecular C-Hâ¯N inter-actions are observed.
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In the title compound, C(22)H(22)N(2)OSe, the fused six-membered ring of the 4,5,6,7-tetra-hydro-benzo[d][1,2,3] selenadiazole group adopts a near to envelope (E form) conformation and the five-membered 1,2,3-selenadiazole ring is essentially planar (r.m.s. deviation = 0.0059â Å). In the crystal, adjacent mol-ecules are inter-linked through weak inter-molecular C-Hâ¯π inter-actions.
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In the title compound, C(25)H(22)N(2)OSe, the fused six-membered cyclo-hexene ring of the 4,5,6,7-tetra-hydro-1,2,3-benzoselenadiazole group adopts a near half-chair conformation and the five-membered 1,2,3-selenadiazole ring is essentially planar (r.m.s. deviation = 0.004â Å). There are weak inter-molecular C-Hâ¯O and C-Hâ¯π inter-actions in the crystal structure. Inter-molecular π-π stacking is also observed between the naphthyl units, with a centroid-centroid distance of 3.529â (15)â Å.
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This paper describes the synthesis of an unprecedented oxo-bridged rheniumI/VII (Re) complex by treating Re2(CO)10 with a pyridyl-linked anthracene-based twisted π-conjugated ligand. The molecular structures of both the ligand and the complex are determined by analyzing IR, NMR, and HR-MS spectra and unequivocally determined using single-crystal X-ray diffraction studies. Unlike previous observations, the complexation occurs uniquely to yield an unprecedented oxo-bridged ReI/VII complex. Such a complex is uncommon, and in most cases, Re(vii) appears as the ReO4- counter ion. The aggregation-induced emission (AIE) feature could have been achieved from this conformationally twisted ligand, but the emission of the ligand was quenched in the aggregated state. The complex exhibited solvatofluorochromic properties with a faint emission. The emission intensity significantly (â¼6 times) increased in DMF after the addition of a water fraction of 90%, resulting in a bright orange emission. The AIE is mainly caused by restricted intramolecular rotation (RIR) and is supported by the polarity and viscosity effects. The nanoaggregate formation is captured by SEM, and DLS studies were used to determine the average particle size. After the complexation, the ligand becomes more rigid, and the RIR effect becomes prominent facilitating the AIE effect. The electron-rich aggregate's intense orange emission was used for the selective and sensitive detection of picric acid (PA) and 2,4,6-trinitrotoluene (TNT) at nanomolar levels amongst other nitroaromatics through emission quenching. The detailed mechanistic studies reveal the active role of dynamic quenching and complementary photo-induced electron transfer between the probe and TNT or PA. The easy electron transfer process from the electron-rich to the electron-poor system is confirmed by calculating the lowest unoccupied molecular orbital energy of the associated levels. The application is further extended for on-site PA and TNT detection by permeating the probe on a paper and detected at 10-3 M concentration with the naked eye. The PA/TNT detection efficiency is also confirmed by mixing PA or TNT with soil.
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INTRODUCTION: Garlic has been reported to stimulate nitric-oxide (NO) synthesis in various cells. The role of aqueous-extract of garlic (AEG) and a purified NO-generating protein from garlic (NGPG) was investigated to control hyperglycemia by hepatic insulin synthesis through NGPG induced synthesis of NO via glucose-activated NO-synthase and glucose transporter-4 (Glut-4) in the hepatocytes. METHODS: Type-1-diabetic mellitus mice were prepared by alloxan treatment, NO was determined by methemoglobin method, insulin synthesis was quantitated by ELISA. TNF-α and NFκß was quantitated by ELISA. The AEG-induced Glut-4 synthesis was determined by in-vitro translation of mRNA from the hepatocytes. The NO-generating protein from AEG was purified to homogeneity by chromatography on DEAE-cellulose and Sephadex G-50 columns and sequenced/characterized by Mass-spectral-analysis. RESULTS: Purified NGPG injection to diabetic mice significantly reduced the blood-sugar and increase insulin level in diabetic animal. It also increases insulin-release, Glut-4 synthesis, glucose-uptake in both liver and ß-cells of diabetic mice. NGPG down regulated pro-inflammatory cytokine TNF-α and the stress responsive NFκB-expression in liver cell of diabetic mice. Injection of AEG to the diabetic mice reduced the blood glucose level from 550 ± 10 mg/dL to 125 ± 10 mg/dL in 16 h with simultaneous increase of plasma NO from 0 nmol/h to 2.5 nmol/h and insulin 2 ± 1.1µunit/mL to 15µunit/mL at 16 h. Oral administration of AEG to adult diabetic mice increased NO, insulin and Glut-4 synthesis in the hepatocytes. CONCLUSION: AEG and the purified-NGPG protein can control hyperglycemia through the stimulation of NO by glucose-activated NO-synthase that would play an important role in the synthesis of insulin/Glut-4 in liver-cells.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Ajo/química , Transportador de Glucosa de Tipo 4/metabolismo , Hipoglucemiantes/farmacología , Insulina/metabolismo , Hígado/efectos de los fármacos , Óxido Nítrico/metabolismo , Aloxano/farmacología , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Glucosa/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Hígado/metabolismo , Ratones , Extractos Vegetales/farmacologíaRESUMEN
Lack of insulin or insulin resistance (IR) plays a central role in diabetes mellitus and makes diabetics prone to acute ischemic heart disease (AIHD). It has likewise been found that many cancer patients, including prostate cancer patients die of AIHD. Previously it has been delineated from our laboratory that dermcidin could induce anomalous platelet aggregation in AIHD and also impaired nitric oxide and insulin activity and furthermore dermcidin was also found in a few types of cancer patients. To determine the role of this protein in prostatic malignancy, a retrospective case-control study was conducted and blood was collected from prostate cancer patients and healthy normal volunteers. So, we measured the level of dermcidin protein and analyzed the IR by Homeostasis Model Assessment (HOMA) score calculation. Nitric oxide was measured by methemoglobin method. HDL, glycated hemoglobin (HbA1c), BMI, hs-cTroponin-T were measured for the validation of the patients' status in the presence of Dermcidin isoform-2 (DCN-2). Multiple logistic regression model adjusted for age and BMI identified that the HOMA score was significantly elevated in prostate cancer patients (OR = 7.19, P<0.001). Prostate cancer patients are associated with lower level of NO and higher level of both proteins dermcidin (OR = 1.12, P<0.001) and hs-TroponinT (OR = 1.76, P<0.001). From the results, it can be interpreted that IR plays a key role in the pathophysiology of prostate cancer where dermcidin was the cause of IR through NO inhibition leading to AIHD was also explained by high-sensitive fifth generation cTroponin-T (hs-cTroponinT) and HbA1c level which are associated with endothelial dysfunction.
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Resistencia a la Insulina , Modelos Cardiovasculares , Isquemia Miocárdica , Neoplasias de la Próstata , Enfermedad Aguda , Anciano , Hemoglobina Glucada/metabolismo , Humanos , Lipoproteínas HDL/sangre , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/sangre , Isquemia Miocárdica/etiología , Proteínas de Neoplasias/sangre , Péptidos/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/complicaciones , Troponina T/sangreRESUMEN
Importance: Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. Objective: To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. Design, Setting, and Participants: PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Interventions: Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Main Outcomes and Measures: Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula. Results: In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman ρ and 0.72 (95% CI, 0.68-0.77) by Kendall τ. Conclusions and Relevance: Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients. Trial Registration: clinicaltrials.gov Identifier: NCT01212991.
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Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Supervivencia sin Progresión , Neoplasias de la Próstata Resistentes a la Castración/terapia , Radiografía , Resultado del TratamientoRESUMEN
Diabetes is now epidemic worldwide. Several hundred-million peoples are presently suffering from this disease with other secondary-disorders. Stress, hypertension, sedentary life-style, carbohydrate/lipid metabolic-disorders due to genetic or environmental factors attributes to type-1 and/or type-2 diabetes. Present investigation demonstrates that stress-induced protein dermcidin isoform-2 (DCN-2) which appears in the serum of diabetic-patients play a key-role in this disease pathogenesis/severity. DCN-2 suppresses insulin production-release from liver/pancreas. It also increases the insulin-resistance. Stress-induction at the onset/progression of this disease is noticed as the high-level of lipid peroxides/low-level of free-thiols in association with increase of inflammatory-markers c-reactive protein and TNF-α. DCN-2 induced decrease in the synthesis of glucose-activated nitric oxide synthase (GANOS) and lower production of NO in liver has been shown here where NO is demonstrated to lower the expression of glucose trabsporter-4 (GLUT-4) and its translocation on liver membrane surface. This finally impairs glucose transport to organs from the extracellular fluid. Low level of glucose uptake further decreases glucose-induced insulin synthesis. The central role of DCN-2 has been demonstrated in type-1/type-2 diabetic individuals, in rodent hepatocytes and pancreatic-cell, tissue-slices, in-vitro and in-vivo experimental model. It can be concluded that stress-induced decrease in insulin synthesis/function, glucose transport is an interactive consequence of oxidative threats and inflammatory events.
Asunto(s)
Diabetes Mellitus/diagnóstico , Diabetes Mellitus/metabolismo , Péptidos/metabolismo , Adulto , Animales , Biomarcadores , Glucemia , Diabetes Mellitus/sangre , Diabetes Mellitus Experimental , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Hepatocitos/metabolismo , Humanos , Insulina/sangre , Insulina/metabolismo , Resistencia a la Insulina , Masculino , Ratones , Persona de Mediana Edad , Modelos Biológicos , Óxido Nítrico Sintasa/metabolismo , Estrés Oxidativo , Péptidos/química , Isoformas de Proteínas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
A trypsin resistant oral insulin preparation was made by incubating insulin for 2 h at 23 °C with previously boiled cow milk at 100 °C that was coagulated with 0.6 M acetic acid. The precipitate was resuspended in the same volume of milk. The immunoblot analysis of the suspended proteins treated with 200 ng of trypsin/ml for 3 h demonstrated that the 80.1% of the insulin in the suspension survived the proteolytic degradation compared to 0% of the hormone survived in the control. The feeding of 0.4 ml (0.08 unit of insulin) of the resuspended proteins followed by 0.2 ml of the same protein to alloxan induced diabetic mice maximally decreased the blood glucose level from 508 ± 10 mg/dl to 130 ± 10 mg/dl in 7 h with simultaneous increase of the basal plasma concentration of insulin from 3 ± 1.1 µunits/ml to 18 ± 1.5 µunits/ml. In control experiment the absence of insulin in the identical milk suspension produced no hypoglycemic effect suggesting milk was not responsible for the hypoglycemic effect of milk-insulin complex. Coming out of insulin-casein complex from the intestinal gut to the circulation was spontaneous and facilitated diffusion transportation which was found from Gibbs free energy reaction.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Insulina/uso terapéutico , Administración Oral , Aloxano , Animales , Glucemia/análisis , Caseínas/metabolismo , Bovinos , Estabilidad de Medicamentos , Insulina/sangre , Insulina/química , Insulina/farmacocinética , Intestino Delgado/metabolismo , Ratones , Leche , Unión Proteica , Distribución Tisular , Tripsina/metabolismoRESUMEN
BACKGROUND: Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naïve metastatic castration-resistant prostate cancer. OBJECTIVE: To assess the effects of enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease. DESIGN, SETTING, AND PARTICIPANTS: One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to enzalutamide (n=872) or placebo (n=845). Subgroup analyses included nonvisceral (only bone and/or nodal; n=1513), visceral (lung and/or liver; n=204), low-volume bone disease (<4 bone metastases; n=867), high-volume bone disease (≥4 bone metastases; n=850), lymph node only disease (n=195). INTERVENTION: Oral enzalutamide (160mg) or placebo once daily while continuing androgen deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Coprimary endpoints (rPFS, OS) were prospectively evaluated in nonvisceral and visceral subgroups. All other efficacy analyses were post hoc. RESULTS AND LIMITATIONS: Enzalutamide improved rPFS versus placebo in patients with nonvisceral disease (hazard ratio [HR], 0.18; 95% confidence interval [CI], 0.14-0.22), visceral disease (HR, 0.28; 95% CI, 0.16-0.49), low- or high-volume bone disease (HR, 0.16; 95% CI, 0.11-0.22; HR, 0.22; 95% CI, 0.16-0.29, respectively), and lymph node only disease (HR, 0.09; 95% CI, 0.04-0.19). For OS, HRs favored enzalutamide (<1) across all disease subgroups, although 95% CI was >1 in patients with visceral disease (HR, 0.82; 95% CI, 0.55-1.23). Enzalutamide was well tolerated in patients with or without visceral disease. CONCLUSIONS: Enzalutamide provided clinically significant benefits in men with chemotherapy-naïve metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease. PATIENT SUMMARY: Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease or widespread bone disease-benefitted from enzalutamide, an active well-tolerated therapy.