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MYSM1 is a chromatin‐binding protein, widely investigated for its functions in haematopoiesis in human and mouse; however, its role in haematologic malignancies remains unexplored. Here, we investigate the cross‐talk between MYSM1 and oncogenic cMYC in the transcriptional regulation of genes encoding ribosomal proteins, and the implications of these mechanisms for cMYC‐driven carcinogenesis. We demonstrate that in cMYC‐driven B cell lymphoma in mouse models, MYSM1‐loss represses ribosomal protein gene expression and protein synthesis. Importantly, the loss of MYSM1 also strongly inhibits cMYC oncogenic activity and protects against B cell lymphoma onset and progression in the mouse models. This advances the understanding of the molecular and transcriptional mechanisms of lymphomagenesis, and suggests MYSM1 as a possible drug target for cMYC‐driven malignancies. [ABSTRACT FROM AUTHOR]

This study in five large greyhound dogs implanted with a VentrAssist left ventricular assist device focused on identification of the precise site and physiological changes induced by or underlying the complication of left ventricular suction. Pressure sensors were placed in left and right atria, proximal and distal left ventricle, and proximal aorta while dual perivascular and tubing ultrasonic flow meters measured blood flow in the aortic root and pump outlet cannula. When suction occurred, end-systolic pressure gradients between proximal and distal regions of the left ventricle on the order of 40-160 mm Hg indicated an occlusive process of variable intensity in the distal ventricle. A variable negative flow difference between end systole and end diastole (0.5-3.4 L/min) was observed. This was presumably mediated by variable apposition of the free and septal walls of the ventricle at the pump inlet cannula orifice which lasted approximately 100 ms. This apposition, by inducing an end-systolic flow deficit, terminated the suction process by relieving the imbalance between pump requirement and delivery from the right ventricle. Immediately preceding this event, however, unnaturally low end-systolic pressures occurred in the left atrium and proximal left ventricle which in four dogs lasted for 80-120 ms. In one dog, however, this collapse progressed to a new level and remained at approximately −5 mm Hg across four heart beats at which point suction was relieved by manual reduction in pump speed. Because these pressures were associated with a pulmonary capillary wedge pressure of −5 mm Hg as well, they indicate total collapse of the entire pulmonary venous system, left atrium, and left ventricle which persisted until pump flow requirement was relieved by reducing pump speed. We suggest that this collapse caused the whole vascular region from pulmonary capillaries to distal left ventricle to behave as a Starling resistance which further reduced right ventricular output thus contributing to a major reduction in pump flow. We contend that similar complications of manual speed control also occur in the human subject and remain a major unsolved problem in the clinical management of patients implanted with rotary blood pumps. [ABSTRACT FROM AUTHOR]

The present study investigates the response of implantable rotary blood pump (IRBP)-assisted patients to exercise and head-up tilt (HUT), as well as the effect of alterations in the model parameter values on this response, using validated numerical models. Furthermore, we comparatively evaluate the performance of a number of previously proposed physiologically responsive controllers, including constant speed, constant flow pulsatility index (PI), constant average pressure difference between the aorta and the left atrium, constant average differential pump pressure, constant ratio between mean pump flow and pump flow pulsatility (ratioPI or linear Starling-like control), as well as constant left atrial pressure (Pla)control, with regard to their ability to increase cardiac output during exercise while maintaining circulatory stability upon HUT. Although native cardiac output increases automatically during exercise, increasing pump speed was able to further improve total cardiac output and reduce elevated filling pressures. At the same time, reduced venous return associated with upright posture was not shown to induce left ventricular (LV) suction. Although Pla control outperformed other control modes in its ability to increase cardiac output during exercise, it caused a fall in the mean arterial pressure upon HUT, which may cause postural hypotension or patient discomfort. To the contrary, maintaining constant average pressure difference between the aorta and the left atrium demonstrated superior performance in both exercise and HUT scenarios. Due to their strong dependence on the pump operating point, PI and ratioPI control performed poorly during exercise and HUT. Our simulation results also highlighted the importance of the baroreflex mechanism in determining the response of the IRBP-assisted patients to exercise and postural changes, where desensitized reflex response attenuated the percentage increase in cardiac output during exercise and substantially reduced the arterial pressure upon HUT. [ABSTRACT FROM AUTHOR]

A clinically intuitive physiologic controller is desired to improve the interaction between implantable rotary blood pumps and the cardiovascular system. This controller should restore the Starling mechanism of the heart, thus preventing overpumping and underpumping scenarios plaguing their implementation. A linear Starling-like controller for pump flow which emulated the response of the natural left ventricle (LV) to changes in preload was then derived using pump flow pulsatility as the feedback variable. The controller could also adapt the control line gradient to accommodate longer-term changes in cardiovascular parameters, most importantly LV contractility which caused flow pulsatility to move outside predefined limits. To justify the choice of flow pulsatility, four different pulsatility measures (pump flow, speed, current, and pump head pressure) were investigated as possible surrogates for LV stroke work. Simulations using a validated numerical model were used to examine the relationships between LV stroke work and these measures. All were approximately linear ( r2 (mean ± SD) = 0.989 ± 0.013, n = 30) between the limits of ventricular suction and opening of the aortic valve. After aortic valve opening, the four measures differed greatly in sensitivity to further increases in LV stroke work. Pump flow pulsatility showed more correspondence with changes in LV stroke work before and after opening of the aortic valve and was least affected by changes in the LV and right ventricular (RV) contractility, blood volume, peripheral vascular resistance, and heart rate. The system (flow pulsatility) response to primary changes in pump flow was then demonstrated to be appropriate for stable control of the circulation. As medical practitioners have an instinctive understanding of the Starling curve, which is central to the synchronization of LV and RV outputs, the intuitiveness of the proposed Starling-like controller will promote acceptance and enable rational integration into patterns of hemodynamic management. [ABSTRACT FROM AUTHOR]

Melanomas display poor response rates to adjuvant therapies because of their intrinsic resistance to proapoptotic stimuli. This study indicates that such resistance can be overcome, at least partly, through die targeting of eEFIA elongation factor with narciclasine, an Amaryllidaceae isocarbostyril controlling plant growth. Narciclasine displays IC50 growth inhibitory values between 30-100 nM in melanoma cell lines, irrespective of their levels of resistance to proapoptotic stimuli. Normal noncancerous cell lines are much less affected. At nontoxic doses, narciclasine also significantly improves (P= 0.004) the survival of mice bearing metastatic apoptosis-resistant melanoma xenografts in their brain. The eEFIA targeting with narciclasine (50 nM) leads to 1) marked actin cytoskeleton disorganization, resulting in cytokinesis impairment, and 2) protein synthesis impairment (elongation and initiation steps), whereas apoptosis is induced at higher doses only (≥200 nM). In addition to molecular docking validation and identification of potential binding sites, we biochemically confirmed that narciclasine directly binds to human recombinant and yeast-purified eEFIA in a nanomolar range, but not to actin or elongation factor 2, and that 5 nM narciclasine is sufficient to impair eEF1A-related actin bundling activity. eEFIA is thus a potential target to combat melanomas regardless of their apoptosis-sensitivity, and this finding reconciles the pleiotropic cytostatic of narciclasine. [ABSTRACT FROM AUTHOR]

The eIF2α kinase general control non-depressible 2 integrates translation initiation rates to amino acid availability. General control non-depressible 2 also regulates translation initiation during synaptic plasticity and GCN2−/− mice show improved memory compared with wild-type mice with a reduced threshold for triggering late long-term potentiation. This property suggests that inhibiting general control non-depressible 2 function might represent a therapeutic avenue for improving memory. We screened for general control non-depressible 2 inhibitors using a small library of known kinase inhibitors and ATP-analogs and identified three compounds – indirubin-3′-monoxime, SP600125 and a SyK inhibitor with activity against general control non-depressible 2. All three compounds inhibit the ability of general control non-depressible 2 to phosphorylate eIF2α in vitro as well as in vivo following UV-treatment of mouse embryonic fibroblasts. Using computer-assisted modeling, we modeled the binding of the inhibitors in the ATP-binding site of general control non-depressible 2. This work provides the molecular basis for undertaking structure–activity relationships of these compounds in order to develop specific inhibitors of general control non-depressible 2. [ABSTRACT FROM AUTHOR]

Background: Peripheral biomarkers reflecting early neurodegeneration change are critical to the development of treatments for Alzheimer's disease (AD). The most widely used indicator of AD neurodegeneration in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with neuroimaging in prodromal disease stage. Method: To identify blood‐based proteins relating to neurodegeneration ("N") in preclinical or prodromal disease stage, we used SOMAscan assay to measure 5033 proteins in two groups of healthy individuals (discovery group = 564, validation group = 497) selected from Generation Scotland cohort. We firstly performed both linear regression and protein co‐expression network to identify differentially expressed proteins and co‐expressed protein modules associated with "N" in the discovery group. We then validated such associations in the validation group. Result: Using linear regression, we identified different proteins that were significantly associated with whole brain volume, cortical volume and hippocampus volume after multiple correction, indicating that the associations between proteins and "N" were dependent on brain regions. From protein co‐expression network analysis, we identified seven modules (from 20 to 2088 proteins) in the discovery group, all of which were significantly preserved in the validation group. Furthermore, several modules were significantly associated with "N" and such associations were affected by sex and APOE genotype. Moreover, we replicated the associations between differentially expressed proteins and modules with "N" in the validation group. Conclusion: Our study is the largest we are aware of to report a plasma biomarker indicative of neurodegeneration in prodromal disease stage both in terms of the number of proteins assayed and in sample size. We identified and validated a groups of proteins in two large independent groups of healthy individuals. These proteins provide tractable targets for further mechanistic studies of neurodegeneration pathology, particularly in preclinical stages of Alzheimer's. [ABSTRACT FROM AUTHOR]

SUMMARY A simple labelling procedure using 99pertechnetate and Versene, a readily obtained chelate, has been shown to have a rapid transit time in the kidneys of the rabbit. Its application to humans must be considered due to the better count rate statistics obtained and the lower radiation dose that would be received by the kidneys. [ABSTRACT FROM AUTHOR]