A REAPPRAISAL OF LOWER TO MIDDLE PALAEOLITHIC BONE RETOUCHERS FROM SOUTHEASTERN FRANCE (MIS 11 TO 3)

International audienceIn southeastern France, many Final Acheulean/Early Middle Palaeolithic and Middle Palaeolithic assemblages have yielded bone retouchers. The oldest are dated to the Middle Pleistocene: from MIS 11 at Terra Amata; MIS 9 at Orgnac 3; and MIS 6-7 at Payre F, Sainte-Anne I and Le Lazaret. However, this early evidence of bone tool use only concerns a few dozen pieces among thousands of faunal and lithic remains. These re-touchers indicate behavioural changes from MIS 11-9 onwards in southeastern France, associated with a mosaic of technological and subsistence changes that became more common during the Middle Palaeolithic. The frequency of these bone artefacts increases during MIS 7, becoming much more numerous after MIS 5, sometimes totaling more than a hundred items at one site, such as Saint-Marcel Cave. Bone retoucher frequency is still highly variable throughout the Middle Palaeolithic and seems to be determined by the type of occupation and activities rather than the associated lithic technologies. This broad, regional comparative analysis contributes to a better understanding of the technical behaviour developed by Neanderthals, as well as their Middle Pleistocene ancestors, and their ability to recover and use bones

Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity

The circadian clock regulator Bmal1 modulates tumorigenesis, but its reported effects are inconsistent. Here, we show that Bmal1 has a context-dependent role in mouse melanoma tumor growth. Loss of Bmal1 in YUMM2.1 or B16-F10 melanoma cells eliminates clock function and diminishes hypoxic gene expression and tumorigenesis, which could be rescued by ectopic expression of HIF1α in YUMM2.1 cells. By contrast, over-expressed wild-type or a transcriptionally inactive mutant Bmal1 non-canonically sequester myosin heavy chain 9 (Myh9) to increase MRTF-SRF activity and AP-1 transcriptional signature, and shift YUMM2.1 cells from a Sox10to a Sox9immune resistant, mesenchymal cell state that is found in human melanomas. Our work describes a link between Bmal1, Myh9, mouse melanoma cell plasticity, and tumor immunity. This connection may underlie cancer therapeutic resistance and underpin the link between the circadian clock, MRTF-SRF and the cytoskeleton

Head to head comparison of 2D vs real time 3D dipyridamole stress echocardiography

Real-time three-dimensional (RT-3D) echocardiography has entered the clinical practice but true incremental value over standard two-dimensional echocardiography (2D) remains uncertain when applied to stress echo. The aim of the present study is to establish the additional value of RT-3D stress echo over standard 2D stress echocardiography. We evaluated 23 consecutive patients (age = 65 ± 10 years, 16 men) referred for dipyridamole stress echocardiography with Sonos 7500 (Philips Medical Systems, Palo, Alto, CA) equipped with a phased – array 1.6–2.5 MHz probe with second harmonic capability for 2D imaging and a 2–4 MHz matrix-phased array transducer producing 60 × 70 volumetric pyramidal data containing the entire left ventricle for RT-3D imaging. In all patients, images were digitally stored in 2D and 3D for baseline and peak stress with a delay between acquisitions of less than 60 seconds. Wall motion analysis was interpreted on-line for 2D and off-line for RT-3D by joint reading of two expert stress ecocardiographist. Segmental image quality was scored from 1 = excellent to 5 = uninterpretable. Interpretable images were obtained in all patients. Acquisition time for 2D images was 67 ± 21 sec vs 40 ± 22 sec for RT-3D (p = 0.5). Wall motion analysis time was 2.8 ± 0.5 min for 2D and 13 ± 7 min for 3D (p = 0.0001). Segmental image quality score was 1.4 ± 0.5 for 2D and 2.6 ± 0.7 for 3D (p = 0.0001). Positive test results was found in 5/23 patients. 2D and RT-3D were in agreement in 3 out of these 5 positive exams. Overall stress result (positive vs negative) concordance was 91% (Kappa = 0.80) between 2D and RT-3D. During dipyridamole stress echocardiography RT-3D imaging is highly feasible and shows a high concordance rate with standard 2D stress echo. 2D images take longer time to acquire and RT-3D is more time-consuming to analyze. At present, there is no clear clinical advantage justifying routine RT-3D stress echocardiography use

A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas

Pheochromocytomas are neural crest–derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1α. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1α activity in tumors

Head to head comparison of 2D vs real time 3D dipyridamole stress echocardiography

Abstract Real-time three-dimensional (RT-3D) echocardiography has entered the clinical practice but true incremental value over standard two-dimensional echocardiography (2D) remains uncertain when applied to stress echo. The aim of the present study is to establish the additional value of RT-3D stress echo over standard 2D stress echocardiography. We evaluated 23 consecutive patients (age = 65 ± 10 years, 16 men) referred for dipyridamole stress echocardiography with Sonos 7500 (Philips Medical Systems, Palo, Alto, CA) equipped with a phased – array 1.6–2.5 MHz probe with second harmonic capability for 2D imaging and a 2–4 MHz matrix-phased array transducer producing 60 × 70 volumetric pyramidal data containing the entire left ventricle for RT-3D imaging. In all patients, images were digitally stored in 2D and 3D for baseline and peak stress with a delay between acquisitions of less than 60 seconds. Wall motion analysis was interpreted on-line for 2D and off-line for RT-3D by joint reading of two expert stress ecocardiographist. Segmental image quality was scored from 1 = excellent to 5 = uninterpretable. Interpretable images were obtained in all patients. Acquisition time for 2D images was 67 ± 21 sec vs 40 ± 22 sec for RT-3D (p = 0.5). Wall motion analysis time was 2.8 ± 0.5 min for 2D and 13 ± 7 min for 3D (p = 0.0001). Segmental image quality score was 1.4 ± 0.5 for 2D and 2.6 ± 0.7 for 3D (p = 0.0001). Positive test results was found in 5/23 patients. 2D and RT-3D were in agreement in 3 out of these 5 positive exams. Overall stress result (positive vs negative) concordance was 91% (Kappa = 0.80) between 2D and RT-3D. During dipyridamole stress echocardiography RT-3D imaging is highly feasible and shows a high concordance rate with standard 2D stress echo. 2D images take longer time to acquire and RT-3D is more time-consuming to analyze. At present, there is no clear clinical advantage justifying routine RT-3D stress echocardiography use.</p