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Supplementary Table S1. Patient Characteristics for patients from the University of California at San Diego; Supplementary Table S2. Fitness of algorithms; Supplementary Table S3. Cross validations of potential models; Supplementary Table S4. Statistical inference of comparing models; Supplementary Figure S1. Scheme of study design;Supplementary Figure S2. Scatter plot; Supplementary Figure S3. AUROC for the individual components analyzed; Supplementary Figure S4. MALDI-TOF analysis of low molecular weight kininogen; Supplementary Figure S5. Glycopeptide analysis of tryptic glycopeptide 44-58; Supplementary Figure S6. Glycopeptide analysis of tryptic glycopeptide 197-208 showing identification of fucosylated glycopeptides; Supplementary Figure S7. Glycopeptide analysis of tryptic glycopeptide 289-300

Supplementary Figure 1 from Novel Changes in Glycosylation of Serum Apo-J in Patients with Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the occurrence of HCC has more than doubled in the United States in the past decade. Early detection is considered key to reducing the mortality of HCC.Methods: Using two-dimensional gel electrophoresis and high-performance liquid chromatography we have analyzed the glycosylation of Apo-J from healthy controls, patients with liver cirrhosis, or those with HCC.Results: Apo-J in the serum from patients with HCC had decreased levels of (β-1,4) triantennary N-linked glycan compared with the healthy controls or patients with liver cirrhosis. We analyzed this change in an independent cohort of 76 patients with HCC, 32 with cirrhosis, and 43 infected with hepatitis C virus using the Datura stramonium lectin (DSL), which binds to (β-1,4) triantennary N-linked glycan. The level of DSL-reactive Apo-J allowed us to differentiate HCC from cirrhosis with an area under the receiver operating characteristic curve (AUROC) of 0.852. When Apo-J was combined with other serum biomarkers such as α-fetoprotein (AFP) and fucosylated kininogen by using a multivariate logistic regression model, the AUROC increased to 0.944, a value much greater than that observed with AFP alone (AUROC of 0.765).Conclusions: The glycosylation of Apo-J is a useful marker when used alone or in combination with outer makers for the early detection of HCC.Impact: The potential use of a combination of AFP, DSL-reactive Apo-J, and fucosylated kininogen as a biomarker of HCC would have great value in the management of patients with liver disease. Cancer Epidemiol Biomarkers Prev; 20(6); 1222–9. ©2011 AACR.

Background: Hepatocellular carcinoma (HCC) has the greatest increase in mortality among all solids tumors in the United States related to low rates of early tumor detection. Development of noninvasive biomarkers for the early detection of HCC may reduce HCC-related mortality.Methods: We have developed an algorithm that combines routinely observed clinical values into a single equation that in a study of >3,000 patients from 5 independent sites improved detection of HCC as compared with the currently used biomarker, alpha-fetoprotein (AFP), by 4% to 20%. However, this algorithm had limited benefit in those with AFP Results: The ability to detect early-stage AFP-negative (AFP Conclusions: An algorithm combining fucosylated kininogen, AFP, and clinical characteristics is highly accurate for early HCC detection.Impact: Our biomarker algorithm could significantly improve early HCC detection and curative treatment eligibility in patients with cirrhosis. Cancer Epidemiol Biomarkers Prev; 26(5); 795–803. ©2017 AACR.

We have previously identified alterations in glycosylation on serum proteins from patients with HCC and developed plate-based assays using lectins to detect the change in glycosylation. However, heterophilic antibodies, which increase with non-malignant liver disease, compromised these assays. To address this, we developed a method of polyethylene glycol (PEG) precipitation that removed the contaminating IgG and IgM but allowed for the lectin detection of the relevant glycoprotein. We found that this PEG-precipitated material itself could differentiate between cirrhosis and HCC. In the analysis of three training cohorts and one validation cohort, consisting of 571 patients, PEG-IgG had AUC values that ranged from 0.713 to 0.810. In the validation cohort, which contained samples from patients at a time of 1–6 months prior to HCC detection or 7+ months prior to detection, the AUC of this marker remained consistent (0.813 and 0.846, respectively). When this marker was incorporated into a biomarker algorithm that also consisted of AFP and fucosylated kininogen, the AUROC increased to 0.816–0.883 in the training cohort and was 0.909 in the external validation cohort. Biomarker performance was also examined though the analysis of partial ROC curves, at false positive values less than 10% (90-ROC), ≤20% (80-ROC) or ≤30% (70-ROC), which highlighted the algorithm’s improvement over the individual markers at clinically relevant specificity values.

Objectives. This study aimed to compare the characteristics of fully and partially vaccinated or unvaccinated coronavirus disease 2019 (COVID-19) patients who were hospitalised in a population of 220,000 habitants. Methods: Retrospective, observational, and population studies were conducted on patients who were hospitalised due to COVID-19 from March to October 2021. We assessed the impact of vaccination and other risk factors through Cox multivariate analysis. Results: A total of 500 patients were hospitalised, among whom 77 (15.4%) were fully vaccinated, 86 (17.2%) were partially vaccinated, and 337 (67.4%) were unvaccinated. Fully vaccinated (FV) patients were older and had a higher Charlson index than those of partially vaccinated and unvaccinated patients (NFV). Bilateral pneumonia was more frequent among NFV (259/376 (68.9%)) than among FV patients (32/75 (42.7%)). The former had more intensive care unit admissions (63/423) than the latter (4/77); OR: 2.80; CI (1.07–9.47). Increasing age HZ: 1.1 (1.06–1.14)) and haematological disease at admission HZ: 2.99 (1.26–7.11)) were independent risk factors for higher mortality during the first 30 days of hospitalisation. The probability of an earlier discharge in the subgroup of 440 patients who did not die during the first 30 days of hospitalisation was related to age (older to younger: HZ: 0.98 (0.97–0.99)) and vaccination status. Conclusions: Among the patients hospitalised because of COVID-19, complete vaccination was associated with less severe forms of COVID-19, with an earlier discharge date. Age and haematological disease were related to a higher mortality rate during the first 30 days of hospitalisation.

Abarema glaucum is a tree species native to Cuba, Hispaniola and Bahamas. It is considered Vulnerable to extinction in Cuba. The evaluation in Cuba also warns of the need to carry out population studies of the species. This work made the assessment of the status of Abarema glaucum in Artemisa, where the species had been reported before the half of 20th century. For this, the population structure was characterized; amount of accumulated aerial biomass in the region was estimated; and the threats to its conservation in the region were identified. Abarema glaucum has less than 250 individuals, with less than 50 mature individuals, dispersed between three sites in Güira de Melena y Alquízar. The diameter and height vary between 0.03 and 36.31 cm, and 0.05 and 15 m, respectively. The accumulated aerial biomass is estimated between 3 and 4 metric tons among 33 adults. The individuals are aggregated with good natural regeneration, but low recruitment towards older age phases. It is a species dispersed in patches of remaining forest in the region, where the risk of fire, logging, trampling, as well as the degradation of its habitat, constitute threats to its conservation. Logging could delay and even prevent flowering in the adults. The logging and the continuous decline of the quality of the habitat are putting the sustainability of the species in the area in danger.

Introduction Adrenocortical Carcinoma (ACC) is a rare and often aggressive malignancy arising from the adrenal cortex. Rarely, ACC can be associated with a paraneoplastic syndrome, such as tumor-associated hypoglycemia due to insulin-like growth factor-2 secretion, hyperreninemic hyperaldosteronism, erythropoietin-associated polycythemia, and leukocytosis due to chemokine release from the tumor. Stauffer syndrome is a paraneoplastic syndrome characterized by reversible cholestasis in the absence of liver metastases, most frequently described in the context of renal cell carcinoma. Our case is the first reported association between Stauffer syndrome and ACC. Clinical Case A 38-year-old man presented with nausea, vomiting, painless jaundice, pruritus, and weight loss. Laboratory evaluation revealed an elevated total bilirubin of 8.7 mg/dL (N Conclusion Our case highlights a unique presentation of paraneoplastic hepatic dysfunction with jaundice associated with newly diagnosed ACC. Although Stauffer syndrome is one of the most characteristic paraneoplastic syndromes associated with renal cell carcinoma and other malignancies, paraneoplastic hepatic dysfunction associated with ACC has not been previously reported. The patient had rapid improvement of hyperbilirubinemia after surgical resection of the tumor. Stauffer syndrome should be considered in patients with ACC with liver dysfunction and jaundice without evidence of liver metastases. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

La trata de personas es una manera de esclavitud moderna y, además, es un delito contra los derechos humanos que va en aumento en la actualidad. En ella las personas son retenidas en contra de su voluntad o engañadas y trasladadas a otro país con fines de explotación laboral o sexual. No es fácil salir de la misma debido a las amenazas y a las coacciones (y rituales) a las que son sometidas. Aquí nos centraremos en las víctimas que han logrado salir de la trata, exponiendo sus experiencias; además de sus estrategias y expectativas de vida tras lograr escapar de esas redes de esclavitud. Human trafficking :is a form of modern-day slavery and is also a growing human rights crime today. People are held against their will or deceived and taken to another country for the purpose of labour or sexual exploitation. It is not easy to get out of it because of the threats and coercion (and rituals) to which they are subjected. Here we will focus on victims who have managed to escape from trafficking, sharing their experiences, as well as their strategies and expectations for their lives after escaping from these slavery networks.

Background COVID-19 infection in elderly patients is more aggressive and treatments have shown limited efficacy. Objective To describe the clinical course and to analyze the prognostic factors associated with a higher risk of mortality of a cohort of patients older than 80 years. To assess the efficacy of immunosuppressive treatments in this population. Methods We analyzed the data from 163 patients older than 80 years admitted to our institution for COVID-19, during March and April 2020. A lasso regression model and subsequent multivariate Cox regression was performed in order to select variables predictive of death. We evaluated the efficacy of immunomodulatory therapy in three cohorts using an adjusted survival analysis. Results The mortality rate was 43%. Mean age was 85.2 years. The disease was considered severe in 76.1% of the cases. Lasso regression and multivariate Cox regression indicated that factors correlated with hospital mortality were: age (HR 1.12, 95%CI: 1.03 - 1.22), alcohol consumption (HR 3.15, 95%CI: 1.27 - 7.84), CRP > 10 mg/dL (HR 2.67, 95%CI: 1.36 - 5.24), and oxygen support with Venturi Mask (HR 6.37, 95%CI: 2.18 - 18.62) or reservoir (HR 7.87, 95%CI: 3.37 - 18.38). Previous treatment with antiplatelets was the only protective factor (HR 0.47, 95%CI: 0.23-0.96). In the adjusted treatment efficacy analysis, we found benefit in the combined use of tocilizumab (TCZ) and corticosteroids (CS) (HR 0.09, 95%-CI:0.01 - 0.74) compared to standard treatment, with no benefit of CS alone (HR 0.95, 95%-CI:0.53 - 1.71). Conclusion Hospitalized elderly patients suffer from a severe and often fatal form of COVID-19 disease. In this regard, several parameters might identify high risk patients upon admission. Combined use of TCZ and CS could improve survival. This article is protected by copyright. All rights reserved.

The study reports a case of a 57-year-old female patient with incidental right adrenal lipoma (LA). The tumor was detected by ultrasound (US) and confirmed by computed tomography (CT). Due to the size of the mass, it was decided to perform a laparoscopic adrenalectomy. During the differential microscopic diagnosis, were considered adrenal lipomatous tumors, myelolipoma, angiomyolipoma and teratomas, among others. In all these neoplasms, LA is a rare tumor, with only 24 cases reported in the anglo-saxon literature revised. It is a benign adrenal gland tumor with generally asymptomatic and non-functioning nature.

Background Although there is evidence of positive effect of periodontal therapy on systemic inflammation, this response is highly variable among subjects. It was the aim of this clinical investigation to determine the impact of periodontal treatment on systemic markers of inflammation in patients with metabolic syndrome (MetS) and periodontitis. Methods In this parallel-arm, double blind, randomized controlled clinical trial, 63 patients with MetS and severe periodontitis were randomly assigned to receive intensive periodontal treatment (IPT; scaling and root planing plus azithromycin 500 mg, q.d., for three days) or minimal periodontal treatment (MPT; supragingival professional mechanical plaque removal plus a placebo). The primary outcome was the impact of the tested interventions on hs-CRP serum levels at 6 months. As secondary outcomes, differences in the levels of cytokines, markers of prothrombotic states, carbohydrate and lipids metabolism, as well as blood pressure, were measured at 3 and 6 months after therapy. Results The ITT population consisted on 63 subjects randomly assigned to either MPT (n = 31) or IPT (n = 32) groups. At baseline, mean hs-CRP was 3.9 mg/L (standard deviation, SD = 2.9) and 3.9 mg/L (SD = 3.4), respectively, and no significant differences in their cardiometabolic risk profiles were detected between groups. After 6 months, unadjusted mean hs-CRP were 2.9 mg/L (standard error, SE = 0.4) and 4.0 (SE = 0.8), respectively. Adjusting for baseline hs-CRP, sex, age, smoking status and body mass index, hs-CRP was 1.2 mg/L (95% confidence interval, [CI 0.4; 2.0]; p = 0.004) lower in the IPT group than in the MPT group. In the secondary outcomes, significant reductions in IL-1β, TNF-α, HbA1c and blood pressure were observed in the IPT group at 3 months, when compared to the MPT group. Conclusion Effective periodontal treatment significantly reduced hs-CRP after 6 months in patients with MetS and severe periodontitis. Periodontal therapy might be useful to reduce cardiovascular risk in these patients. Trial registration: ClinicalTrials.gov Registration Number: NCT03960216.

Objective To identify factors associated with poor anticoagulation control with vitamin K antagonists (VKA) among outpatients with nonvalvular atrial fibrillation (NVAF) attended in Neurology and Internal Medicine in Spain. Methods Cross-sectional and multicenter study, from the ALADIN database, of outpatients with NVAF treated with VKA and attended in Internal Medicine and Neurology in Spain. Rates of anticoagulation control were determined with the direct and Rosendaal methods, considering data from the 6 months before the inclusion. Results Out of 1337 patients included in the ALADIN study, 750 were taking VKA, and complete information about INR values in the last 6 months was available in 383 patients. Mean scores of Charlson Index, CHADS2, CHA2DS2-VASc and HAS-BLED were 1.94 ± 1.54; 3.10 ± 1.26; 4.63 ± 1.54, and 2.20 ± 0.90, respectively. 46.2% and 47.0% of patients had an adequate anticoagulation control according to the direct and Rosendaal methods, respectively. Inadequate anticoagulation control according to the direct method was associated with diabetes (OR: 2.511; 95% CI: 1.144–5.659), prior labile INR (OR: 35.371; 95% CI: 15.058–83.083) and the determination of >6 INR controls in the last 6 months (OR: 4.747; 95% CI: 2.094–10.759), and according to the Rosendaal method, with prior labile INR (p Conclusions Despite the high thromboembolic risk, only a little more than a half of patients were well controlled. Factors associated with poor anticoagulation control were diabetes, labile INR, >6 INR controls and HAS-BLED.

Resumen Objetivo Identificar los factores asociados con el mal control de la anticoagulacion con antagonistas de la vitamina K (AVK) en pacientes con fibrilacion auricular no valvular (FANV) atendidos en consultas de Neurologia y Medicina Interna de Espana. Metodos Estudio transversal, multicentrico, anidado en el estudio ALADIN, de sujetos con FANV, tratados con AVK, atendidos en consultas de Medicina Interna o Neurologia de Espana. El grado de control de la anticoagulacion se estudio mediante el metodo directo y el de Rosendaal, considerando los 6 meses previos a la inclusion. Resultados De los 1.337 pacientes incluidos en ALADIN, 750 estaban tratados con AVK, con informacion completa sobre el INR de los ultimos 6 meses en 383 pacientes. Las puntuaciones medias del indice de Charlson, CHADS2, CHA2DS2-VASc y HAS-BLED fueron 1,94 ± 1,54; 3,10 ± 1,26; 4,63 ± 1,54 y 2,20 ± 0,90, respectivamente. El 46,2% y el 47,0% de los pacientes presentaban un control adecuado de la anticoagulacion por los metodos directo y Rosendaal, respectivamente. El control inadecuado de la anticoagulacion se asocio por el metodo directo con diabetes (OR: 2,511; IC 95%: 1,144-5,659), antecedentes de INR inestable (OR: 35,371; IC 95%: 15,058-83,083) y la realizacion de > 6 controles en los ultimos 6 meses (OR: 4,747; IC 95%: 2,094-10,759), y por el metodo de Rosendaal, con los antecedentes de INR inestable (p Conclusiones Pese al alto riesgo tromboembolico, solo estaban bien controlados algo mas de la mitad. Los factores asociados al mal control de la anticoagulacion fueron la diabetes, INR inestable, > 6 controles de INR y el HAS-BLED.

Aneurysms of the pulmonary arteries and trunk are rare entities. The Waterston shunt is a palliative procedure for children with cyanotic CHD due to obstruction of the pulmonary outflow. Described complications are distortion of the pulmonary artery and pulmonary arterial hypertension. We report a patient with a giant right pulmonary artery aneurysm in relation to a Waterston shunt.

Tamoxifen is the most common antiestrogen used in the chronic treatment of breast cancer. In these cells, it mainly binds to intracellular receptors (estrogen receptor alpha, ERα) and antagonizes the binding of its cognate ligand, 17β-estradiol, thereby preventing uncontrolled hormone-dependent cellular proliferation and growth. In the last decade, in our laboratories we have developed and characterized different tamoxifen derivatives, including a novel fluorescent tamoxifen conjugate: FLTX1. FLTX1 is formed by the covalent binding of tamoxifen to a common fluorescent biomarker NBD. This new prodrug was originally designed as a fluorescent biomarker to localize intracellular targets, which not only keeps the pharmacological activity of tamoxifen but also adds a luminescent functionality. Strikingly, the quantum efficiency of FLTX1 is so high that laser emission has been obtained as an emerging property. In this review, we will show its laser properties under three different configurations. First, as amplified spontaneous emission or mirrorless laser; second, through the evanescent field of WGMs of a ring resonator around an optical fiber; and finally as random laser in uterine tissues impregnated with the prodrug. Further, we observed another emergent property for FLTX1: this molecule, but not tamoxifen alone or NBD, was able to generate reactive oxygen species (ROS) upon irradiation. This property is extremely interesting as FLTX1 might be used for photodynamic therapy. Under this paradigm, FLTX1 would act as a sensitizer in ERα-overexpressing cells (which feature the most prevalent form of hormone-dependent breast cancer), causing cell death in ERα+ cells but reducing damage to other non-cancer (healthy) cells or surrounding tissues. We show here time resolved fluorescence results that suggest molecular aggregations, which could explain the subsequent generation of ROS. This is an original cancer therapy strategy that combines the pharmacological properties of a new tamoxifen derivative and its laser dye features with a highly selective photodynamic therapy., Supported by Research grant SAF2014-61644-EXP from MINECO (Spain) to M.D. Partially supported by Agencia Estatal de Investigación (AEI, grant ref. MAT2016-79866-R to F.L.), SAF2015-65113-C2-1-R and SAF2017-84454-R (from MINECO) to A.E. and R.M., respectively. DH and DQA were hired by Universidad de La Laguna. FL was recipient of contract from Torres Quevedo Programme (MINECO) and incorporated in BIOSIGMA SL (Spain).

Resumen Fundamento y objetivo Analizar si el ancho de distribucion eritrocitario (ADE) se comporta como factor pronostico de mortalidad tras el alta hospitalaria en pacientes mayores de 70 anos y si su capacidad pronostica es superior a la de otros parametros de laboratorio. Pacientes y metodo Estudio longitudinal prospectivo en 426 pacientes ingresados en el Servicio de Medicina Interna que sobrevivieron a un ingreso hospitalario. Se recogieron variables sociodemograficas, comorbilidad, situacion funcional, situacion cognitiva y parametros de la enfermedad que origina el ingreso (diagnostico, parametros analiticos, estancia). El seguimiento se realizo durante un ano mediante entrevista telefonica, en la que se recogieron datos sobre la situacion vital y, si procedia, fecha de fallecimiento. El efecto del ADE sobre la mortalidad se evaluo mediante regresion logistica y su capacidad pronostica mediante el area bajo la curva ROC. Resultados Cada punto porcentual de incremento del ADE se asocio con una mayor mortalidad al ano, con una odds ratio de 1,19 (intervalo de confianza del 95% [IC 95%] 1,08-1,31). La mortalidad en cada tercil del ADE fue 15,6% en el inferior, 21,5% en el intermedio y 30,5% en el mas elevado. Un modelo clinico suplementado con el ADE mejora su capacidad predictora de mortalidad evaluada mediante curva ROC. La mejora de reclasificacion neta de dicha prediccion es del 1,71% (IC 95% 0,07-3,35) (p = 0,04). Conclusion El presente estudio aporta nuevas evidencias de asociacion del ADE con mortalidad en una cohorte de pacientes ancianos que sobreviven a un ingreso hospitalario. El ADE fue el unico parametro de laboratorio analizado que mejoraba la capacidad pronostica de mortalidad a un ano.

We show that androgens, testosterone and 5α-dihydrotestosterone (DHT), acutely (∼40 min) provoke the mechanical potentiation of spontaneous and agonist-induced contractile activity in mouse colonic longitudinal smooth muscle. The results using flutamide, finasteride, cycloheximide, and actinomycin D indicate that androgen-induced potentiation is dependent on androgen receptors, requires reduction of testosterone to DHT, and occurs independently of transcriptional and translational events. Using permeabilized colonic smooth muscle preparations, we could demonstrate that mechanical potentiation is entirely due to calcium sensitization of contractile machinery. In addition, DHT (10 nm) increased phosphorylation of both 20-kDa myosin light chain (LC20) [regulatory myosin light chain, (MLC)] and CPI-17 (an endogenous inhibitor of MLC phosphatase). Paralleling these findings, inhibition of Rho-associated Rho kinase (ROK) and/or protein kinase C (PKC) with, respectively, Y27632 and chelerythrine, prevented LC20 phosphorylation and abolished calcium sensitization. In addition, inhibition of ROK prevents CPI-17 phosphorylation, indicating that ROK is located upstream PKC-mediated CPI-17 modulation in the signalling cascade. Additionally, androgens induce a rapid activation of RhoA and its translocation to the plasma membrane to activate ROK. The results demonstrate that androgens induce sensitization of colonic smooth muscle to calcium through activation of ROK, which in turn, activates PKC to induce CPI-17 phosphorylation. Activation of this pathway induces a potent steady stimulation of LC20 by inhibiting MLC phosphatase and displacing the equilibrium of the regulatory subunit towards its phosphorylated state. This is the first demonstration that colonic smooth muscle is a physiological target for androgen hormones, and that androgens modulate force generation of smooth muscle contractile machinery through nongenomic calcium sensitization pathways.

Tamoxifen is a selective estrogen receptor modulator that competitively binds the ligand-binding domain of estrogen receptors. Binding of tamoxifen displaces its cognate ligand, 17β-estradiol, thereby hampering the activation of estrogen receptors. Cellular labeling of ER is typically carried out using specific antibodies which require permeabilization of cells, incubation with secondary antibodies, and are expensive and time consuming. In this article, we describe the usefulness of FLTX1, a novel fluorescent tamoxifen derivative, which allows the labeling of estrogen receptors in immunocytochemistry and immunohistochemistry studies, both under permeabilized and non-permeabilized conditions. Further, besides labeling canonical estrogen receptors, this novel fluorescent probe is also suitable for the identification of unconventional targets such membrane estrogen receptors as well as other noncanonical targets, some of which are likely responsible for the number of undesired side effects reported during long-term tamoxifen treatments.

In this study, a series of new 4,4'-diaminotriphenylmethanes was efficiently synthesized from aromatic aldehydes and 2,5-dimethoxybenzenamine under microwave irradiation in the presence of Sc(OTf)3 as a catalyst. Antiproliferative activity was assessed by using the MCF-7 estrogen receptor (ER)-positive breast cancer cell line, and antagonist/agonist transcriptional activities were determined. Docking studies and competition studies of triphenylmethanes and radiolabeled estradiol determined that these compounds do not bind the ER, indicating that triphenylmethane-induced changes in proliferative and transcriptional activities differ from conventional mechanisms of action triggered by other selective ER modulators.

We have previously shown that the triphenylethylene antiestrogen tamoxifen reversibly inhibited spontaneous contractile activity in isolated duodenal muscle. Now, we have synthesized different quaternary ammonium salts of tamoxifen by changing the substituents on the nitrogen of the alkylaminoethoxy side-chain, to obtain plasma membrane impermeable compounds. Synthesized molecules were N-desmethyl-tamoxifen-hydrochloride, ethylbromide-tamoxifen and butylbromide-tamoxifen, which differed in the size of their ionic side-chain. All compounds rapidly and reversibly inhibited spontaneous and CaCl(2)-induced contractions in mouse duodenum and uterus. Dose-response analyses revealed a structure-activity relationship where the larger the side-chain the higher the inhibitory potency. Fourier analyses on triphenylethylene-relaxed duodenal tissues showed that harmonic components of contractile activity were readily recovered upon exposure to the L-type calcium channel agonist 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-pyridine-3-carboxilic acid methyl ester (BAY-K644). Likewise, BAY-K644 completely reversed triphenylethylene-induced effects on uterine tonic tension. Our experiments suggest that impermeant tamoxifen derivatives relax visceral smooth muscle through a membrane-mediated non-genomic mechanism that involves inhibition of L-type calcium channels.

17-β-Estradiol, the stereoisomer 17-α-estradiol and the synthetic estrogen diethylstilbestrol (DES), all caused a rapid (

17-beta-Estradiol, the stereoisomer 17-alpha-estradiol and the synthetic estrogen diethylstilbestrol (DES), all caused a rapid (

Background: Streptococcus pneumoniae is the leading cause of community-acquired pneumonia in the elderly, and in recent years it has arisen as an important pathogen in HIV-infected patients. However, there is a scarcity of information on clinical and therapeutic problems associated with pneumococcal infections in other immuno-compromised patients. The objective of this study was to assess the most relevant epidemiologic aspects, clinical features and prognostic factors of pneumococcal bacteremia in immunocompromised hosts without AIDS.Methods: This was a retrospective analysis of patients with pneumococcemia, carried out in a 600-bed, university-affiliated hospital in Madrid, Spain. Two-hundred and sixty patients were evaluated retrospectively; 69 (26.5%) immunocompromised patients based on strict case definitions were compared with a group composed of 191 non-immunocompromised hosts with a variety of chronic conditions. Conventional management of pneumococcal bacteremia according to clinical standards was assessed. The MICs of penicillin and other β-lactam antibiotics, and related mortality and hospital mortality at 30 days, were measured.Results: A comparison of clinical manifestations of pneumococcemia between immunocompromised patients and non-immunocompromised patients did not show differences in the presence of fever, obtundation, type of lung involvement, frequency of primary bacteremia, or meningitis. Hospital-acquired pneumococcemia was significantly more frequent in immunocompromised patients (34.7% versus 6.8%, P

A new method for the estimation of properties of pure organic compounds is presented. Estimation is performed at three levels. The primary level uses contributions from simple groups that allow describing a wide variety of organic compounds, while the higher levels involve polyfunctional and structural groups that provide more information about molecular fragments whose description through first-order groups is not possible. The presented method allows estimations of the following properties: normal boiling point, critical temperature, critical pressure, critical volume, standard enthalpy of formation, standard enthalpy of vaporization, standard Gibbs energy, normal melting point and standard enthalpy of fusion. The group-contribution tables have been developed from regression using a data set of more than 2000 compounds ranging from C=3–60, including large and complex polycyclic compounds. Compared to the currently used group-contribution methods, the new method makes significant improvements both in accuracy and applicability.

A new method is proposed to estimate the liquid viscosities at ambient temperature (20°C) of pure organic compounds from chemical structure. Estimation is performed by using a new structural approach (GIG), which considers the contributions of interactions between bonding groups in the molecule instead of the contributions of simple groups. Compared to other group-contribution methods, the proposed method demonstrates significant improvements in accuracy.

A family of models is proposed to estimate the critical constants and normal boiling points of hydrocarbons from chemical structure. Estimation is performed by using a new structural approach (GIC), which considers the contributions of interactions between bonding groups in the molecule instead of the contributions of simple groups. Compared to the typical group-contribution techniques, the proposed models demonstrate significant improvements in accuracy as well as the ability to distinguish among isomers.

A family of models proposed in this paper estimate the critical constants and normal boiling points of pure organic compounds from chemical structure by using a new structural approach called group-interaction contributions, which considers the contributions of interactions between bonding groups in the molecule instead of the contributions of simple groups. Compared to the conventional group-contribution techniques, the proposed models demonstrate significant improvements in accuracy, as well as the ability to distinguish among isomers.

Adding new functionalities to efficient drugs is an appealing challenge, which improves their applications both in basic research and clinical practice, provided the new drug preserves its original bioactivity. We describe herein the appearance of significant optical properties, such as optical gain and laser emission, due to the chemical modification of a blockbuster antitumoral drug by attachment of 7-nitrobenzo[c][1,2,5]-oxadiazol-4-yl (NBD) fluorescent tag to Tamoxifen, the most widely drug used in the treatment of breast cancer.

To examine whether red cell distribution width (RDW) performs as a mortality predictor after hospital discharge in patients over 70 years of age and if its prognostic power is superior to other laboratory parameters.Longitudinal and prospective study of 426 patients admitted to the Internal Medicine Department who survived hospitalization. Sociodemographic and comorbidity factors, functional and cognitive status as well as disease parameters causing admission (diagnosis, analytical parameters, length of stay) were collected. Patients were followed for one year by telephone interview and data were collected regarding vital status and, if appropriate, death date. RDW effect on mortality was assessed using logistic regression and prognostic capability by the area under the ROC curve.Each percentage point rise in RDW was associated with increased mortality at one year with an odds ratio of 1.19 (95% confidence interval [95% CI] 1.08 to 1.31). Mortality in each tertile of RDW was 15.6% in the lowest, 21.5% in the middle and 30.5% in the highest. A clinical model supplemented with RDW improved mortality predictive ability assessed by ROC curve. Net reclassification improvement of the prediction rule was 1.71% (95% CI 0.07 to 3.35) p=0.04.This study provides new evidence of the RDW association with mortality in a cohort of elderly patients who survived hospitalization. RDW was the only laboratory parameter that improved the one-year prognostic mortality ability.

[EN] External amplified spontaneous emission (ASE) efficiency around 30% is reported for an optically active molecule, which at the same time shows antitumor activity. The complex is formed by the covalent binding of an anticancer drug, tamoxifen, commonly applied in breast cancer therapy, and nitro-2-1,3-benzoxadiazol-4-yl (NBD) dye, which is frequently used as a biomarker in hydrophobic environments, such as lipid membranes. A laser-like pump threshold around 100 kW/cm(2) was found in solutions of the fluorescent drug diluted in acetone or in oil. Agreement with an ASE spatial propagation model, as well as the lack of optical feedback in the walls of the dilution cuvette confirms that ASE is the physical mechanism that explains the high efficiency observed. The waveguide character and the polarization dependence of ASE are also studied. Highly efficient optical gain in such systems suggests new biophotonic applications. (C) 2013 Elsevier B. V. All rights reserved., This study has been supported by research grants from Agencia Canaria de Investigacion, Innovacion y Sociedad de la Informacion, Gobierno de Canarias, through Project Sol-SubC200801000088 and Ministerio de Economia y Competividad Grant Numbers SAF2010-22114-C02-01 and CTQ2009-07109.

Tamoxifen is a selective estrogen receptor modulator extensively used on estrogen receptor-positive breast cancer treatment. However, clinical evidences demonstrate the increased incidence of undesirable side effects during chronic therapies, the most life threatening being uterine cancers. Some of these effects are related to tissue-dependent estrogenic actions of tamoxifen, but the exact mechanisms remain poorly understood. We have designed and synthesized a novel fluorescent tamoxifen derivative, FLTX1, and characterized its biological and pharmacological activities. Using confocal microscopy, we demonstrate that FLTX1 colocalizes with estrogen receptor α (ERα). Competition studies showed that FLTX1 binding was totally displaced by unlabeled tamoxifen and partially by estradiol, indicating the existence of non-ER-related triphenylethylene-binding sites. Ligand binding assays showed that FLTX1 exhibits similar affinity for ER than tamoxifen. FLTX1 exhibited antiestrogenic activity comparable to tamoxifen in MCF7 and T47D cells transfected with 3xERE-luciferase reporter. Interestingly, FLTX1 lacked the strong agonistic effect of tamoxifen on ERα-dependent transcriptional activity. Additionally, in vivo assays in mice revealed that unlike tamoxifen, FLTX1 was devoid of estrogenic uterotrophic effects, lacked of hyperplasic and hypertrophic effects, and failed to alter basal proliferating cell nuclear antigen immunoreactivity. In the rat uterine model of estrogenicity/antiestrogenicity, FLTX1 displayed antagonistic activity comparable to tamoxifen at lower doses, and only estrogenic uterotrophy at the highest dose. We conclude that the fluorescent derivative FLTX1 is not only a suitable probe for studies on the molecular pharmacology of tamoxifen, but also a potential therapeutic substitute to tamoxifen, endowed with potent antiestrogenic properties but devoid of uterine estrogenicity., This study was supported by Grants SAF2007-66148-C02-02 (MD), SAF2010-22114-C02-01/02 (MD/RM), SAF2009-13296-C02-02 (LFP), and CTQ2009-07109 (AB) from Spanish Ministry of Science and Innovation and European Regional Development Fund Programme. We are grateful to Fundación del Instituto Canario de Investigacion del Cancer (FICIC, Spain) for financial support in the period 2007–2012. J.M.A. was hired from FICIC.

Estrogens exert a plethora of actions conducted to brain preservation and functioning. Some of these actions are initiated in lipid rafts, which are particular microstructures of the plasma membrane. Preservation of lipid raft structure in neurons is essential for signal transduction against different injuries, such as Alzheimer's disease (AD). These membrane structures appear to be disrupted as this neuropathology evolves, and that may largely contribute to dysfunction of raft resident proteins involved in intracellular signalling. This review includes a survey of some protein interactions that are involved in the structural maintenance and signal transduction mechanisms for neuronal survival against AD. Particularly relevant are the rapid mechanisms developed by estrogen to prevent neuronal death, through membrane estrogen receptors (mER) interactions with a voltage-dependent anion channel (VDAC) and other protein markers within neuronal lipid rafts. These interactions may have important consequences in estrogen mechanisms to achieve neuroprotection against amyloid beta (Abeta-induced toxicity).

Numerous studies indicate that estrogens are crucial in normal brain functioning and preservation against different injuries. At the neuronal membrane, estrogens, binding to estrogen receptors (ERs) or other surface targets, exert rapid actions involving a plethora of signaling pathways that may converge in neuronal survival. Emerging work reveals that at least part of these actions may require the compartmentalization of ERs in signaling platforms, composed of macromolecular signaling proteins and particular lipid composition integrated in lipid rafts. These particular microstructures may provide the optimal microenvironment to trigger multiple ER interactions that may be crucial for neuroprotection against different brain impairments, such as Alzheimer's disease (AD). In this order of ideas, recent evidence has demonstrated that a membrane ER (mER) physically interacts with a voltage-dependent anion channel (VDAC) in lipid rafts from septal, hippocampal and cortical neurons, and these interactions may have important consequences in the alternative mechanisms developed by estrogens to achieve neuroprotection against amyloid beta (Aβ)-induced toxicity. This review includes a survey of some of the rapid mechanisms developed by estrogen to prevent neuronal death, and the ER interactions that are involved in the structural maintenance and signal transduction mechanisms important for neuronal survival against AD neuro-pathology. A special emphasis is put on the biological relevance of neuronal membrane VDAC in Aβ-related neurotoxicity, and the potential modulation of this channel as a part of a signaling complex with mER, which may be modified in AD brains.

We have demonstrated that chemically modified anticancer drugs can provide random laser (RL) when infiltrated in a biological tissue. A fluorescent biomarker has been covalently bound to tamoxifen, which is one of the most frequently used drugs for breast cancer therapy. The light emitted by the drug-dye composite is scattered in tissue, which acts as a gain medium. Both non-coherent and coherent RL regimes have been observed. Moreover, the analysis of power Fourier transforms of coherent RL spectra indicates that the tissues show a dominant random laser cavity length of about 18 µm, similar to the average size of single cells. These results show that RL could be obtained from other drugs, if properly marked with a fluorescent tag, which could be appealing for new forms of combined opto-chemical therapies.

Compelling evidence accumulated over the past three decades have demonstrated that, besides their ability to antagonize estrogen binding to their intracellular specific estrogen receptors (ER), selective estrogen receptor modulators (SERMs) can affect a number of biochemical processes in eukaryotic cells. Experimental data from in vivo and in vitro studies have revealed that SERMs and estrogens are surprisingly pleiotropic molecules affecting molecular targets in both estrogen receptor positive (ER+) and negative (ER–) cells. Such “alternative” actions of SERMs and estrogens are typically independent of canonical ERs and do not involve transcriptional or translational events, thereby mediated nongenomically, and usually initiated (and accomplished) within seconds to minutes after presentation of the molecule (Falkestein et al. 2000; Nadal el al. 2001). The spectrumof SERM-induced acute actions includes a wide set of molecular targets, frommodulation of ion channels and signaling molecules to alteration of membrane fluidity. In the following sections we review data from different laboratories, including ours, in the context of cellular and molecular evidences for acute nongenomic effects of SERMs observed at pharmacological circulating concentrations. Special emphasis will be placed on actions that might underlie clinically relevant beneficial effects as well as undesirable side effects.

17-beta-Estradiol, the stereoisomer 17-alpha-estradiol and the synthetic estrogen diethylstilbestrol (DES), all caused a rapid (3 min) dose-dependent reversible relaxation of mouse duodenal spontaneous activity, reduced basal tone and depressed the responses to CaCl(2) and KCl. The steroidal antiestrogen 7alpha-[9-[(4,4,5,5,5,-pentafluoropenty)sulphinyl]nonyl]-estra-1,3,5(19)-triene-3,17beta-diol (ICI182,780) failed to either mimic or prevent the effect of 17-beta-estradiol. The effect of estrogens was unrelated to activation of nitric oxide (NO), mitogen-activated protein kinase (MAPK), protein kinase A (PKA), protein kinase G (PKG) or protein kinase C (PKC). Estrogen-induced relaxation was partially reversed by 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-pyridine-3-carboxilic acid methyl ester (BAY-K8644), depolarization, or by application of tetraethylammonium or 4-aminopyridine, but not by glibenclamide, apamin, charybdotoxin, paxilline or verruculogen. The effects of BAY-K8644 and K(+) channel blockers were synergistic, and allowed relaxed tissues to recover spontaneous activity and basal tone. We hypothesize that the rapid non-genomic spasmolytic effect of estrogens on mouse duodenal muscle might be triggered by an estrogen-receptor-independent mechanism likely involving activation of tetraethylamonium- and 4-aminopyridine-sensitive K(+) channels and inhibition of L-type Ca2(+) channels on the smooth muscle cells.

New methods for the estimation of the octanol/water partition coefficient (Kow) and aqueous solubility (Ws) at ambient temperature are presented. The property values are estimated by using a three-level group-contribution estimation approach requiring only molecular structural information. The primary level uses contributions from simple first-order groups that allow for the description of a wide variety of organic compounds, whereas the higher levels (second- and third-order groups) involve polyfunctional and structural groups that provide more information about molecular fragments whose description through first-order groups is not possible. The group-contribution values were calculated by linear regression analysis using a data set of 9560 values for Kow and 2087 values for Ws. The data set included compounds ranging from C3 to C70, including large and heretocyclic compounds. Compared to other currently used group-contribution methods, the new methods make significant improvements in accuracy with loga...