Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.     

The spatial relationship between neurons and astrocytes in HIV-associated dementia

Specific neuronal spatial distributional patterns have previously been correlated with increasing severity of HIV-associated dementia (HAD). As astrocytes are also a putative site of neurotoxicity, we investigated the spatial relationships of astrocytes with pyramidal and interneurons in the superior frontal gyrus from 29 patients who died from acquired immunodeficiency syndrome. Frontal cortical brain tissue was taken from diseased HIV patients who had been assessed for the presence and severity of HAD using the Memorial Sloan-Kettering Scale. No correlation was found between neuronal density and severity of dementia. However, the pattern of astrocytes became more clustered as dementia progressed. Bivariate spatial pattern analysis of neuronal populations with astrocytes revealed that, with increasing dementia severity, astrocytes and large pyramidal neurons increasingly “repelled” each other, while astrocytes and interneurons evidenced increasing “attraction.” This implies that astrocytes may be more likely to be situated in the vicinity of surviving interneurons but less likely to be situated near surviving large pyramidal neurons in the setting of progressing HAD.     

Altered immune function associated with disordered neural connectivity and executive dysfunctions: A neurophysiological study on children with autism spectrum disorders

Previous studies have shown that children with autism spectrum disorders (ASDs) have impaired executive function, disordered neural connectivity, and abnormal immunologic function. The present study examined whether these abnormalities were associated. Seventeen high-functioning (HFA) and 17 low-functioning (LFA) children with ASD, aged 8–17 years, participated voluntarily in the study. The two groups of children were compared on their general intelligence in terms of IQ; executive function as measured by the Hong Kong List Learning Test, D2 Test of Concentration, Five Point Test, Children's Color Trail Test, Tower of California Test, and Go/No-Go task; a non-executive task as measured by the Picture Completion Task; neural connectivity as measured by theta coherence in the anterior and posterior regions; and immunologic function as measured by the level of circulating CD3+ CD8+ suppressor/cytotoxic T lymphocytes in a blood sample. Results on executive function showed that LFA children performed significantly poorer than HFA children as shown on their lower Executive Composite as well as individual executive function scores. However, there was no group difference on the Picture Completion Task. Results on neural connectivity showed that LFA children demonstrated a different pattern of electroencephalography (EEG) coherence from HFA children as shown in the significantly elevated theta coherence in the anterior network, as well as at the left intra-hemispheric (LA-LP) and right-to-left inter-hemisphere (RA-LP) connections of LFA children. In immunologic function, results showed that LFA children had significantly elevated level of suppressor/cytotoxic T lymphocytes (CD3+ CD8+) (p < 0.05). In addition, the executive dysfunction, disordered neural connectivity, and abnormal immunologic function were found to be associated. These results provided some initial evidence to support the notion that immunologic factors are associated with neuronal damage, measureable by EEG coherence and manifested as executive dysfunctions.     

Identification of rare copy number variants in high burden schizophrenia families

Over the last years, genome‐wide studies consistently showed an increased burden of rare copy number variants (CNVs) in schizophrenia patients, supporting the “common disease, rare variant” hypothesis in at least a subset of patients. We hypothesize that in families with a high burden of disease, and thus probably a high genetic load influencing disease susceptibility, rare CNVs might be involved in the etiology of schizophrenia. We performed a genome‐wide CNV analysis in the index patients of eight families with multiple schizophrenia affected members, and consecutively performed a detailed family analysis for the most relevant CNVs. One index patient showed a DRD5 containing duplication. A second index patient presented with an NRXN1 containing deletion and two adjacent duplications containing MYT1L and SNTG2. Detailed analysis in the subsequent families showed segregation of the identified CNVs. With this study we show the importance of screening high burden families for rare CNVs, which will not only broaden our knowledge concerning the molecular genetic mechanisms involved in schizophrenia but also allow the use of the obtained genetic data to provide better clinical care to these families in general and to non‐symptomatic causal CNV carriers in particular. © 2013 Wiley Periodicals, Inc.     

Left ventricular assist device-associated infections

The left ventricular assist device (LVAD) is a mechanical pump that supplements or replaces the function of a damaged left ventricle. Although LVAD support is associated with improved survival and quality of life, infectious complications remain a major limitation. The authors examine the epidemiology of LVAD-associated infections and review current diagnostic, treatment, and management strategies. Novel evidence-based approaches to infection prevention remain critical because the number of patients receiving long-term mechanical support continues to burgeon.     

Access to the next wave of biologic therapies (Abatacept and Tocilizumab) for the treatment of rheumatoid arthritis in England and Wales

Patients in England and Wales with rheumatoid arthritis (RA) receive treatment from the National Health Service (NHS) with therapies approved by the European Medicines Agency (EMA), under guidance from the National Institute for Health and Clinical Excellence (NICE). This document overviews the current NICE guidelines for the treatment of RA and identifies scenarios when such guidance may not represent the optimum management strategy for individual patients. Specifically, we consider the use of tocilizumab or abatacept as the most appropriate treatments for some patients. In such scenarios, it may be possible for the clinician to secure access to the required therapy through an application procedure known as an 'individual funding request', the process of which is described in detail here. At present, it is unclear the extent to which the proposed reform of the NHS will affect the role of NICE in providing guidance and setting standards of care. Until the full impact of the proposed changes are realized, individual funding requests will remain a valuable way of securing the optimal treatment for all patients suffering from RA.