Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of plasma cells. The incidence of MM worldwide is increasing with greater than 140 000 people being diagnosed with MM per year. Whereas 5-year survival after a diagnosis of MM has improved from 28% in 1975 to 56% in 2012, the disease remains essentially incurable. In this review, we summarize our current understanding of MM including its epidemiology, genetics and biology. We will also provide an overview of MM management that has led to improvements in survival, including recent changes to diagnosis and therapies. Areas of unmet need include the management of patients with high-risk MM, those with reduced performance status and those refractory to standard therapies. Ongoing research into the biology and early detection of MM as well as the development of novel therapies, such as immunotherapies, has the potential to influence MM practice in the future.

• Keywords
• clinical presentation, plasma cell disease, risks factors, survival, treatment,
• MeSH
• Cyclin D1 genetics   MeSH
• Exosome Multienzyme Ribonuclease Complex genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Histone Demethylases genetics   MeSH
• Immunotherapy methods   MeSH
• Humans MeSH
• Survival Rate MeSH
• Multiple Myeloma diagnosis   epidemiology   genetics   therapy   MeSH
• Mutation MeSH
• Biomarkers, Tumor genetics   MeSH
• Plasma Cells immunology   pathology   MeSH
• Repressor Proteins genetics   MeSH
• Risk Factors MeSH
• Transcriptional Elongation Factors genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• CCND1 protein, human MeSH Browser
• CDCA7L protein, human MeSH Browser
• Cyclin D1 MeSH
• DIS3 protein, human MeSH Browser
• ELL2 protein, human MeSH Browser
• Exosome Multienzyme Ribonuclease Complex MeSH
• Histone Demethylases MeSH
• KDM1A protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• Repressor Proteins MeSH
• Transcriptional Elongation Factors MeSH

The RNA exosome processes a wide variety of RNA and mediates RNA maturation, quality control and decay. In marked contrast to its high processivity in vivo, the purified exosome exhibits only weak activity on RNA substrates in vitro. Its activity is regulated by several auxiliary proteins, and protein complexes. In budding yeast, the activity of exosome is enhanced by the polyadenylation complex referred to as TRAMP. TRAMP oligoadenylates precursors and aberrant forms of RNAs to promote their trimming or complete degradation by exosomes. This chapter provides protocols for the purification of TRAMP and exosome complexes from yeast and the in vitro evaluation of exosome activation by the TRAMP complex. The protocols can be used for different purposes, such as the assessment of the role of individual subunits, protein domains or particular mutations in TRAMP-exosome RNA processing in vitro.

• Keywords
• Air1, Air2, Degradation assay, Mtr4, Noncanonical poly(A) polymerase, Noncoding RNAs, Polyadenylation assay, RNA exosome, RNA quality control, Rrp6, TAP purification, TRAMP4, Trf4,
• MeSH
• Cell Nucleus metabolism   MeSH
• Exosome Multienzyme Ribonuclease Complex metabolism   MeSH
• Exosomes metabolism   MeSH
• Polyadenylation physiology   MeSH
• RNA metabolism   MeSH
• Saccharomyces cerevisiae Proteins metabolism   MeSH
• Saccharomyces cerevisiae metabolism   MeSH
• Serine Endopeptidases metabolism   MeSH
• RNA Stability physiology   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Exosome Multienzyme Ribonuclease Complex MeSH
• RNA MeSH
• Saccharomyces cerevisiae Proteins MeSH
• Serine Endopeptidases MeSH
• tunicate retinoic acid-inducible modular protease MeSH Browser

: Worldwide, breast cancer (BC) is the most common malignancy in women, in regard to incidence and mortality. In recent years, the negative role of obesity during BC development and progression has been made abundantly clear in several studies. However, the distribution of body fat may be more important to analyze than the overall body weight. In our review of literature, we reported some key findings regarding the role of obesity in BC development, but focused more on central adiposity. Firstly, the adipose microenvironment in obese people bears many similarities with the tumor microenvironment, in respect to associated cellular composition, chronic low-grade inflammation, and high ratio of reactive oxygen species to antioxidants. Secondly, the adipose tissue functions as an endocrine organ, which in obese people produces a high level of tumor-promoting hormones, such as leptin and estrogen, and a low level of the tumor suppressor hormone, adiponectin. As follows, in BC this leads to the activation of oncogenic signaling pathways: NFκB, JAK, STAT3, AKT. Moreover, overall obesity, but especially central obesity, promotes a systemic and local low grade chronic inflammation that further stimulates the increase of tumor-promoting oxidative stress. Lastly, there is a constant exchange of information between BC cells and adipocytes, mediated especially by extracellular vesicles, and which changes the transcription profile of both cell types to an oncogenic one with the help of regulatory non-coding RNAs.

• Keywords
• abdominal fat, adiponectin, breast cancer, exosomes, hormone dependency, leptin, menopause, miRNA, obesity,
• MeSH
• Obesity, Abdominal complications   metabolism   physiopathology   MeSH
• Adiponectin adverse effects   metabolism   MeSH
• Estrogens adverse effects   metabolism   MeSH
• Exosome Multienzyme Ribonuclease Complex metabolism   MeSH
• Leptin immunology   metabolism   MeSH
• Humans MeSH
• Menopause metabolism   MeSH
• MicroRNAs metabolism   MeSH
• Cell Transformation, Neoplastic metabolism   MeSH
• Tumor Microenvironment immunology   MeSH
• Breast Neoplasms etiology   metabolism   physiopathology   MeSH
• Signal Transduction genetics   MeSH
• Adipose Tissue immunology   metabolism   MeSH
• Inflammation physiopathology   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Adiponectin MeSH
• Estrogens MeSH
• Exosome Multienzyme Ribonuclease Complex MeSH
• Leptin MeSH
• MicroRNAs MeSH

RNA metabolism is altered following DNA damage, but the underlying mechanisms are not well understood. Through a 14-3-3 interaction screen for DNA damage-induced protein interactions in human cells, we identified protein complexes connected to RNA biology. These include the nuclear exosome targeting (NEXT) complex that regulates turnover of noncoding RNAs termed promoter upstream transcripts (PROMPTs). We show that the NEXT subunit RBM7 is phosphorylated upon DNA damage by the MAPKAPK2 kinase and establish that this mediates 14-3-3 binding and decreases PROMPT binding. These findings and our observation that cells lacking RBM7 display DNA damage hypersensitivity link PROMPT turnover to the DNA damage response.

• Keywords
• 14-3-3, DNA damage response, MAPKAPK2, UV, nuclear exosome,
• MeSH
• Exosome Multienzyme Ribonuclease Complex metabolism   MeSH
• Phosphorylation MeSH
• Intracellular Signaling Peptides and Proteins metabolism   MeSH
• Humans MeSH
• MAP Kinase Signaling System MeSH
• RNA, Untranslated metabolism   MeSH
• DNA Damage physiology   MeSH
• Protein Serine-Threonine Kinases metabolism   MeSH
• 14-3-3 Proteins metabolism   MeSH
• Ultraviolet Rays MeSH
• Protein Binding MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Exosome Multienzyme Ribonuclease Complex MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• MAP-kinase-activated kinase 2 MeSH Browser
• RNA, Untranslated MeSH
• Protein Serine-Threonine Kinases MeSH
• 14-3-3 Proteins MeSH

Pontocerebellar hypoplasia type 1 (PCH1) is characterized by cerebellar and anterior horn motor neuron degeneration and loss, signs of spinal muscular atrophy plus. Patients manifest severe perinatal weakness, hypotonia, and respiratory insufficiency, causing death frequently before the age of 1 year. Recently, causative mutations in EXOSC3 were reported in a majority of PCH1 patients, but the detailed clinical phenotype caused by EXOSC3 mutations, genotype-phenotype correlations, and prevalent mutations in specific ethnic groups is not yet known. Three unrelated Czech Roma patients with PCH1 were investigated clinically, electrophysiologically, neuroradiologically, and neuropathologically (patients 1 and 2). The entire coding region of the EXOSC3 gene, including the adjacent intron sequences, was sequenced in all three patients. The same mutation c.92G→C, p.G31A in EXOSC3 was found in all three affected patients in homozygous state and in heterozygous state in the parents from two of the families. Haplotype analysis with four flanking microsatellite markers showed identical haplotype in 9 out of 11 haplotypes carrying the c.92G→C, p.G31A mutation. Furthermore, four heterozygotes for this mutation were found in anonymous DNA samples from 90 unrelated Roma individuals. All four of these samples shared the same haplotype. No heterozygous sample was found among 120 anonymous DNA samples from Czech non-Roma individuals with no familial relation. It may therefore be concluded that EXOSC3 c.92G→C, p.G31A mutation is a founder mutation with high prevalence among the Czech Roma causing a similar and particularly severe phenotype of PCH1. These observations from the Czech Roma may have consequences also for other Roma from other countries. PCH1 caused by EXOSC3 founder mutation c.92G→C, p.G31A extends the list of autosomal recessive disorders rare among the general population but more frequent among Roma at least in the Czech Republic.

• MeSH
• Exosome Multienzyme Ribonuclease Complex genetics   MeSH
• Phenotype MeSH
• Haplotypes MeSH
• Homozygote MeSH
• Infant MeSH
• Humans MeSH
• Mutation * MeSH
• Infant, Newborn MeSH
• Olivopontocerebellar Atrophies genetics   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• RNA-Binding Proteins genetics   MeSH
• Roma genetics   MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• EXOSC3 protein, human MeSH Browser
• Exosome Multienzyme Ribonuclease Complex MeSH
• RNA-Binding Proteins MeSH