Survey for Transiting Extrasolar Planets in Stellar Systems. II. Spectrophotometry and Metallicities of Open Clusters

We present metallicity estimates for seven open clusters based on spectrophotometric indices from moderate-resolution spectroscopy. Observations of field giants of known metallicity provide a correlation between the spectroscopic indices and the metallicity of open cluster giants. We use \chi^2 analysis to fit the relation of spectrophotometric indices to metallicity in field giants. The resulting function allows an estimate of the target-cluster giants' metallicities with an error in the method of \pm0.08 dex. We derive the following metallicities for the seven open clusters: NGC 1245, [m/H]=-0.14\pm0.04; NGC 2099, [m/H]=+0.05\pm0.05; NGC 2324, [m/H]=-0.06\pm0.04; NGC 2539, [m/H]=-0.04\pm0.03; NGC 2682 (M67), [m/H]=-0.05\pm0.02; NGC 6705, [m/H]=+0.14\pm0.08; NGC 6819, [m/H]=-0.07\pm0.12. These metallicity estimates will be useful in planning future extra-solar planet transit searches since planets may form more readily in metal-rich environments.Comment: 38 pages, including 12 figures. Accepted for publication in A

Melphalan 140mg/m2 or 200mg/m2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party

Melphalan at a dose of 200mg/m2 is standard conditioning prior to autologous haematopoietic stem cell transplantation for multiple myeloma, but a dose of 140mg/m2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine if melphalan 200 and melphalan 140 are equally effective and tolerable in clinically relevant patient subgroups we analysed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, haematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 (n=245) and melphalan 200 (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 versus melphalan 140: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favoured melphalan 140 for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 and melphalan 140 patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favour melphalan 200 or melphalan 140 for key transplant outcomes (NCT01362972)

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

A disilene base adduct with a dative Si–Si single bond.

An experimental and theoretical study of the base- stabilized disilene 1 is reported, whichforms at lowtemper- atures in the disproportionation reaction of Si 2 Cl 6 or neo- Si 5 Cl 12 with equimolar amounts of NMe 2 Et. Single-crystal X- ray diffraction and quantum-chemical bonding analysis dis- close an unprecedented structure in silicon chemistry featuring adative Si!Si single bond between two silylene moieties, Me 2 EtN!SiCl 2 !Si(SiCl 3 ) 2 .The central ambiphilic SiCl 2 group is linked by dative bonds to the amine donor and the bis(trichlorosilyl)silylene acceptor,which leads to push–pull stabilization. Based on experimental and theoretical examina- tions aformation mechanism is presented that involves an autocatalytic reaction of the intermediately formed anion Si(SiCl 3 ) 3 ¢ with neo-Si 5 Cl 12 to yield 1

Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro

Osteoclast (OC) development in response to nuclear factor kappa-Β ligand (RANKL) is critical for bone homeostasis in health and in disease. The early and direct chromatin regulatory changes imparted by the BET chromatin readers Brd2-4 and OC-affiliated transcription factors (TFs) during osteoclastogenesis are not known. Here, we demonstrate that in response to RANKL, early OC development entails regulation of two alternative cell fate transcriptional programmes, OC vs macrophage, with repression of the latter following activation of the former. Both programmes are regulated in a non-redundant manner by increased chromatin binding of Brd2 at promoters and of Brd4 at enhancers/super-enhancers. Myc, the top RANKL-induced TF, regulates OC development in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TFs. These insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate pathological OC activation

Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma

Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct myeloma transcriptome profiles are primarily driven by myeloma initiating events (MIE) and converge into a mutually exclusive overexpression of the CCND1 and CCND2 oncogenes. Here, with reference to their normal counterparts, we find that myeloma PC enhanced chromatin accessibility combined with paired transcriptome profiling can classify MIE-defined genetic subgroups. Across and within different MM genetic subgroups, we ascribe regulation of genes and pathways critical for myeloma biology to unique or shared, developmentally activated or de novo formed candidate enhancers. Such enhancers co-opt recruitment of existing transcription factors, which although not transcriptionally deregulated per se, organise aberrant gene regulatory networks that help identify myeloma cell dependencies with prognostic impact. Finally, we identify and validate the critical super-enhancer that regulates ectopic expression of CCND2 in a subset of patients with MM and in chronic lymphocytic leukemia

The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma

Multiple myeloma is a malignancy of plasma cells (PC) initiated and driven by primary and secondary genetic events. Nevertheless, myeloma PC survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B cell development in both human and mouse cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma PC, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the PC lineage-defining transcription factor IRF4, and thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a non-canonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology

Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma

Understanding the biological and clinical impact ofcopy number aberrations (CNA)for the development of precision therapies in cancer remains anunmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNAconferring adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although severalgenes across chr1q portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here, with reference to the 3D chromatin structure, we integrate MMpatient multi-omics datasets with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent amongst these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional programme. Together, PBX1 and FOXM1 activate a proliferative gene signature which predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small-molecule inhibitor (T417) is selectively toxic against chr1q-amplified myeloma and solid tumour cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapystrategies in multiple myeloma and other types of cancer

The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation

VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis