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Funding sponsor Funding number Acronym Balearic Islands Health Research Institute, EU-COST 35/2011, CA16112, Fondo de Investigación para la Salud, IDISBA CB12/03, CIBEROBN CB06/03, Margalida Comas DG R+D+I, Ministry of Science, Spain, European Commission 201630.10, EAT2BENICE_H2020_SFS2016, European Research Council 2013–2018, 340918, Generalitat Valenciana PROMETEO/2017/017, Instituto de Salud Carlos III, Funding sponsor Funding number Acronym Balearic Islands Health Research Institute EU-COST 35/2011, CA16112 Fondo de Investigación para la Salud IDISBA CB12/03, CIBEROBN CB06/03 Margalida Comas DG R+D+I Ministry of Science, Spain European Commission See opportunities by EC See opportunities (opens in new window) 201630.10, EAT2BENICE_H2020_SFS2016 EC European Research Council See opportunities by ERC See opportunities (opens in new window) 2013–2018, 340918 ERC Generalitat Valenciana See opportunities by GVA See opportunities (opens in new window) PROMETEO/2017/017 GVA Instituto de Salud Carlos III 2013ACUP00194, PI13/00233, PI13/00272, PI13/00462, PI13/00492, PI13/00673, PI13/00728, PI13/01056, PI13/01090, PI13/01123, PI13/02184, PI14/00618, PI14/00636, PI14/00696, PI14/00728, PI14/00853, PI14/00972, PI14/01206, PI14/01374, PI14/01471, PI14/01722, PI14/01919, PI16/00366, PI16/00381, PI16/00473, PI16/00501, PI16/00533, PI16/00662, PI16/01094, PI16/01120, PI16/01522, PI16/01873, PI17/00215, PI17/00508, PI17/00525, PI17/00532, PI17/00764, PI17/00855, PI17/00926, PI17/01183, PI17/01347, PI17/01441, PI17/01732, PI17/01827, PI19/00017, PI19/00309, PI19/00386, PI19/00576, PI19/00781, PI19/00957, PI19/01032, PI19/01226, PI19/01332, PI19/01560, PI20/00138, PI20/00339, PI20/00456, PI20/00557, PI20/00886, PI20/01158, PI20/01532, PI20/01802, Consejería de Salud y Familias, Junta de Andalucía PI0137/2018, PI0458/2013, PS0358/2016

Objective To determine the predictors of early, intermediate and late biochemical recurrence (BR) following minimally invasive radical prostatectomy in patients with localized prostate cancer (PC). Material and methods We included 6195 patients with cT1-3N0M0 prostate cancer treated using radical laparoscopic prostatectomy (RLP) and radical robot-assisted prostatectomy at our institution between 2000 and 2016. None of the patients underwent adjuvant therapy. BR is defined as PSA levels ≥0.2 ng/dL. The time to BR is divided into terciles to identify the variables associated with early ( 36 months) recurrence. We employed logistic regression models to determine the risk factors associated with each interval. Results We identified 1148 (18.3%) patients with BR. The median time to BR was 24 months (IQR, 0.98–53.18). The multivariate analysis showed that preoperative PSA levels, lymph node invasion, positive margins and RLP are associated with early recurrence (p ≤ 0.029 for all). Laparoscopic surgery was the only predictor of intermediate recurrence (p = 0.001). The predictors of late recurrence included a pathological Gleason score ≥7, stage ≥pT3, positive margins and RLP (p ≤ 0.02 for all). Conclusions The patients with high-risk prostate cancer can develop late recurrence and require long-term follow-up. Identifying patients with higher PSA levels and lymph node invasion has an important predictive role in the first year after surgery. The association between RLP and BR warrants further assessment.

Differentiating nicotinic acetylcholine receptors (nAChR) to target the high-affinity nicotine α4β2 subtype is a major challenge in developing effective addiction therapies. Although cytisine 1 and varenicline 2 (current smoking-cessation agents) are partial agonists of α4β2, these drugs display full agonism at the α7 nAChR subtype. Site-specific modification of (−)-cytisine via Ir-catalyzed C‒H activation provides access to C(10) variants 6–10, 13, 14, 17, 20, and 22, and docking studies reveal that C(10) substitution targets the complementary region of the receptor binding site, mediating subtype differentiation. C(10)-modified cytisine ligands retain affinity for α4β2 nAChR and are partial agonists, show enhanced selectivity for α4β2 versus both α3β4 and α7 subtypes, and critically, display negligible activity at α7. Molecular dynamics simulations link the C(10) moiety to receptor subtype differentiation; key residues beyond the immediate binding site are identified, and molecular-level conformational behavior responsible for these crucial differences is characterized. Molecular locksmithing is the use of precision chemical keys for biological locks. Nicotinic acetylcholine receptors (nAChR) associated with acetylcholine neurotransmission are linked to public health issues, notably tobacco addiction. Why is this important? Smoking kills seven million people annually and imposes a huge burden in terms of healthcare and lost productivity. The ability to design a molecule to achieve high receptor selectivity is paramount for the success of smoking cessation: poor selectivity is typically accompanied by (adverse) side effects. We have modified cytisine, a known “nicotinic activator,” in a very direct and versatile manner to suppress a particular characteristic: activation of the α7 subtype of nAChR. Computational molecular simulation of the protein-ligand complexes links these structural changes to a ligand's activity, facilitating the design of precision “molecular keys” for better discrimination of receptor subtypes and offering the potential of more targeted therapies. Efficient access to C(10) of (−)-cytisine via C‒H activation provides access to enantiomerically pure nicotinic acetylcholine receptor ligands that target the high-affinity nicotine α4β2 subtype with enhanced selectivity. These C(10) cytisine variants retain a partial agonist profile at the α4β2 subtype but, critically, display negligible activity at the α7 receptor subtype. Using computational methods, Gallagher and colleagues link receptor selectivity to key protein residues associated with, as well as beyond, the immediate ligand binding site.

Introduction: Stage IIIB-IV non-small cell lung cancer patients with mutations in the EGF receptor gene (EGFR) usually derive clinical benefit from to tyrosine kinase inhibitors (EGFR TKIs) but ultimately relapse. In preclinical studies, we have showed that anti-EGF antibodies generated by vaccination significantly increased the antitumor activity of TKIs in EGFR-mut cell lines, blocking EGFR, Erk1/2, Akt and STAT3 activation and delaying emergence of resistance. Based on these findings, the EPICAL trial was initiated (ClinicalTrials.gov number, NCT03623750). Methods: The EPICAL was a single arm, phase 1b, single arm study to evaluate the safety and efficacy of first line anti-EGF vaccination combined with afatinib. The trial enrolled advanced NSCLC patients with sensitizing EGFR mutations confirmed in a central laboratory. Patients received 40 mg/day of afatinib and five intramuscular anti-EGF vaccinations every 14 days and then every three months until progression. Four medical centers in Spain participated, with a target enrollment of 30 patients. However, the COVID-19 outbreak forced an early termination of the study in March 2020 with only 23 patients included. Serial blood samples were collected and used to evaluate the levels of selected growth factors by ELISA and biological activity by addition of sera to in vitro cultures of EGFR-mut cells followed by Western blotting. Results: Of the 23 patients enrolled in the trial, nine (39%) had exon 19 in-frame deletions, twelve (52%) exon 21 substitutions and two (9%) exon 18 missense mutations. Combination treatment was well tolerated and no SAES related to anti-EGF vaccination were reported. Objective response and disease control rates were 78.3% (95%CI=53.6-92.5) and 95.7% (95%CI=78.1-99.9), respectively. At data cut-off, with a median follow-up of 11.4 months (95%CI=8.1-15.2), the median progression-free survival was 17.4 months (95% CI=13.22-NA) and median survival not reached (95% CI=15.21-NA). Median PFS for patients with exon 19 deletions and exon 21 point mutations were 13.9 months (95%CI=8.7-NR) and 17.4 months (95%CI=13.2-NR), respectively. Three months after initiation of treatment, high titers of anti-EGF antibodies were detected in all patients and serum EGF and TGFα levels were found to be significantly lower compared to baseline levels. Finally, treatment with post-vaccination patient’s sera inhibited EGFR, AKT and ERK1/2 phosphorylation in EGFR-mut cells growing in vitro. Conclusion: The combination of an anti–EGF vaccine with afatinib is well tolerated and induces a sustained immunogenic effect. Vaccination against EGF might enhance the clinical efficacy of EGFR TKIs. Keywords: anti-EGF vaccination, EGFR-mutant non-small cell lung cancer, EGFR inhibitors

Objectives To evaluate the incidence and risk factors of pressure ulcers (PU) in adult patients admitted to intensive care units (ICUs), as well as the outcome (including ICU and hospital mortality) of these patients. Methods Epidemiological cohort multicenter prospective study, evaluating patients admitted for a period of 31 days (June 01 to July 01, 2015) until hospital discharge. Epidemiological and clinical data were collected daily until ICU discharge, as was the incidence of PU, either new or present on admission. Setting 10 general adult ICUs. Results We evaluated 332 patients, 52.1% male, mean age 63.1 years. The most common cause of admission was medical diseases (50.3%), and the mean APACHE II score was 14.9. A total of 45 patients (13.6%) had PU; the most common sites were sacral, calcaneal, ears, and trochanter. The incidence of PU was related to predictive factors, such as the Braden Scale and length of lack of nutrition. The presence of PU was strongly related to unfavorable outcomes, such as Mechanical Ventilation (MV) duration and ICU and hospital mortality. Conclusions PU incidence is related to severity of the patient’s condition and predicted by Braden Scale score. The presence of PU is also related to adverse outcomes, such as MV duration and ICU and hospital mortality. It was also shown that patients with PU have a higher incidence of medical complications, such as acute renal failure, pneumonia, and the need for vasoactive drugs.

Purpose To evaluate whether patients with prostate cancer have worse functional urinary recovery with focal brachytherapy (FBT) at the base versus the apex of the prostate. Methods and Materials The functional outcomes of patients treated with FBT at the base of the prostate were compared with those of patients treated with FBT at the apex. Urinary symptoms, continence, and erectile dysfunction were measured using the International Prostate Symptom Score (IPSS), International Continence Score (ICS), and International Index of Erectile Function (IIEF-5) questionnaires, respectively, at baseline and at 6, 12, and 24 months after treatment. Results Twenty-eight and 13 patients were treated with FBT at the apex and the base, respectively, of the prostate. A significant difference between groups was found in the IPSS score at 6 months (mean IPSS: apex 6.4 ± 4.7, base 10.6 ± 5.7; p = 0.02), but not at baseline or at 12 and 24 months after treatment. On multivariate analysis, only FBT at the base of the prostate remained an independent predictor of worsening urinary symptoms (odds ratio, 5.8; p = 0.04). Conclusions At 6 months after FBT, significantly less urinary toxicity was found in patients who underwent FBT at the apex versus the base of the prostate. Continence and sexual side effects were minimal in all patients.

Bio-LNG which is produced by liquefaction of synthetic natural gas from biomass (bio-SNG) is a valuable renewable fuel as it has high energy density and transportability. Cryogenic technology is a promising option for integration of the gas upgrading and liquefaction systems with the main biomass gasification and methane synthesis plant. This study investigates the feasibility of this technology for future commercial bio-SNG production plants based on indirect gasification technology, similar to that adopted by Goteborg Energi for the GoBiGas project. Simulation program Aspen Plus and pinch analysis tool Pro_PI are used to compare conventional gas cleaning and liquefaction technology and cryogenic technology. The cryogenic unit achieves the targeted product specifications and capacity, and the calculated performance is comparable to published data for commercial units. The results show that the integrated plant with cryogenic technology has a higher power requirement than the plant with conventional technology. Cryogenic technology is still under development, therefore there is a high potential for performance improvement by application of energy efficiency measures. In addition, high purity liquid CO2 is produced at very low temperature as a by-product which could generate additional revenue.

Using Dutch administrative data, we assess the work and earnings capacity of disability insurance (DI) recipients by estimating employment and earnings responses to benefit cuts. Reassessment of DI entitlement under more stringent criteria removed 14.4 percent of recipients from the program and reduced benefits by 20 percent, on average. In response, employment increased by 6.7 points and earnings rose by 18 percent. Recipients were able to increase earnings by 0.64 euro for each 1.00 euro of DI income lost. Female and younger recipients, as well as those with more subjectively defined disabilities, were able to increase earnings most. The earnings response declined as claim duration lengthened, suggesting that earnings capacity deteriorates while on DI. The deterioration was steepest for male, younger and fully disabled recipients. Working while claiming partial disability benefits appears to slow the deterioration of earnings capacity.

Resumen Objetivos Evaluar el temor previo a la administracion, dolor postinyeccion, la dificultad de manejo y el grado de satisfaccion de jeringa versus pluma de etanercept subcutaneo. Monitorizar la utilidad de la formacion proporcionada por enfermeria previa al inicio de la pluma y las preferencias de los pacientes tras haber utilizado ambos dispositivos. Metodo Estudio prospectivo de una cohorte de pacientes durante 6 meses. La recogida de datos se hizo a traves de cuestionarios. Analisis estadistico: SPSS 18.00. Se utilizaron la prueba de rangos y la de McNemar, considerandose como nivel de significacion un α = 0,05. Resultados Se incluyeron 29 sujetos, 69% mujeres, con una edad media de 52,5 ± 10,9 anos. El 48% eran artritis reumatoide, el 28% artritis psoriasica, el 21% espondilitis anquilosante y el 3% espondiloartropatia indiferenciada. Comparando el dispositivo de jeringa con el de pluma, no se encontraron diferencias estadisticamente significativas ni en el temor, ni en el dolor, ni en la dificultad de manejo del dispositivo (p = 0,469; p = 0,812 y p = 0,169 respectivamente). A los 6 meses, el 59% de los pacientes refirieron estar satisfechos o muy satisfechos con la pluma, el 93% encontraron el taller de enfermeria util o muy util y el 55% prefirieron la pluma. Conclusiones La pluma de etanercept es otra opcion de dispositivo subcutaneo para los pacientes con artritis cronica. El presente trabajo sugiere que los talleres educacionales por enfermeria previos al inicio de dicha terapia subcutanea son recomendables.

Introduction The biologics used in the management of rheumatoid arthritis (RA) in recent years have comprehensively permitted to understand their security, as shown in registries such as BIOBADASER. The present manuscript represents an observational cohort study to describe the safety perinfusional profile of those intravenous treatments. Objectives To confirm the safety profile of biological therapies in routine clinical practice, after the administration of intravenous drugs and 24 h post-administration. Material and methods We evaluated a cross-sectional cohort of 114 patients with RA (according to the American College of Rheumatology ACR criteria), attending within one month in 2009 the nursing clinics of day care hospital of 12 Catalonian hospitals. All patients were treated with intravenous biological agents. We recorded the age, sex, current and previous drug treatments. We also collected data about previous vaccination and premedication received and any adverse event occurring at the time of drug administration or within 24 h. If an adverse event occurred, it was categorized by MedDRAv11.0 International Dictionary, and categorized in terms of intensity (mild, moderate, severe), relationship to drug administration according to Karch and Lasagna algorithm (unrelated, unlikely, possible, probable, definite) and the further measures taken. Results 111 patients met the inclusion criteria, with a mean age of 56.06 years (SD: 12.12), 90 of them women (81.1%) and mean time since diagnosis of the disease of 11.97 years (SD: 7.95). 24 patients (21.6%) had a history of allergy. 12 adverse events were observed in 7 patients, 9 of which at the time of administration and 3 in 24 h after. There were no serious adverse events and only one of the adverse events (AEs) was rated as moderate (urticaria). The remaining AEs were mild.

Resumen Introduccion El uso de biologicos ha permitido conocer de manera exhaustiva su seguridad gracias a registros como BIOBADASER. El presente trabajo permite, con un estudio observacional de cohortes, describir el perfil de seguridad perinfusional de dichos tratamientos por via intravenosa. Objetivos Conocer el perfil de seguridad en la practica clinica, tras la administracion de biologicos por via intravenosa y durante las 24 h posteriores. Material y metodos Cohorte transversal de 114 pacientes con AR tratados con agentes biologicos (criterios ACR) durante un mes de 2009 por enfermeria de hospital de dia de 12 centros hospitalarios catalanes. Se analizaron la edad, el sexo, los tratamientos actuales y previos, los datos de vacunacion previa y la premedicacion. Se registro tambien cualquier acontecimiento adverso (AA) durante la administracion o en las 24 h posteriores. Se clasifico segun el diccionario internacional MedDRAv11.0 y se describieron la intensidad (leve, moderada, severa), la relacion con la administracion del farmaco segun el algoritmo de Karch y Lasagna (no relacionada, improbable, posible, probable, definitiva) y las medidas emprendidas. El analisis estadistico se realizo mediante SPSS 18.0. Resultados Ciento once con criterios de inclusion (edad media ± desviacion estandar 56,06 ± 12,12 anos), 90 mujeres (81,1%) y evolucion de 11,97 ± 7,95 anos; 24 pacientes (21,6%) con antecedentes de alergia. Se observaron 12 AA en 7 pacientes, 9 de ellos durante la administracion y 3 en las 24 h posteriores. No hubo ningun acontecimiento adverso grave y uno de los AA se califico de intensidad moderada (urticaria). El resto de los AA fueron de intensidad leve.

Epigenetic modifications have been shown to be important in developmental tumors as Ewing sarcoma. We profiled the DNA methylation status of 15 primary tumors, 7 cell lines, 10 healthy tissues and 4 human mesenchymal stem cells lines samples using the Infinium Human Methylation 450K. Differential methylation analysis between Ewing sarcoma and reference samples revealed 1166 hypermethylated and 864 hypomethylated CpG sites (Bonferroni p < 0.05, delta-beta-value with absolute difference of >0.20) corresponding to 392 and 470 genes respectively. Gene Ontology analysis of genes differentially methylated in Ewing sarcoma samples showed a significant enrichment of developmental genes. Membrane and cell signal genes were also enriched, among those, 11 were related to caveola formation. We identified differential hypermethylation of CpGs located in the body and S-Shore of the PTRF gene in Ewing sarcoma that correlated with its repressed transcriptional state. Reintroduction of PTRF/Cavin-1 in Ewing sarcoma cells revealed a role of this protein as a tumor suppressor. Restoration of caveolae in the membrane of Ewing sarcoma cells, by exogenously reintroducing PTRF, disrupts the MDM2/p53 complex, which consequently results in the activation of p53 and the induction of apoptosis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

The α4β2 nicotinic acetylcholine receptor (nAChR) is the most abundant nAChR in the brain. Here it modulates the release of a wide range of neurotransmitters, affecting a wide range of brain functions such as cognition, mood and reward.The nAChR belongs to the Cys loop family of ligand gated ion channels. It assembles as a pentameric structure of one of two stoichiometries, (α4β2)2α4 and (α4β2)2β2. These receptors respond to ACh with low and high sensitivity, respectively. The ACh binding sites are located at the α4(+)/β2(-) interfaces in the N-terminal region of the protein, which is extracellularly positioned. The (α4β2)2α4 receptor has been recently shown to house an additional functional ACh binding site at its signature α4(+)/α4(+) interface. The remaining interfaces, β2(+)/α4(-) interfaces, are thought to bind allosteric modulators, but their contribution to receptor function is not known. However, it has been speculated, on the basis of the role of equivalent interfaces in allostery in other Cys loop ligand gated ion channels such as the GABAA receptor and α3β2 nAChR) that they may house binding sites for allosteric modulators.Using fully concatenated (α4β2)2α4 nACh receptors in conjunction with functional mutagenesis and substituted cystine accesibility methods (SCAM) we have examined whether the β2(+)/α4(-) interfaces impact receptor function. Our results suggest that β2(+)/α4(-) interface in the (α4β2)2α4 nAChR receptors may be a central part of an allosteric pathway that modulates the function of the α4(+)/α4(-) interface.

Dolutegravir (S/GSK1349572) is a second-generation HIV-1 integrase inhibitor (INI) in advanced clinical development. It has shown good antiviral activity in most patients with prior raltegravir failure, although changes at the integrase codon 148, particularly when combined with other mutations, confer reduced susceptibility and may impair dolutegravir activity. Mutations believed to be associated with dolutegravir resistance at positions 92, 101, 124, 148, 153, and 193 were assessed in patients either INI-naïve or experiencing failure to raltegravir-based regimens. The integrase coding region was sequenced using an in-house nested-PCR protocol. HIV-1 subtyping was carried out using the Stanford algorithm. A total of 638 plasma samples were analyzed from 535 INI-naïve and 103 raltegravir-experienced patients. Non-B subtypes were recognized in 20.8% patients. Mutations L101I and T124A were significantly more prevalent in patients with non-B subtypes (66.9% vs. 45.7% for L101I; 61.7% vs. 25.9% for T124A; and 39.1% vs. 12.7% for L101I+T124A; p0.001 in all cases). E92Q and Q148H/R were only seen in raltegravir-experienced patients and exclusively infected with subtype B (1.9% vs. 0%, p=0.026, for E92Q and 12.6% vs. 0%, p0.001, for Q148H/R). On the contrary, T124A was more frequent in INI-naïve than raltegravir-experienced patients (35.1% vs. 24.3%, p=0.040). S153Y/F was absent in this dataset. Polymorphic changes L101I and T124A were more frequent in HIV-1 non-B than B subtypes. T124A was more frequent in INI-naïve patients but E92Q and Q148H/R were only seen in raltegravir-experienced individuals. Thus, both HIV-1 subtype and raltegravir exposure may influence the antiviral activity of dolutegravir.

This paper introduces a simple Sum-over-Paths (SoP) formulation of string edit distances accounting for all possible alignments between two sequences, and extends related previous work from bioinformatics to the case of graphs with cycles. Each alignment @?, with a total cost C(@?), is assigned a probability of occurrence P(@?)=exp[[email protected](@?)]/Z where Z is a normalization factor. Therefore, good alignments (having a low cost) are favored over bad alignments (having a high cost). The expected cost @?"@?"@?"PC(@?)exp[[email protected](@?)]/Z computed over all possible alignments @[email protected]?P defines the SoP edit distance. When @q->~, only the best alignments matter and the measure reduces to the standard edit distance. The rationale behind this definition is the following: for some applications, two sequences sharing many good alignments should be considered as more similar than two sequences having only one single good, optimal, alignment in common. In other words, sub-optimal alignments could also be taken into account. Forward/backward recurrences allowing to efficiently compute the expected cost are developed. Virtually any Viterbi-like sequence comparison algorithm computed on a lattice can be generalized in the same way; for instance, a SoP longest common subsequence is also developed. Pattern classification tasks performed on five data sets show that the new measures usually outperform the standard ones and, in any case, never perform significantly worse, at the expense of tuning the parameter @q.

Introduction Metastatic disease in soft-tissue sarcomas (STSs) lack successful treatments. Mortality rates are indeed quite high. Dinaciclib is a representative of the new CDK inhibitor class of drugs. It preferentially targets CDK1 and CDK9, involved respectively in cell cycle and transcription regulation. Data in literature shows that Dinaciclib is a good candidate for combinatorial therapies. Material and methods We analysed Dinaciclib apoptotic induction (visualised by Flow Cytometry) in a series of different STSs established cell lines. Cell lines were thus categorised as Dinaciclib-sensitive or Dinaciclib-tolerant. Differences in relevant protein expression behaviour during treatment led to hypothesis proposal for key regulators. Validation of targets was performed by siRNA technology prior to engage in drug combination testing. Drugs safety and efficiency was finally addressed by in vivo experiments. Results and discussions Relevant differences in apoptotic extent and timing among cell lines were found. Responses varied from more that 75% of cell death (72 hour treatment) in liposarcoma 402–91 to a mere 25% in leiomyosarcoma SK-LMS-1. The inhibition status of anti-apoptotic protein Bcl-xL was identified as the main determinant of the rhythm and extent of apoptotic demise. Dinaciclib-tolerant cells kept Bcl-xL active for longer times and get rid of BIM faster than sensitive cells. Both Bcl-xL knock-down and chemical Bcl-xL inhibitors (BH3-mimetics) overcame Dinaciclib tolerance and triggered complete annihilation of cell cultures (95% of cell death after 24 hour). Once safely escalated, drug combination effectiveness was tested on mice engrafted tumours. Conclusion The group of CDK inhibitors can be employed as therapeutic agents for STSs. Levels of the Bcl-2 family of proteins inform about cell proneness to trigger apoptotic cell death. This information can be used to design combination approaches involving BH3-mimetics that enhance efficiency and reduce treatment resistance.

Carcinomas are widely thought to derive from epithelial cells with malignant progression often associated with an epithelial-mesenchymal transition (EMT). We have characterized tumors generated by spontaneously transformed human mesenchymal cells (TMC) previously obtained in our laboratory. Immunohistopathological analyses identified these tumors as poorly differentiated carcinomas, suggesting that a mesenchymal-epithelial transition (MET) was involved in the generation of TMC. This was corroborated by microarray and protein expression analysis that showed that almost all mesenchymal-related genes were severely repressed in these TMC. Interestingly, TMC also expressed embryonic antigens and were able to integrate into developing blastocysts with no signs of tumor formation, suggesting a dedifferentiation process was associated with the mesenchymal stem cell (MSC) transformation. These findings support the hypothesis that some carcinomas are derived from mesenchymal rather than from epithelial precursors.

The trends in the composition of the disability insurance (DI) program show the strong increase in the incidence of mental disorders in its rolls over the past decade. In fact, the OECD reports that the share of individuals with mental health conditions represents one third of all DI claimants, a value almost 10 percentage points larger than in 2000 (OECD, 2009). Mark Duggan (2015) claims in a Testimony before the Senate Budget Committee, that it is the liberalization of the medical eligibility criteria for DI which has led to higher application rates from individuals with ”subjective” health conditions in the US. Such developments may be becoming the greatest challenge of the program for most industrialized countries, all the more given the low employment participation of the mentally ill, half that of individuals with other health condi- tions (OECD, 2009). If this is due to the strong work incapability arising from such type of conditions, DI is much needed as an earnings loss compensation for this incapability. However, if this simply points to a stronger distaste for work from the mentally ill, the distorted work incentives from DI can be easing their exit from the labor market.

The complexes [(η 5 -C 5 H 5 )Fe(CO) 2 (SCCR)] (R= t Bu, SiMe 3 ) have been obtained by reaction of [(η 5 -C 5 H 5 )Fe(CO) 2 I] and the corresponding LiSCCR. These are the first examples of mononuclear iron compounds containing alkynethiolate ligands. The crystal structure of [(η 5 -C 5 H 5 )Fe(CO) 2 (SCCSiMe 3 )] has been determined by X-ray diffraction. The role of [(η 5 -C 5 H 5 )Fe(CO) 2 (SCCSiMe 3 )] as a metalloligand in its reactions with metal carbonyls has been explored.

Introduction The incidence of thrombosis associated with pancreatic cancer chemotherapy is high (22-36%), however the incidence in BDT is unknown. Table 1 . Clinical characteristics No VTE (n = 110) VTE (n = 26) Male 61 (55.5%) 15 (57.7%) Female 49 (44.5%) 11 (42.3%) Age, years Median (range) 64.5 (36.0-85.4) 64.3 (36.7-82.5) ECOG 0-1 75 (68.2%) 18 (69.2%) ECOG ≥ 2 21 (19.1%) 4 (15.4%) Unknown 14 (12.7%) 4 (15.4%) Central venous catheter No 93 (84.5%) 19 (73.1%) Yes 11 (10.0%) 4 (15.4%) Unknown 6 (5.5%) 3 (11.5%) Previous ATE: No 99 (90%) 24 (92.3%) Yes 11 (10%) 2 (7.7%) Previous VTE: No 107 (97.3%) 25 (96.2%) Yes 3 (2.7%) 1 (3.8%) Tumor site: Gallbladder 22 (20.0%) 4 (15.4%) Intrahepatic bile duct 40 (36.4%) 13 (50%) Perihilar bile duct 23 (20.9%) 6 (23.1%) Distal extrahepatic bile duct 17 (15.4%) 1 (3.8%) Unspecified/undetermined 8 (7.3%) 2 (7.7%) Stage Localized 28 (25.5%) 5 (19.2%) Locally advanced 32 (29.1%) 6 (23.1%) Mestastatic 47 (42.7%) 15 (57.7%) Unknown 3 (2.7%) 0 Khorana: 0-1 93 (84.5%) 21 (80.8%) 2 9 (8.2%) 2 (7.7%) ≥ 3 1 (0.9%) 0 Unknown 7 (6.4%) 3 (11.5%) Aim The aim of this study is to analyze the incidence of incidental and symptomatic VTE, and its chronological pattern, in patients with BDT receiving chemotherapy in ambulatory setting. Materials and Methods We conducted a retrospective study to determine the incidence of VTE in patients with BDT, treated at 6 hospitals of the Cancer & Thrombosis Working Group of the Spanish Society of Medical Oncology (SEOM). 136 consecutive patients diagnosed and treated with chemotherapy, were identified between January 2008 and December 2012 and included in this analysis. Results Clinical characteristics in Table 1. With a median follow up of 16.6 months (range 0.4-98.2), VTE was identified in 26 patients (19.1%): 10 pulmonary embolism, 9 deep vein thrombosis and 7 visceral vein thrombosis. All VTE occurred in patients with active tumor (2 locally advanced, 24 metastatic). 46% of the events were incidentally diagnosed. 62% of the events occurred in the first 6 months after diagnosis of cancer. Eight events were identified during the diagnostic workup of the neoplasm. Only 1 patient had a VTE recurrence (superficial venous thrombosis). A non-significant trend towards lower survival (OS) in patients with VTE (median OS 20.9 months vs 13.6 months; p = 0.066) was observed. Conclusions The incidence of VTE in patients undergoing chemotherapy for BDT in the ambulatory setting is high, but lower than that described in pancreatic cancer.