Cancer biomarkers: Written in blood

http://www.nature.com/news/cancer-biomarkers-written-in-blood-1.15624

DNA circulating in the bloodstream could guide cancer treatment — if researchers can work out how best to use it.

But researchers have found ways to get a richer view of a patient's cancer, and even track it over time. When cancer cells rupture and die, they release their contents, including circulating tumour DNA (ctDNA): genome fragments that float freely through the bloodstream. Debris from normal cells is normally mopped up and destroyed by 'cleaning cells' such as macrophages, but tumours are so large and their cells multiply so quickly that the cleaners cannot cope completely.

The first practical use of circulating DNA came in another field. Dennis Lo, a chemical pathologist now at the Chinese University of Hong Kong, reasoned that if tumours could flood the blood with DNA, surely fetuses could, too. In 1997, he successfully showed that pregnant women carrying male babies had fetal Y chromosomes in their blood6. That discovery allowed doctors to check a baby's sex early in gestation without disturbing the fetus, and ultimately to screen for developmental disorders such as Down's syndrome without resorting to invasive testing. It has revolutionized the field of prenatal diagnostics (see Nature 507, 19; 2014).

Despite its promise, ctDNA is not yet ready for a starring role in the clinic. For one thing, the most sensitive techniques for detecting it, such as BEAMing, rely on some knowledge of which mutations to look for. This knowledge can be provided by taking a biopsy, sequencing its mutations, designing patient-specific molecular probes that target them, and using those probes to analyse later blood samples — a laborious approach that must be repeated for each patient. The alternative is to use exome sequencing, as Rosenfeld's team did. This requires no previous knowledge about the cancer, but it is prohibitively expensive to sequence and analyse every sample at the depth required to detect rare mutant fragments.

Cell and tissue types

http://en.wikipedia.org/wiki/Connective_tissue
Connective tissue (CT) is a fibrous tissue and the most diverse tissue.^[1] It is one of the four traditional classes of tissues (the others being epithelial, muscle, and nervous tissue). CT is found throughout the body.
The special CT subtype includes cartilage,bone, adipose tissue, blood, hematopoietic tissue (tissue that makes blood cells), and lymphatic tissue, as well as the most abundant protein in mammals, Type-I collagen, which makes up about 25% of the total protein content of the mammalian body.

http://en.wikipedia.org/wiki/Muscle_tissue
Muscle tissue is one of four basic biological tissues present in animals. It is a soft tissue that composes muscles.

http://en.wikipedia.org/wiki/Nervous_tissue
Nervous tissue is the main component of the nervous system - the brain, spinal cord, and nerves-which regulates and controls body functions. It is composed of neurons, which transmit impulses, and the neuroglia cells, which assist propagation of the nerve impulse as well as provide nutrients to the neuron.
 
http://en.wikipedia.org/wiki/Epithelium
Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective absorption, protection, transcellular transport and detection of sensation. In Greek "epi" means, "on, upon," and "thele" meaning "nipple".


http://en.wikipedia.org/wiki/Neuron
A neuron ( /ˈnjʊərɒn/ newr-on; also known as a neurone or nerve cell) is an electricallyexcitable cell that processes and transmits information through electrical and chemical signals. A chemical signal occurs via a synapse, a specialized connection with other cells. 
 
http://en.wikipedia.org/wiki/Neuroglia 
Glial cells, sometimes called neuroglia or simply glia (Greek γλία, γλοία "glue"; pronounced in English as either /ˈɡliːə/ or /ˈɡlaɪə/), are non-neuronal cells that maintainhomeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomic nervous system.
Microglia -  are specialized macrophages capable of phagocytosis that protect neurons of the central nervous system.
Macroglia 

• CNS: Astrocytes ("star", many functions, blood-brain barrier, ion homeostasis, nutrient support), Oligodendrocytes ("few branches", insulate axons), Ependymal cells, Radial glia, 

• PNS: Schwann cells, Satellite cells, Enteric glial cells

Blood vessel directs cells

http://www.nature.com/nature/journal/v486/n7404/full/486442b.html

The first blood vessel formed in the embryo — the dorsal aorta — coordinates the formation of the sympathetic nervous system and the medulla of the adrenal gland, both of which marshal the body's fight-or-flight response.

The nervous system and the adrenal medulla are derived from progenitor neural-crest cells — some of which migrate towards the dorsal aorta during early development. Yoshiko Takahashi of Kyoto University in Japan and her colleagues studied developing chick and mouse embryos and found that the dorsal aorta secretes bone morphogenetic proteins. These stimulate the production of signalling molecules that, in turn, attract some of the neural-crest cells. Bone morphogenetic proteins are then involved in the formation of the separate lineages that give rise to the adrenal gland and the sympathetic nervous system.

 Science 336, 1578–1581 (2012)

Regulatory Sequences in Eukaryotic Protein-Coding Genes

http://www.ncbi.nlm.nih.gov/books/NBK21745/

Once transcription start sites in eukaryotic DNA had been identified, analysis of the DNA sequences controlling initiation of transcription could begin. In this section, we take a closer look at various elements in the transcription-control regions that regulate transcription of eukaryotic protein-coding genes.

Transcription of genes with promoters containing a TATA box or initiator element begins at a well-defined initiation site. However,transcription of many protein-coding genes has been shown to begin at any one of multiple possible sites over an extended region, often 20 – 200 base pairs in length. As a result, such genes give rise to mRNAs with multiple alternative 5′ ends. These genes, which generally are transcribed at low rates (e.g., genes encoding the enzymes of intermediary metabolism, often called “housekeeping genes”), do not contain a TATA box or an initiator. Most genes of this type contain a CG-rich stretch of 20 – 50 nucleotides within ≈100 base pairs upstream of the start-site region. As we discuss later, a transcription factor called SP1 recognizes these CG-rich sequences. The dinucleotide CG is statistically underrepresented in vertebrate DNAs, and the presence of CG-rich regions just upstream from start sites is a distinctly nonrandom distribution. Such CpG islands, as they often are called, can be identified by their susceptibility to restriction enzymes (e.g., HpaII) that have CG in their recognition sequences. The presence of a CpG island in a newly cloned DNA fragment suggests that it may contain a transcription-initiation region. 

http://www.ncbi.nlm.nih.gov/pubmed/17123746

Prevalence of the initiator over the TATA box in human and yeast genes and identification of DNA motifs enriched in human TATA-less core promoters.
Yang C, Bolotin E, Jiang T, Sladek FM, Martinez E.

76% of human core promoters lack TATA-like elements, have a high GC content, and are enriched in Sp1-binding sites. 

Aptamers - strong binding of single-stranded oligos

Latin ‘aptus’ meaning “to fit” and is based on the strong binding of single stranded oligos to specific targets based on structural conformation.

http://www.genelink.com/newsite/products/aptamers.asp

Duplication hotspots - genomic hotspots

The human genome is enriched in interspersed segmental duplications that sensitize approximately 10% of our genome to recurrent microdeletions and microduplications as a result of unequal crossing over. We review the recent discovery of recurrent rearrangements within these genomic hotspots and their association with both syndromic and non-syndromic diseases. Studies of common complex genetic disease show that a subset of these recurrent events plays an important role in autism, schizophrenia and epilepsy. The genomic hotspot model may provide a powerful approach for understanding the role of rare variants in common disease.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746670/?tool=pubmed

microdeletions, segmental duplication, array CGH