A symbolic Neanderthal accumulation of large herbivore crania.

This work examines the possible behaviour of Neanderthal groups at the Cueva Des-Cubierta (central Spain) via the analysis of the latter's archaeological assemblage. Alongside evidence of Mousterian lithic industry, Level 3 of the cave infill was found to contain an assemblage of mammalian bone remains dominated by the crania of large ungulates, some associated with small hearths. The scarcity of post-cranial elements, teeth, mandibles and maxillae, along with evidence of anthropogenic modification of the crania (cut and percussion marks), indicates that the carcasses of the corresponding animals were initially processed outside the cave, and the crania were later brought inside. A second round of processing then took place, possibly related to the removal of the brain. The continued presence of crania throughout Level 3 indicates that this behaviour was recurrent during this level's formation. This behaviour seems to have no subsistence-related purpose but to be more symbolic in its intent.

Two-Step Resist Deposition of E-Beam Patterned Thick Py Nanostructures for X-ray Microscopy.

Patterned elements of permalloy (Py) with a thickness as large as 300 nm have been defined by electron beam lithography on X-ray-transparent 50 nm thick membranes in order to characterize their magnetic structure via Magnetic Transmission X-ray Microscopy (MTXM). To avoid the situation where the fragility of the membranes causes them to break during the lithography process, it has been found that the spin coating of the resist must be applied in two steps. The MTXM results show that our samples have a central domain wall, as well as other types of domain walls, if the nanostructures are wide enough.

Macrocyclization as a Source of Desired Polypharmacology. Discovery of Triple PI3K/mTOR/PIM Inhibitors.

The PI3K/AKT/mTOR and PIM kinase pathways contribute to the development of several hallmarks of cancer. Cotargeting of these pathways has exhibited promising synergistic therapeutic effects in liquid and solid tumor types. To identify molecules with combined activities, we cross-screened our collection of PI3K/(±mTOR) macrocycles (MCXs) and identified the MCX thieno[3,2-d]pyrimidine derivative 2 as a moderate dual PI3K/PIM-1 inhibitor. We report the medicinal chemistry exploration and biological characterization of a series of thieno[3,2-d]pyrimidine MCXs, which led to the discovery of IBL-302 (31), a potent, selective, and orally bioavailable triple PI3K/mTOR/PIM inhibitor. IBL-302, currently in late preclinical development (AUM302), has recently demonstrated efficacy in neuroblastoma and breast cancer xenografts. Additionally, during the course of our experiments, we observed that macrocyclization was essential to obtain the desired multitarget profile. As a matter of example, the open precursors 35-37 were inactive against PIM whereas MCX 28 displayed low nanomolar activity.

Omipalisib inspired macrocycles as dual PI3K/mTOR inhibitors.

Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway occurs frequently in a wide range of human cancers and is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells. Compounds targeting this pathway are under active development as anticancer therapeutics and some of them have reached advanced clinical trials or been approved by the FDA. Dual PI3K/mTOR inhibitors combine multiple therapeutic efficacies in a single molecule by inhibiting the pathway both upstream and downstream of AKT. Herein, we report our efforts on the exploration of novel small molecule macrocycles (MCXs) as dual PI3K/mTOR inhibitors. Macrocyclization is an attractive approach used in drug discovery, as the semi-rigid character of these structures could provide improved potency, selectivity and favorable pharmacokinetic properties. Importantly, this strategy allows access to new chemical space thus obtaining a better intellectual property position. A series of MCXs based on GSK-2126458, a known clinical PI3K/mTOR inhibitor is described. These molecules showed potent biochemical and cellular dual PI3K/mTOR inhibition, demonstrated strong antitumoral effects in human cancer cell lines, and displayed good drug-like properties. Among them, MCX 83 presented remarkable selectivity against a panel of 468 kinases, high in vitro metabolic stability, and favorable pharmacokinetic parameters without significant CYP450 and h-ERG binding inhibition. This profile qualified this compound as a suitable candidate for future in vivo PK-PD and efficacy studies in mouse cancer models.

A hierarchical architecture for recognising intentionality in mental tasks on a brain-computer interface.

A brain-computer interface (BCI), based on motor imagery EEG, uses information extracted from the electroencephalography signals generated by a person who intends to perform any action. One of the most important issues of current research is how to detect automatically whether the user intends to send some message to a certain device. This study presents a proposal, based on a hierarchical structured system, for recognising intentional and non-intentional mental tasks on a BCI system by applying machine learning techniques to the EEG signals. First-level clustering is performed to distinguish between intentional control (IC) and non-intentional control (NC) state patterns. Then, the patterns recognised as IC are passed on to a second stage where supervised learning techniques are used to classify them. In BCI applications, it is critical to correctly classify NC states with a low false positive rate (FPR) to avoid undesirable effects. According to the literature, we selected a maximum FPR of 10%. Under these conditions, our proposal achieved an average test accuracy of 66.6%, with an 8.2% FPR, for the BCI competition IIIa dataset. The main contribution of this paper is the hierarchical approach, based on machine learning paradigms, which performs intentional and non-intentional discrimination and, depending on the case, classifies the intended command selected by the user.

Predictors of Outcome Following Tenotomy in Patients with Recalcitrant Epicondylopathy.

BACKGROUND: Elbow tendinopathies are associated with tenderness, pain, and functional disability with ensuing socioeconomic costs. There is lack of consensus regarding the best treatment for patients recalcitrant to first-line conservative treatments. Percutaneous needle tenotomy is considered a regenerative approach that injures the tendon to elicit a healing response. OBJECTIVE: To investigate whether demographic characteristics, clinical factors, baseline sonographic entities, or their interactions are related to the likelihood of responding positively to needle tenotomy over a 1-year follow-up period. DESIGN: Prospective case series. SETTING: Tertiary institutional hospital. PARTICIPANTS: Patients with elbow tendinopathy for whom conservative treatments had failed and who had persistent symptoms lasting for at least 3 months. METHODS: Patients underwent needle tenotomy with or without PRP followed by a lighter needle tenotomy within a 2-week interval as part of treatment. MAIN OUTCOME MEASUREMENTS: Disabilities of the Arm, Shoulder and Hand (DASH) and Visual Analogue Scale for pain (VAS-P) scores were assessed before intervention (baseline) and at 6 weeks and 3, 6, and 12 months after intervention. A generalized linear mixed effects model was created to examine whether injectate type, clinical, demographic, or pretreatment sonographic entities or their interactions influenced clinical outcomes. RESULTS: The authors analyzed 74 elbows (71 patients). At baseline, analyzed patients (mean age: 49.48 years; 51.35% women) scored 43.30 and 5.83 on the DASH and VAS-P, respectively. Pretreatment tendon vascularization was a predictor of pain (P = .011) and DASH score changes (P = .019). The linear mixed effect model revealed that male gender and hypercholesterolemia were associated with enhanced functional recovery, (P = .020 and P < .001, respectively). Moreover, the interactions between pretreatment vascular status (P = .039), echotexture (P = .037) and enthesophytes (P = .028) influenced the temporal pattern of functional recovery after needle tenotomy. CONCLUSIONS: Baseline patient characteristics, such as gender and hypercholesterolemia, along with ultrasound features may be predictive of outcomes following needle tenotomy for elbow tendinopathy. LEVEL OF EVIDENCE: IV (NCT01945528).

Platelet-rich Plasma and Mesenchymal Stem Cells: Exciting, But are we there Yet?

Joint conditions incapacitate free movement driving to a sedentary lifestyle, a major risk factor for chronic diseases. Regenerative procedures, involving the use of mesenchymal stem/stromal cells along with platelet-rich plasma (PRP), can help patients with these conditions. We describe the main characteristics of cellular products (bone marrow concentrate, stromal vascular fraction of adipose tissue, and mesenchymal stem/stromal cells derived from these tissues), and the potential benefits of combination with PRP in 3 scenarios: PRP lysates used during laboratory cell expansion; PRP to prime cellular products or the host tissue before cell implantation; PRP used as a vehicle for cell transplantation and to provide trophic signals. Clinical studies exploring the benefits of combination products are limited to case series and few controlled studies, involving either arthroscopy or percutaneous injections. Combination products are making their way to clinics but further experimental and clinical research is needed to establish protocols and indications.

CISNE: An accurate description of dose-effect and synergism in combination therapies.

The precise determination of dose-effect curves and the combination effect of drugs is of crucial importance in the development of new therapies for the most dreadful diseases. We have found that the current implementations of the theory of Chou et al. are not accurate enough in some circumstances and might lead to erroneous predictions of synergistic or antagonistic behaviour. We have identified the source of inaccuracies and fixed it thereby improving the accuracy of those methods. Here we explain the main features of our approach and demonstrate its higher accuracy as compared to the standard methods. Therefore, this new implementation might have a huge impact in the reliability of future research on new Combination Therapies.

MicroRNA-31 Emerges as a Predictive Biomarker of Pathological Response and Outcome in Locally Advanced Rectal Cancer.

Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision has emerged as the standard treatment for locally advanced rectal cancer (LARC) patients. However, many cases do not respond to neoadjuvant CRT, suffering unnecessary toxicities and surgery delays. Thus, identification of predictive biomarkers for neoadjuvant CRT is a current clinical need. In the present study, microRNA-31 expression was measured in formalin-fixed paraffin-embedded (FFPE) biopsies from 78 patients diagnosed with LARC who were treated with neoadjuvant CRT. Then, the obtained results were correlated with clinical and pathological characteristics and outcome. High microRNA-31 (miR-31) levels were found overexpressed in 34.2% of cases. Its overexpression significantly predicted poor pathological response (p = 0.018) and worse overall survival (OS) (p = 0.008). The odds ratio for no pathological response among patients with miR-31 overexpression was 0.18 (Confidence Interval = 0.06 to 0.57; p = 0.003). Multivariate analysis corroborated the clinical impact of miR-31 in determining pathological response to neoadjuvant CRT as well as OS. Altogether, miR-31 quantification emerges as a novel valuable clinical tool to predict both pathological response and outcome in LARC patients.

MicroRNA-21 predicts response to preoperative chemoradiotherapy in locally advanced rectal cancer.

PURPOSE: The treatment of choice for locally advanced rectal cancer is preoperative chemoradiotherapy. Despite half of patients do not respond and suffer unnecessary toxicities and surgery delays, there are no biomarkers to guide preoperative CRT outcome. MicroRNA-21 has been related to acquisition of 5-fluorouracil resistance; however, its potential predictive value of response to preoperative chemoradiotherapy in locally advanced rectal cancer remains unknown. METHODS: Nighty-two patients diagnosed with locally advanced rectal cancer who were preoperatively treated with chemoradiotherapy were selected for this study. Moreover, microRNA-21 expression was quantified in formalin-fixed paraffin-embedded biopsies from this cohort, and the results obtained were correlated with clinical and molecular characteristics, pathological response, and outcome. RESULTS: MicroRNA-21 was found overexpressed in 77.6% cases, and significantly correlated with tumor grade after preoperative chemoradiotherapy (P = 0.013) and with pathological response (P = 0.013). The odds ratio of having miR-21 overexpression and not getting a respond to chemoradiotherapy resulted in 9.75 CI 2.24 to 42. Sensitivity, specificity, negative predictive values, and positive predictive value were 86.6, 60, 42.8, and 92%, respectively. Multivariate analysis confirmed the clinical significance of miR-21 determining preoperative chemoradiotherapy response. CONCLUSIONS: MicroRNA-21 expression efficiently predicts preoperative chemoradiotherapy pathological response in locally advanced rectal cancer.

Platelet-rich plasma (PRP) in chronic epicondylitis: study protocol for a randomized controlled trial.

BACKGROUND: Tendinopathy is a difficult problem to manage and can result in significant patient morbidity. Currently, the clinical use of platelet-rich plasma (PRP) in painful tendons is widespread but its efficacy remains controversial. METHODS/DESIGN: This study is a single-center, randomized double-blind controlled trial. Eighty patients will be allocated to have ultrasound (US)-guided needling combined with a leukocyte-depleted (that is, pure) PRP or lidocaine each alternate week for a total of two interventions. Outcome data will be collected before intervention, and at 6 weeks, 3, 6, and 12 months after intervention. MAIN OUTCOME MEASURE: Changes in pain and activity levels, as assessed by Disabilities of the Arm, Shoulder and Hand (DASH-E, Spanish version) score, at 6 months. We will compare the percentage of patients in each group that achieve a successful treatment defined as a reduction of at least 25% in the DASH-E score. Secondary outcome measures include changes in DASH-E at 3 and 12 months, changes in pain as assessed by the visual analogue scale (VAS) at the 6-week, 3-, 6-, and 12-month follow-up, changes in sonographic features and neovascularity, and percentage of patients in each group with adverse reactions at 3, 6, and 12 months. DISCUSSION: The results of this study will provide insights into the effect of pure PRP in tendon and may contribute to identifying the best protocol for PRP application in tendinopathies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01945528.