Déjà vu: a reappraisal of the taphonomy of quarry VM4 of the Early Pleistocene site of Venta Micena (Baza Basin, SE Spain).

Venta Micena, an Early Pleistocene site of the Baza Basin (SE Spain), preserves a rich and diverse assemblage of large mammals. VM3, the main excavation quarry of the site, has been interpreted as a den of the giant hyaena Pachycrocuta brevirostris in the plain that surrounded the Baza palaeolake. Taphonomic analysis of VM3 has shown that the hyaenas scavenged the prey previously hunted by the hypercarnivores, transported their remains to the communal den, and consumed the skeletal parts according to their marrow contents and mineral density. In a recent paper (Luzón et al. in Sci Rep 11:13977, https://doi.org/10.1038/s41598-021-93261-1 , 2021), a small sample of remains unearthed from VM4, an excavation quarry ~ 350 m distant from VM3, is analysed. The authors indicate several differences in the taphonomic features of this assemblage with VM3, and even suggest that a different carnivore could have been the agent involved in the bone accumulation process. Here, we make a comparative analysis of both quarries and analyse more skeletal remains from VM4. Our results indicate that the assemblages are broadly similar in composition, except for slight differences in the frequency of megaherbivores, carnivores and equids according to NISP values (but not to MNI counts), the degree of bone weathering, and the intensity of bone processing by the hyaenas. Given that VM4 and VM3 were not coeval denning areas of P. brevirostris, these differences suggest that during the years when the skeletal remains were accumulated by the hyaenas at VM3, the rise of the water table of the Baza palaeolake that capped with limestone the bones was delayed compared to VM4, which resulted in their more in-depth consumption by the hyaenas.

Correction: Preoperative chemoradiotherapy for rectal cancer: the sensitizer role of the association between miR-375 and c-Myc.

[This corrects the article DOI: 10.18632/oncotarget.19393.].

The value of lncRNA FENDRR and FOXF1 as a prognostic factor for survival of lung adenocarcinoma.

It is increasingly evident that non-coding RNAs play a significant role in tumour development. However, we still have a limited knowledge of the clinical significance of long non-coding RNAs (lncRNAs) in lung cancer. The FENDRR is a long coding RNA (also named FOXF1-AS1) located in the vicinity of the protein-coding gene FOXF1 at 16q24.1 chromosomal region. The present study aimed to define the clinic pathological significance of the long-non-coding RNA FENDRR in lung adenocarcinomas. FENDRR expression measured by quantitative PCR was found significantly downregulated (p<0.001) in lung adenocarcinoma samples in comparison with their normal adjacent tissues (n=70). RNA in situ hybridization (RNA-FISH) corroborated independently the down-regulation of FENDRR. Interestingly, the expression of FENDRR correlated positively (p<0.001) with the expression of its protein-coding neighbor gene FOXF1. Additionally, FOXF1 expression was also found downregulated in adenocarcinomas compared to normal samples (p<0.001) and its expression was significantly correlated with overall survival alone (p=0.003) or in combination with FENDRR expression (p=0.01). In conclusion, our data support that FENDRR and FOXF1 expression is decreased in lung adenocarcinoma and should be considered as new potential diagnostic/prognosis biomarkers.

First-in-man randomised comparison of the Angiolite durable fluoroacrylate polymer-based sirolimus-eluting stent versus a durable fluoropolymer-based everolimus-eluting stent in patients with coronary artery disease: the ANGIOLITE trial.

AIMS: The durable fluoroacrylate polymer-based sirolimus-eluting stent (Angiolite SES) has shown promising preclinical and clinical results regarding inflammatory vascular reaction and neointimal healing. We aimed to compare performance between the Angiolite SES and an everolimus-eluting stent (EES) in patients with coronary artery disease. METHODS AND RESULTS: The ANGIOLITE trial, a prospective, randomised, multicentre trial, compared the restenosis parameters of both stents in de novo coronary lesions. The primary endpoint was late lumen loss at six-month angiographic follow-up. In-stent healing was assessed by optical coherence tomography (OCT). The main clinical endpoint was target lesion failure (TLF) evaluated up to 24 months. A total of 223 patients were randomised 1:1 to EES or SES. At six months, in-stent late lumen loss was 0.08 mm (±0.38) for EES vs 0.04 mm (±0.39) for SES (difference=-0.04 mm, 95% CI: -0.15, 0.07, p for non-inferiority=0.002). By OCT, the rate of uncovered to total number of struts score >30% was comparable between the groups whereas neointimal thickness was reduced in the SES arm (9.0% [7.6, 10.6] vs 9.9% [8.5, 11.3], p=0.41; and 86.4 [81.6, 91.2] µm vs 72.1 [68.2, 76.0] µm, p<0.01, respectively). At 24 months, TLF occurred in eight patients (7.6% [3.3, 14.5]) in the EES arm and in seven patients (7.1% [2.9, 14.0]) in the SES arm (p=0.88). The definite/probable stent thrombosis rate was comparable between the groups (1.9% [0.2, 6.7] vs 1.0% [0.0, 5.5] EES vs SES, respectively; p=0.59). CONCLUSIONS: This trial demonstrates similar antirestenotic efficacy at midterm follow-up of the Angiolite SES vs an EES. Clinical endpoints were comparable between the groups at two-year follow-up. Visual summary. Main results of the ANGIOLITE trial.

The earliest cut marks of Europe: a discussion on hominin subsistence patterns in the Orce sites (Baza basin, SE Spain).

Ancient evidence of human presence in Europe is recorded in several Early Pleistocene archaeopalaeontological sites from Spain, France and Italy. This is the case of Barranco León (BL) and Fuente Nueva-3 (FN-3), two localities placed near the town of Orce (depression of Baza and Guadix, SE Spain) and dated to ~1.4 Ma. At these sites, huge assemblages of Oldowan tools and evidence of defleshing, butchering and marrow processing of large mammal bones have been recovered together with a deciduous tooth of Homo sp. in the case of level BL-D. In this study, we: (i) describe in detail the anthropic marks found in the bone assemblages from these sites; (ii) analyse patterns of defleshment, butchery and marrow processing, based on the modifications identified in the cortical surface of the fossils; and (iii) discuss on the subsistence strategies of the first hominins that inhabited the European subcontinent during Early Pleistocene times.

Abciximab offers greater benefits to insulin-dependent diabetic patients undergoing coronary stent implantation.

INTRODUCTION AND OBJECTIVES: Abciximab use does not exceed 25% in most of the studies on diabetic patients undergoing stent implantation. The aim of this study was to evaluate whether abciximab could be more beneficial in different subgroups such as insulin-dependent (ID) patients and whether its use could provide additional benefits to those afforded by drug-eluting stents in these patients. PATIENTS AND METHODS: A total of 373 consecutive diabetics [223 non-insulin-dependent (NID) and 150 ID patients] who had undergone stent implantation were examined with a follow-up of 25.6+/-16.2 months. Abciximab was used in 21.7%. RESULTS: The abciximab-treated group had a lower rate of revascularization (26.8% vs. 15.8%. P=.02). The results by subgroups were as follows: NID nonabciximab, 23.5%; NID abciximab, 19% (P=NS); ID nonabciximab, 32.7%; ID abciximab, 12.2% (P=.05). In multivariate analysis, the restenosis predictors were insulin dependency (OR, 2.7), abciximab use (OR, 0.18), stent diameter (OR, 0.18). CONCLUSIONS: Abciximab use in diabetics with stent implantation has a favorable effect by reducing the need for new revascularization. This benefit is more evident in ID patients; the negative prognosis effect of being insulin-dependent is eliminated, and the percentage of events in this population over a long follow-up period is equal to those in NID patients.

Three new strategies to improve the accuracy of monothermal caloric screening testing.

OBJECTIVE: The objective was to find a way to estimate the value of inter-ear difference (IED) through monothermal caloric screening testing (MCST) that can be used at any laboratory, controlling and minimising the resulting error. METHODS: We retrospectively included in this study 2304 patients from our department to whom a videonystagmography with caloric testing was performed between 2003 and 2011. The IED was calculated in 3 different ways: Using the values of the 4 caloric stimulations (bithermal form) and using only the 2 same-temperature values (warm monothermal and cool monothermal forms). We studied 3 strategies to improve the accuracy of MCST: Analysis of variables that could impair the prediction, delimitation of a grey area of insufficient prediction and location of a maximum utility cut-off point. RESULTS: Correcting Jongkees' formula with the value for spontaneous nystagmus makes it possible to include subjects with spontaneous nystagmus or nystagmus inversion. Establishing 2 cut-off points to classify the subjects avoids approximately 38% of bithermal stimulations performed with a sensitivity and specificity of 95%. Maximum utility was obtained diagnosing as healthy those subjects with IED values lesser than or equal to 16% in warm MCST when the pathological IED was set as greater than 20%. CONCLUSION: New statistical tools help clinicians to make decisions that affect their patients based on the results of MCST.

Clinical and angiographic follow-up in patients with Cypher or Taxus stents in populations with high percentage of trial-excluded lesions.

BACKGROUND: Drug-eluting stents (DESs) are being used in real life in patients with complex lesions usually excluded from the published trials. It is reasonable to think that the results could be worse, and the performance may be different between DES when these complex lesions are included. METHODS AND MATERIAL: To investigate this issue, we studied our first 82 patients with DES (54 patients with Cypher (C) and 28 patients with Taxus (T) (129 lesions, with 1.57 lesions per patient). Seventy-one complex lesions were treated with C stent, 41 with T stent, and 17 with no DES. It was a high-risk population, as reflected by 64% unstable angina and 40% diabetes mellitus. Of the 112 DES complex lesions treated, 38% would have been excluded from the Sirius and Taxus IV trials. RESULTS: The main data on intra-segment angiographic measures showed a late luminal loss lower for the C stent than for the T stent (0.17+/-0.45 and 0.44+/-0.6, P=.02, respectively). The restenosis and target lesion revascularization percentages were also lower for the C stent (8.4% vs. 24.4%, P=.07 and 5.6% vs. 17.1%, P<.05, respectively). In the complex lesions without restenosis, 28% would have been excluded from the trials, while in complex lesions with restenosis, there were 53% (P=.05) (with a homogeneous percentage between the C and T groups). The predictor variables of restenosis in the 112 DES-treated complex lesions were length (P=.03, IC=0.97-1.6) and the pre-reference diameter (P=.06). CONCLUSIONS: In our experience, the C stent is superior to the T stent when treating populations with a high percentage of complex lesions excluded from the trials.

[Pulsating thoracic mass as a main symptom of gigantic pseudoaneurysm of the ascending aorta]. / Masa pulsátil torácica como síntoma principal de seudoaneurisma gigante de aorta ascendente.

The pseudoaneurysms of the ascending aorta are very infrequent but their diagnosis is important because of the associated high mortality. They usually appear in patients who have undergone aortic-related surgery, but the time that passes until they appear can be very prolonged and suspicious signs and symptoms can be quite anodyne. We present two cases of pseudoaneurysms of ascending aorta in two patients who underwent cardiovascular operations several months before, which were of such a considerable size that the first and practically the only symptoms were the sudden appearance of a pulsating thoracic mass because of pseudoaneurysm compression at this site.

[Rupture and intracoronary entrapment of an angioplasty guidewire with the X-Sizer thromboatherectomy catheter during rescue angioplasty]. / Rotura y atrapamiento intracoronario de una guía de angioplastia con el extractor de trombos X-Sizer en una angioplastia de rescate.

The X-Sizer thromboatherectomy catheter represents an important advance for thrombectomy in thrombus-containing lesions, especially in patients who require primary and rescue angioplasty. Although it is safe, some complications have been reported as its use becomes more widespread. To our knowledge, the intracoronary breakage and retention of the angioplasty guidewire has not been reported. We describe a case of this rare complication and analyze the causes, prevention and treatment alternatives.

[Giant left main coronary aneurysm without associated coronary lesions]. / Aneurisma gigante del tronco común de la arteria coronaria izquierda sin lesiones coronarias asociadas.

Left main coronary artery aneurysms are very infrequent (0.1%) and the majority are related to atherosclerotic obstructive lesions. Only a few isolated cases without associated coronary lesions have been reported until now. The management of these patients is not well established, thus both conservative and surgical treatments have been postulated. We present a case of giant left main coronary artery aneurysm with a diameter of 27.7 x 18.6 mm (the biggest reported until now) without coronary tree associated stenosis. It was treated conservatively with oral anticoagulation only and the 5 years evolution has been favourable.

[Prognostic role of systemic hypertension and diabetes mellitus in patients with unstable angina undergoing coronary stenting]. / Papel pronóstico de la hipertensión arterial y de la diabetes mellitus en los pacientes con angina inestable tratados con stents coronarios.

BACKGROUND AND OBJECTIVES: The adverse effects of systemic hypertension and diabetes mellitus in coronary patients are well known, although their long-term prognostic influence on patients with unstable angina (UA) undergoing percutaneous coronary intervention (PCI) with coronary stenting is uncertain. The aim of this study was to determine the influence of these pathologies in this population at 3-year follow-up. PATIENTS AND METHOD: We studied 279 consecutive patients with UA who underwent coronary stenting. 129 (46.2%) of them had hypertension and 60 (24.7%) had diabetes. Clinical follow-up was obtained in 92.14% after 3 years. RESULTS: Although the need for new PCI at the target lesion was higher for patients with hypertension and diabetes (12.1 vs 8.4%; p=0.31, and 14.5 vs 8.6%; p=0.16, respectively), the differences were not significant with respect to the control groups. Multivariate analysis showed hypertension (OR=4.71; CI 95%, 1.01-42.2; p=0.04) and ejection fraction (OR=0.95; CI 95%, 0.91-0.99; p=0.03) to be predictors of mortality, and diabetes to be a predictor of myocardial infarction and infarction resulting in death (OR=3.01; CI 95%, 1.13-8.02; p=0.02, and OR=2.68; CI 95%, 1.03-6.95; p=0.04, respectively). CONCLUSIONS: Hypertension was the only independent long-term predictor of mortality in our series of patients with UA who underwent coronary stenting. Diabetes was the only predictor of myocardial infarction or for the combined event of infarction and death. Risk of myocardial infarction was threefold as high in this diabetic patient population, and was the main cause of mortality.

[Nonselected use of direct coronary stenting. The DISCO 2 trial]. / Uso amplio de stenting coronaro directo. Estudio DISCO 2.

INTRODUCTION AND OBJECTIVES: Direct coronary stenting yields immediate long-term clinical results similar to those obtained with balloon predilation, with the advantage of lower costs and procedural times. Until now, direct stenting has been attempted only for selected lesions, so that the potential scope of its use in everyday practice remains unknown. The DISCO 2 trial was designed to identify the number and type of lesions that could be safely treated by direct stenting. Patients and method. 1,269 lesions (886 patients) were treated consecutively in 7 different hospitals. Direct stenting was attempted in all cases, except for total chronic occlusions, severe tortuosity or calcification of the vessel, lesions in the sinus ostium, or bifurcated lesions and vessel diameter < 2.4 mm. If the procedure failed, the stent was recovered and the lesion dilated with a balloon before a second attempt at stenting. RESULTS: Direct stenting was attempted in 585 lesions (54.9% of all electively implanted stents and 46.1% of all angioplasties). This was successful in 553 (94.6%) and failed in 32 (5.4%). In 30 of these latter patients a stent was implanted after predilation. Predictors of failure were tortuosity, location in the nonproximal right coronary artery, age > 65 years and type B2 or C lesion. After 6 months of follow-up the total incidence of major adverse cardiovascular events in patients treated with direct stenting was 6.2%, with a target lesion revascularization rate of 4.45%. CONCLUSIONS: In a mostly nonselected sample of coronary lesions, direct stenting was as safe as stenting with predilation. More than half of all elective stenting procedures can be attempted safely without balloon predilation. Greater need for predilation was associated with tortuosity, nonproximal right coronary artery location, older age and lesion complexity (B2, C). The 6-month clinical outcome was excellent, with a low rate of repeat revascularization.

Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest.

Polycomb group (PcG) proteins are key epigenetic regulators of hematopietic stem cell (HSC) fate. The PcG members Ezh2 and Ezh1 are important determinants of embryonic stem cell identity, and the transcript levels of these histone methyltransferases are inversely correlated during development. However, the role of Ezh1 in somatic stem cells is largely unknown. Here we show that Ezh1 maintains repopulating HSCs in a slow-cycling, undifferentiated state, protecting them from senescence. Ezh1 ablation induces significant loss of adult HSCs, with concomitant impairment of their self-renewal capacity due to a potent senescence response. Epigenomic and gene expression changes induced by Ezh1 deletion in senesced HSCs demonstrated that Ezh1-mediated PRC2 activity catalyzes monomethylation and dimethylation of H3K27. Deletion of Cdkn2a on the Ezh1 null background rescued HSC proliferation and survival. Our results suggest that Ezh1 is an important histone methyltransferase for HSC maintenance.

Bmi1 is critical to prevent Ikaros-mediated lymphoid priming in hematopoietic stem cells.

Preservation of hematopoietic hierarchy requires a constant and reciprocal interplay between chromatin-specific epigenetic regulators and lineage-modifying transcription factors. The polycomb member Bmi1 is a key factor in hematopoietic stem cell (HSC) maintenance, but its specific physiological role in subsequent hematopoietic lineage-specific commitments is unclear. Here, we generated conditional Bmi1 knockout (Bmi1-KO) mice. Selective ablation of Bmi1 in the hematopoietic system induced extensive upregulation of Ikaros and concomitant Ikaros-dependent lymphoid-lineage transcriptional priming, which is marked by their loss of H2A ubiquitination and increased H3K4 trimethylation in Bmi1-KO long-term HSCs (LT-HSCs). Removal of Ikaros in Bmi1-null LT-HSCs significantly diminished the hematopoietic defects seen in conditional Bmi1-KO mice. These alterations resulted in recovering the Bmi1-KO exhausted quiescent stem-cell pool, whereas the block in Bmi1-KO lymphoid-progenitor differentiation was rescued, allowing the development of mature lymphoid cells. Together, our results indicate that Ikaros is a critical Bmi1 target in vivo that prevents premature lineage specification of HSCs.

[Benign paroxysmal positional vertigo: analysis of our population and role of caloric tests]. / Vértigo posicional paroxístico benigno: análisis de nuestra población y del papel de las pruebas calóricas.

INTRODUCTION AND OBJECTIVES: Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo in those patients who seek medical care. Although videonystagmography seems the most indicated diagnostic test, we tried to decrease the requested caloric tests to optimise resources and reduce associated costs. METHODS: We developed a diagnostic-therapeutic algorithm for patients with suspected BPPV whose provocation tests are positive to evaluate the need for caloric testing. We analysed the results of its application on 98 patients who were referred to our Neuro-otology Unit over 15 months requesting videonystagmography and caloric tests. RESULTS: Only 24% of the requested tests were performed. No significant difference was found in our recurrence rate compared with other series of Spanish patients. CONCLUSIONS: Videonystagmography and caloric tests are not strictly necessary in most patients with BPPV and they should be performed only in patients whose diagnosis is unclear.

miR-33-mediated downregulation of p53 controls hematopoietic stem cell self-renewal.

Hematopoietic stem cells (HSCs) are defined by their exclusive capacity to both self-renew and to give rise to multipotent progenitors (MPPs) that in turn differentiate into the mature blood cell lineages. The tumor suppressor p53, in addition to its role in the regulation of the cell cycle, plays an important role in HSC self-renewal, although it has not fully resolved. Here we report that in super-p53 mice (sp53), which carry one extra gene dose of p53, the miR-33 is downregulated in HSCs and highly expressed in MPPs. Transplantation assays of miR-33-transduced sp53 HSC results in a significant acquisition of repopulating capacity and a decrease of recipients survival. Moreover, high levels of miR-33 represses the endogenous level of p53 protein in murine embryonic fibroblasts (MEFs), leads both to neoplastic transformation and anchorage independent growth of MEFs, and displays a decrease of apoptotic response using tumor-derived cell lines. Accordingly, we demonstrate that miR-33-mediated downregulation of p53 is dependent on the binding of miR-33 to two conserved motifs in the 3'UTR of p53. Together, these data show that the miR-33 modifies HSC repopulating efficiency of sp53 mice by impairing the p53 function. Defining the role of miR-33 in controlling the HSC self-renewal through p53 may lead to the prevention and treatment of hematopoietic disorders.