Long-term Clinical Outcomes of a Spanish Cohort of Metastatic Renal Cell Carcinoma Patients with a Complete Response to Sunitinib.

INTRODUCTION: The long-term clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) and a complete response (CR) to the tyrosine kinase inhibitor (TKI) sunitinib are poorly known. The characteristics of these patients could reveal previously undetected associations with clinical variables. PATIENTS AND METHODS: This observational, retrospective study (ATILA) used data from a registry of patients with mRCC who had received first-line sunitinib and had achieved CR from 2007 to 2018 in Spain. RESULTS: Sixty-two patients with CR were included; 48 patients (77.4%) received sunitinib in monotherapy and 14 (22.6%) combined with or followed by local treatment. Median age was 58.5 years (range, 32-81). Most patients (79.0%) had clear cell histology and had undergone previous nephrectomy (90.3%). The majority (70.2%) had an intermediate IMDC prognosis, 23% favorable and 7.0% poor. The median time on treatment with sunitinib was 28.2 months (IQR, 16.7-41.0) and the median time to CR was 10.9 months (IQR, 7.2-19.3). After a median follow-up of 8 years (range, 3-13 years), the median PFS was not reached. The overall median duration of complete response was 64.1 months (IQR, 32.2-99.4). The tolerance and safety profile of sunitinib was consistent with previous reports. CONCLUSION: Durable CR to sunitinib was observed in patients regardless the prognosis group, metastasis site or histology type, with 75% of patients remaining in CR after 10 years. CLINICALTRIALS: gov: NCT03916458.

Body Contouring Using a Combination of Pulsed Ultrasound and Unipolar Radio Frequency: A Prospective Pilot Study.

OBJECTIVE: To assess the efficacy and safety of a new non-invasive body contouring device in patients with localized fat in abdomen or in abdomen and hips. Additionally, we also evaluated the patient satisfaction with the procedure. METHODS: Prospective and non-randomized open label study. The patients underwent four sessions, separated by 1 week each, with the Alma PrimeX, a non-invasive body contouring device that combines pulsed non-focus ultrasound and a Unipolar radiofrequency. The primary end point was the mean change in fat tissue thickness, assessed by diagnostic ultrasound, from baseline to 3-months after the last treatment-session. RESULTS: Fifteen subjects were evaluated. As compared to pre-treatment thickness, Hodges-Lehmann median difference (95% CI) was - 85.3 (- 107.5 to - 62.0) mm, p = 0.0001; - 70.3 (- 95.0 to - 48.5) mm, p = 0.0001; - 100.0 (- 140.5 to - 49.5) mm, p = 0.0039; and - 71.8 (- 132.5 to - 23.0) mm, p = 0.0078 in infraumbilical, supraumbilical, right hip, and left hip, respectively. Pretreatment fat volume was significantly reduced from 32.9% to 31.2%, p = 0.0006. The median (interquartile range) degree of patient satisfaction was 4.0 (1.0-5.0), with 13 (86.7%) patients being "Highly satisfied" or "Satisfied" with the treatment results. The most common adverse event was discomfort, followed by erythema. All the adverse events were mild and were successfully resolved without treatment. CONCLUSIONS: Combine therapy of a Pulsed non-focus ultrasound and Unipolar radiofrequency using the non-invasive device Alma PrimeX was an effective and safe treatment for reducing fat tissue thickness in abdomen and hips in patients with localized fat. Patients' satisfaction with the procedure was high. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Multiple roles of Pol epsilon in eukaryotic chromosome replication.

Pol epsilon is a tetrameric assembly that plays distinct roles during eukaryotic chromosome replication. It catalyses leading strand DNA synthesis; yet this function is dispensable for viability. Its non-catalytic domains instead play an essential role in the assembly of the active replicative helicase and origin activation, while non-essential histone-fold subunits serve a critical function in parental histone redeposition onto newly synthesised DNA. Furthermore, Pol epsilon plays a structural role in linking the RFC-Ctf18 clamp loader to the replisome, supporting processive DNA synthesis, DNA damage response signalling as well as sister chromatid cohesion. In this minireview, we discuss recent biochemical and structural work that begins to explain various aspects of eukaryotic chromosome replication, with a focus on the multiple roles of Pol epsilon in this process.

Clinical Factors Associated With Long-Term Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Axitinib: Real-World AXILONG Study.

BACKGROUND: Axitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified. PATIENTS AND METHODS: Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months vs. disease progression/refractory patients [RP]). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed. RESULTS: In total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 vs. 26.5 months; P = .009). In LR vs. RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 vs. 10.9 months P < .001). The safety profile was manageable and consistent with known data. CONCLUSIONS: This study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib.

The dawn of the Middle Paleolithic in Atapuerca: the lithic assemblage of TD10.1 from Gran Dolina.

The Atapuerca localities present evidence of a long series of hominin occupations from the Early Pleistocene onward and are a key site for understanding the continuity and discontinuity of Western European technological and settlement dynamics. The TD10 unit from Gran Dolina is located in the upper part of the sequence and divided into four lithostratigraphic subunits (TD10.4 to TD10.1, from bottom to top) dated between ca. 450 ka and ca. 250 ka (Marine Isotope Stage 11 to Marine Isotope Stage 8). The technological analysis of the lithic assemblages belonging to the TD10.1 sequence aims to determine the trends among its archeological levels and check its relation to late Middle Pleistocene technological evolution and site functionality. Archeostratigraphic studies have identified several occupation events within its approximately 1.5 m of thickness, whose artifact densities and occupational models differ. However, no remarkable technical differences have been observed among them. Lithic assemblages from those events show more evolved features than other Atapuerca Mode 2 assemblages. These changes are reflected in the selective raw material management strategies; more hierarchized and predetermined reduction methods; and the progressive decrease of large cutting tools in the lithic assemblages with respect to flake tools, the latter defined by a greater typological diversification. These technological changes did not lead to a clear break with respect to previous technological models and were accompanied by other sporadic but significant changes in subsistence and behavioral strategies (bone tools and retouchers; lithic recycling, and so on), which were consolidated during the Middle Paleolithic. Hence, the archeological record from the TD10.1 subunit of Gran Dolina reflects a local stratigraphic transition from Mode 2 to Mode 3 technocomplexes, paralleling that observed in other sites in southwestern Europe.

Is type of work associated with physical activity and sedentary behaviour in women with fibromyalgia? A cross-sectional study from the al-Ándalus project.

OBJECTIVES: To analyse the association between the type of work (productive vs reproductive work) and the levels of physical activity and sedentary behaviour in women with fibromyalgia. METHOD: This cross-sectional study involved 258 women with fibromyalgia from southern Spain. Of them, 55% performed reproductive work (unpaid, associated with caregiving and domestic roles) exclusively, while 45% had productive job (remunerated, that results in goods or services). Physical activity of light, moderate and vigorous intensity in the leisure time, at home, at work, and totally were measured through the leisure time physical activity instrument and with the physical activity at home and work instrument, respectively. Sedentary behaviour was measured by the Sedentary Behaviour Questionnaire. RESULTS: After adjusting for age, fat percentage, education level and marital status, the multivariate analysis of covariance model informed the existence of significant differences between type of work groups (p<0.001). Women with productive work engaged in more light physical activity at work (mean difference =448.52 min; 95 % CI 179.66 to 717.38; p=0.001), and total physical activity of light (809.72 min; 535.91 to 1085.53; p<0.001) and moderate (299.78 min; 97.31 to 502.25; p=0.004) intensity. Women with reproductive work engaged in more light physical activity at home (379.14; 175.64 to 582.64; p<0.001). Leisure time physical activity and sedentary behaviour were similar in both groups (p>0.05 for all comparisons). CONCLUSIONS: Women with productive work had greater levels of physical activity compared with those who only did reproductive work, except for physical activity at home. Having productive work might facilitate movement of women with fibromyalgia towards a more active lifestyle.

Transcription factor dimerization activates the p300 acetyltransferase.

The transcriptional co-activator p300 is a histone acetyltransferase (HAT) that is typically recruited to transcriptional enhancers and regulates gene expression by acetylating chromatin. Here we show that the activation of p300 directly depends on the activation and oligomerization status of transcription factor ligands. Using two model transcription factors, IRF3 and STAT1, we demonstrate that transcription factor dimerization enables the trans-autoacetylation of p300 in a highly conserved and intrinsically disordered autoinhibitory lysine-rich loop, resulting in p300 activation. We describe a crystal structure of p300 in which the autoinhibitory loop invades the active site of a neighbouring HAT domain, revealing a snapshot of a trans-autoacetylation reaction intermediate. Substrate access to the active site involves the rearrangement of an autoinhibitory RING domain. Our data explain how cellular signalling and the activation and dimerization of transcription factors control the activation of p300, and therefore explain why gene transcription is associated with chromatin acetylation.

Gemcitabine-erlotinib versus gemcitabine-erlotinib-capecitabine in the first-line treatment of patients with metastatic pancreatic cancer: Efficacy and safety results of a phase IIb randomised study from the Spanish TTD Collaborative Group.

BACKGROUND: Gemcitabine and erlotinib have shown a survival benefit in the first-line setting in metastatic pancreatic cancer (mPC). The aim of this study was to assess whether combining capecitabine (C) with gemcitabine + erlotinib (GE) was safe and effective versus GE in patients with mPC. PATIENTS AND METHODS: Previously untreated mPC patients were randomised to receive G (1000 mg/m2, days 1, 8, 15) + E (100 mg/day, days 1-28) + C (1660 mg/m2, days 1-21) or GE, q4 weeks, until progression or unacceptable toxicity. Primary end-point: progression-free survival (PFS); secondary end-points: overall survival (OS), response rate, relationship of rash with PFS/OS and safety. RESULTS: 120 patients were randomised, median age 63 years, ECOG status 0/1/2 33%/58%/8%; median follow-up 16.5 months. Median PFS in the gemcitabine-erlotinib-capecitabine (GEC) and GE arms was 4.3 and 3.8 months, respectively (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.58-1.31; p = 0.52). Median OS in the GEC and GE arms was 6.8 and 7.7 months, respectively (HR: 1.09, 95% CI: 0.72-1.63; p = 0.69). Grade 3/4 neutropenia (GEC 43% versus GE 15%; p = 0.0008) and mucositis (GEC 9% versus GE 0%; p = 0.03) were the only statistically significant differences in grade 3/4 adverse events. PFS and OS were significantly longer in patients with rash (grade ≥1) versus no rash (grade = 0): PFS 5.5 versus 2.0 months (HR = 0.39, 95% CI: 0.26-0.6; p < 0.0001) and OS: 9.5 versus 4.0 months (HR = 0.51, 95% CI: 0.33-0.77; p = 0.0014). CONCLUSION: PFS with GEC was not significantly different to that with GE in patients with mPC. Skin rash strongly predicted erlotinib efficacy. The study was registered with ClinicalTrials.gov: NCT01303029.

Structure of p300 in complex with acyl-CoA variants.

Histone acetylation plays an important role in transcriptional activation. Histones are also modified by chemically diverse acylations that are frequently deposited by p300, a transcriptional coactivator that uses a number of different acyl-CoA cofactors. Here we report that while p300 is a robust acetylase, its activity gets weaker with increasing acyl-CoA chain length. Crystal structures of p300 in complex with propionyl-, crotonyl-, or butyryl-CoA show that the aliphatic portions of these cofactors are bound in the lysine substrate-binding tunnel in a conformation that is incompatible with substrate transfer. Lysine substrate binding is predicted to remodel the acyl-CoA ligands into a conformation compatible with acyl-chain transfer. This remodeling requires that the aliphatic portion of acyl-CoA be accommodated in a hydrophobic pocket in the enzymes active site. The size of the pocket and its aliphatic nature exclude long-chain and charged acyl-CoA variants, presumably explaining the cofactor preference for p300.

Cytomegalovirus encephalitis in a hemodialysis patient: a rare association.

Haemodialysis patients are at greater risk of infections than individuals not on dialysis due to their immunosuppressive state caused by several factors (uraemia, vascular access, inflammation, malnutrition). However, infections affecting the central nervous system are not frequent in this population. We present the case of a 77-year-old man with end-stage renal disease who was admitted to the emergency department for a decreased level of consciousness and fever. Although the initial clinical suspicion oriented to a urinary infection, the lack of improvement forced us to perform a lumbar puncture. Five days after cerebrospinal fluid was cultured, cytomegalovirus was isolated and ganciclovir initiated.

Dialysis catheter related bacteriemia by Gordonia rubropertincta and Sputi in two hemodialysis patients / Bacteriemia relacionada por Gordonia rubropertincta y Sputi en 2 pacientes en hemodiálisis

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Sorting signals for PIN1 trafficking and localization.

PIN-FORMED (PIN) family proteins direct polar auxin transport based on their asymmetric (polar) localization at the plasma membrane. In the case of PIN1, it mainly localizes to the basal (rootward) plasma membrane domain of stele cells in root meristems. Vesicular trafficking events, such as clathrin-dependent PIN1 endocytosis and polar recycling, are probably the main determinants for PIN1 polar localization. However, very little is known about the signals which may be involved in binding the µ-adaptin subunit of clathrin adaptor complexes (APs) for sorting of PIN1 within clathrin-coated vesicles, which can determine its trafficking and localization. We have performed a systematic mutagenesis analysis to investigate putative sorting motifs in the hydrophilic loop of PIN1. We have found that a non-canonical motif, based in a phenylalanine residue, through the binding of µA(µ2)- and µD(µ3)-adaptin, is important for PIN1 endocytosis and for PIN1 traffcking along the secretory pathway, respectively. In addition, tyrosine-based motifs, which also bind different µ-adaptins, could also contribute to PIN1 trafficking and localization.

The Structure of the Plakin Domain of Plectin Reveals an Extended Rod-like Shape.

Plakins are large multi-domain proteins that interconnect cytoskeletal structures. Plectin is a prototypical plakin that tethers intermediate filaments to membrane-associated complexes. Most plakins contain a plakin domain formed by up to nine spectrin repeats (SR1-SR9) and an SH3 domain. The plakin domains of plectin and other plakins harbor binding sites for junctional proteins. We have combined x-ray crystallography with small angle x-ray scattering (SAXS) to elucidate the structure of the plakin domain of plectin, extending our previous analysis of the SR1 to SR5 region. Two crystal structures of the SR5-SR6 region allowed us to characterize its uniquely wide inter-repeat conformational variability. We also report the crystal structures of the SR7-SR8 region, refined to 1.8 Å, and the SR7-SR9 at lower resolution. The SR7-SR9 region, which is conserved in all other plakin domains, forms a rigid segment stabilized by uniquely extensive inter-repeat contacts mediated by unusually long helices in SR8 and SR9. Using SAXS we show that in solution the SR3-SR6 and SR7-SR9 regions are rod-like segments and that SR3-SR9 of plectin has an extended shape with a small central kink. Other plakins, such as bullous pemphigoid antigen 1 and microtubule and actin cross-linking factor 1, are likely to have similar extended plakin domains. In contrast, desmoplakin has a two-segment structure with a central flexible hinge. The continuous versus segmented structures of the plakin domains of plectin and desmoplakin give insight into how different plakins might respond to tension and transmit mechanical signals.

Sorting Motifs Involved in the Trafficking and Localization of the PIN1 Auxin Efflux Carrier.

In contrast with the wealth of recent reports about the function of µ-adaptins and clathrin adaptor protein (AP) complexes, there is very little information about the motifs that determine the sorting of membrane proteins within clathrin-coated vesicles in plants. Here, we investigated putative sorting signals in the large cytosolic loop of the Arabidopsis (Arabidopsis thaliana) PIN-FORMED1 (PIN1) auxin transporter, which are involved in binding µ-adaptins and thus in PIN1 trafficking and localization. We found that Phe-165 and Tyr-280, Tyr-328, and Tyr-394 are involved in the binding of different µ-adaptins in vitro. However, only Phe-165, which binds µA(µ2)- and µD(µ3)-adaptin, was found to be essential for PIN1 trafficking and localization in vivo. The PIN1:GFP-F165A mutant showed reduced endocytosis but also localized to intracellular structures containing several layers of membranes and endoplasmic reticulum (ER) markers, suggesting that they correspond to ER or ER-derived membranes. While PIN1:GFP localized normally in a µA (µ2)-adaptin mutant, it accumulated in big intracellular structures containing LysoTracker in a µD (µ3)-adaptin mutant, consistent with previous results obtained with mutants of other subunits of the AP-3 complex. Our data suggest that Phe-165, through the binding of µA (µ2)- and µD (µ3)-adaptin, is important for PIN1 endocytosis and for PIN1 trafficking along the secretory pathway, respectively.

Impact on clinical practice of the implementation of guidelines for the toxicity management of targeted therapies in kidney cancer. The protect-2 study.

BACKGROUND: The impact of such recommendations after their implementation of guidelines has not usually been evaluated. Herein, we assessed the impact and compliance with the Spanish Oncology Genitourinary Group (SOGUG) Guidelines for toxicity management of targeted therapies in metastatic renal cell carcinoma (mRCC) in daily clinical practice. METHODS: Data on 407 mRCC patients who initiated first-line targeted therapy during the year before and the year after publication and implementation of the SOGUG guideline program were available from 34 Spanish Hospitals. Adherence to SOGUG Guidelines was assessed in every cycle. RESULTS: Adverse event (AE) management was consistent with the Guidelines as a whole for 28.7% out of 966 post-implementation cycles compared with 23.1% out of 892 pre-implementation cycles (p = 0.006). Analysis of adherence by AE in non-compliant cycles showed significant changes in appropriate management of hypertension (33% pre-implementation vs. 44.5% post-implementation cycles; p < 0.0001), diarrhea (74.0% vs. 80.5%; p = 0.011) and dyslipemia (25.0% vs. 44.6%; p < 0.001). CONCLUSIONS: Slight but significant improvements in AE management were detected following the implementation of SOGUG recommendations. However, room for improvement in the management of AEs due to targeted agents still remains and could be the focus for further programs in this direction.

Purification and Structural Analysis of Plectin and BPAG1e.

Plectin and BPAG1e belong to the plakin family of high-molecular-weight proteins that interconnect the cytoskeletal systems and anchor them to junctional complexes. Plectin and BPAG1e are prototypical plakins with a similar tripartite modular structure. The N- and C-terminal regions are built of multiple discrete structural domains, while the central rod domain mediates dimerization by coiled-coil interactions. Owing to the mosaic organization of plakins, the structure of their constituent individual domains or small multi-domain segments can be analyzed isolated. Yet, understanding the integrated function of large regions, oligomers, and heterocomplexes of plakins is difficult due to the large and segmented structure. Here, we describe methods for the production of plectin and BPAG1e samples suitable for structural and biophysical analysis. In addition, we discuss the combination of hybrid methods that yield information at several resolution levels to study the complex, multi-domain, and flexible structure of plakins.

[Population-based studies on alcohol-related harm in Spain]. / Estudios poblacionales en España sobre daños relacionados con el consumo de alcohol.

Based on the review of scientific papers and institutional reports on the subject and analysis of some secondary data, we assess the alcohol-related harm in Spain between 1990 and 2011. In 2011 they could be attributable to alcohol, 10% of the total mortality of the population aged 15-64, and about 30% of deaths due to traffic accidents. Among the population aged 15-64 years at least 0.8% had alcohol use disorders, an additional 5% could have harmful alcohol consumption that would need clinical evaluation, and about 20% had had some acute alcohol intoxication (AAI) in the last year. The AAI accounted for approximately 0.5-1.1 % of hospital emergency visits. Social costs of alcohol could represent 1% of gross domestic product. The prevalence of alcohol-related harm was significantly higher in men than women, with a male/female ratio greater than three for alcohol-related mortality and serious injuries, and this situation has hardly changed in the last 20 years. Alcohol-related harm has followed a downward trend, except for AAI. In 1990-2011 the standardized mortality rates related to alcohol decreased by half. Large gaps in knowledge and uncertainties on alcohol-related harm in Spanish population, clearly justify the institutional support for the research in this field and the implementation of a comprehensive monitoring system.

Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation.

CBP and p300 are histone acetyltransferases (HATs) that associate with and acetylate transcriptional regulators and chromatin. Mutations in their catalytic 'cores' are linked to genetic disorders, including cancer. Here we present the 2.8-Å crystal structure of the catalytic core of human p300 containing its bromodomain, CH2 region and HAT domain. The structure reveals that the CH2 region contains a discontinuous PHD domain interrupted by a RING domain. The bromodomain, PHD, RING and HAT domains adopt an assembled configuration with the RING domain positioned over the HAT substrate-binding pocket. Disease mutations that disrupt RING attachment led to upregulation of HAT activity, thus revealing an inhibitory role for this domain. The structure provides a starting point for understanding how chromatin-substrate targeting and HAT regulation are coupled and why mutations in the p300 core lead to dysregulation.