Chromosomal instability is a defining feature of clonal myeloma plasma cells that results in the perpetual accumulation of genomic aberrations. In addition to its role in protein homeostasis, the ubiquitinproteasome system is also involved in the regulation of DNA damage-repair proteins. In the present study, we show that proteasome inhibition induces a "BRCAness" state in myeloma cells (MM), with depletion of their nuclear pool of ubiquitin and abrogation of H2AX polyubiquitylation, an essential step for the recruit- IntroductionGenomic integrity is continuously challenged by both exogenous and endogenous stressors. 1 To counteract DNA damage, cells have evolved repair mechanisms specific for many types of lesions. [2][3][4][5][6] Single-strand DNA breaks (SSBs) are repaired through the nucleotide excision repair or the base excision repair machinery, which require the activation of poly-ADP-ribose polymerase (PARP). PARP1, and to a lesser extent PARP2, bind DNA SSBs and catalyze the synthesis and addition of large chains of poly-ADP-ribose (PAR) polymers on target proteins, including the histones H1 and H2B and PARP1 itself. These polymers serve to recruit variable proteins needed to activate DNA-damage repair (DDR). [7][8][9] If persistent or left unrepaired, SSBs encountered by replication forks lead to the formation of potentially lethal double-strand DNA breaks (DSBs). These genomic DSBs encountered in the S/G 2 phases are predominantly repaired by the homologous recombination (HR) pathway, in which the MRN (MRE11-RAD50-NBS1) complex senses the DSBs and initiates a dynamic protein recruitment to DNA-repair foci. 10,11 MRN first recruits the ATM kinase to the vicinity of the lesions, with resulting ATM-mediated phosphorylation of the histone variant H2AX that leads to the accumulation of the MDC1 protein and its binding partners. These include the MRN complex and RNF8 and RNF168, 2 ubiquitin ligases that initiate histone H2AX Lys63 mono-and polyubiquitylation at sites of DNA damage. This histone ubiquitylation allows for a second wave of protein accumulation, including factors such as 53BP1 and the BRCA1 A complex that are critically important for DSB repair and for the maintenance of genomic integrity. [12][13][14] Deregulation of the DDR machinery fuels the genomic instability needed to drive cancer-cell development and clonal evolution. Recognition of these deregulated DDR pathways has led to the discovery of novel therapeutics that result in synthetic lethality in transformed cells. Recent studies have demonstrated the efficacy of targeting PARP1 in tumors with impaired HR resulting from the homozygous loss of the BRCA1 or BRCA2 genes. [15][16][17] Furthermore, genetic screens have identified a host of HR-related genes (including RAD51, ATR, and PCNA) that upon deletion or silencing render cells hypersensitive to PARP inhibitors. 18 Therefore, tumor cells with any HR deficiency or "BRCAness" are likely to be particularly sensitive to PARP inhibitors because they are unable to cope effectively with the ...

Integrin-␤7 (ITGB7) mRNA is detected in multiple myeloma (MM) cells and its presence is correlated with

No abstract

All-electronic DNA biosensors based on graphene field-effect transistors (GFETs) offer the prospect of simple and cost-effective diagnostics. For GFET sensors based on complementary probe DNA, the sensitivity is limited by the binding affinity of the target oligonucleotide, in the nM range for 20 mer targets. We report a ∼20 000× improvement in sensitivity through the use of engineered hairpin probe DNA that allows for target recycling and hybridization chain reaction. This enables detection of 21 mer target DNA at sub-fM concentration and provides superior specificity against single-base mismatched oligomers. The work is based on a scalable fabrication process for biosensor arrays that is suitable for multiplexed detection. This approach overcomes the binding-affinity-dependent sensitivity of nucleic acid biosensors and offers a pathway toward multiplexed and label-free nucleic acid testing with high accuracy and selectivity.

Tumor cells craft microenvironment to overcome growth disadvantages and adjust to escape the immunosurveillance during tumorigenesis and metastasis. The evolving adaption to the changing microenvironment is exemplified by the development of strategies to deal with hypoxia resulted from fast proliferation of the tumor cells. In this study, we found that hypoxia hepatocellular carcinoma (HCC) cells recruited Regulatory T cells (Tregs) and expressed more Chemokine (C-C motif) ligand 28 (CCL28). Deletion of CCL28 inhibited Treg recruitment. Furthermore, overexpression of CCL28 promoted tumor growth and Treg infiltration in vivo. Enhanced angiogenesis and VEGF expression was also observed. Moreover, inhibition of HIF1α reversed hypoxia-induced CCL28 upregulation. Taken together, our results demonstrate that HCC recruits Tregs to promote angiogenesis under hypoxic condition by upregulating CCL28 expression. These findings establish a link between Tregs and hypoxia in HCC growth and may provide a new potential therapeutic target for treating HCC.