Although there are many kinds of NETs, they are treated as a group of tissue because the cells of these neoplasms share common features, such as looking similar, having special secretory granules, and often producing biogenic amines and polypeptidehormones.[1]

Traditionally, neuroendocrine tumors have been classified by their anatomic site of origin. NETs can arise in many different areas of the body, and are most often located in the intestine, pancreas or the lungs. The various kinds of cells that can give rise to NETs are present in endocrine glands and are also diffusely distributed throughout the body, most commonly Kulchitsky cells or similar enterochromaffin-like cells, that are relatively more common in the gastrointestinal and pulmonary systems.[5]

Within the broad category of neuroendocrine tumors there are many different tumor types:[7] this outline is presented to facilitate retrieving information. Neuroendocrine tumors are uncommon in many of these areas, and frequently represent only a very small proportion of the tumors or cancers at these locations.

Neuroendocrine lesions are graded histologically according to markers of cellular proliferation, rather than cellular polymorphism. The following grading scheme is currently recommended for all gastroenteropancreatic neuroendocrine neoplasms by the World Health Organisation[33]:

G

Mitotic count (per 10 HPF)

Ki-67 index (%)

GX

Grade cannot be assessed

G1

< 2

< 3%

G2

2 to 20

3% - 20%

G3

> 20

> 20%

If mitotic count and ki67 are discordant, the figure which gives the highest grade is used.

Currently there is no one staging system for all neuroendocrine neoplasms. Well differentiated lesions generally have their own staging system based on anatomical location, whereas poorly differentiated and mixed lesions are staged as carcinomas of that location. For example, gastric NEC and mixed adenoneuroendocrine cancers are staged as a primary carcinoma of the stomach.[35]

Conceptually, there are two main types of NET within this category: those which arise from the gastrointestinal (GI) system and those that arise from the pancreas. In usage, the term "carcinoid" has often been applied to both, although sometimes it is restrictively applied to NETs of GI origin (as herein), or alternatively to those tumors which secrete functional hormones or polypeptides associated with clinical symptoms, as discussed.[citation needed]

Carcinoids most commonly affect the small bowel, particularly the ileum, and are the most common malignancy of the appendix. Many carcinoids are asymptomatic and are discovered only upon surgery for unrelated causes. These coincidental carcinoids are common; one study found that one person in ten has them.[42] Many tumors do not cause symptoms even when they have metastasized.[43] Other tumors even if very small can produce adverse effects by secreting hormones.[44]

A carcinoid crisis with profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure[1] can occur if large amounts of hormone are acutely secreted,[46] which is occasionally triggered by factors such as diet,[46] alcohol,[46] surgery[1][46] chemotherapy,[46] embolization therapy or radiofrequency ablation.[1]

Occasionally, haemorrhage or the effects of tumor bulk are the presenting symptoms. Bowel obstruction can occur, sometimes due to fibrosing effects of NET secretory products[44] with an intense desmoplastic reaction at the tumor site, or of the mesentery.

Pancreatic neuroendocrine tumors (PanNETs) are often referred to as "islet cell tumors",[48][49] or "pancreatic endocrine tumors"[2]

The PanNET denomination is in line with current WHO guidelines. Historically, PanNETs have also been referred to by a variety of terms, and are still often called "islet cell tumors" or "pancreatic endocrine tumors".[50] originate within the pancreas. PanNETs are quite distinct from the usual form of pancreatic cancer, adenocarcinoma, which arises in the exocrine pancreas. About 95 percent of pancreatic tumors are adenocarcinoma; only 1 or 2% of clinically significant pancreas neoplasms are GEP-NETs.[citation needed]

Well or intermediately differentiated PanNETs are sometimes called islet cell tumors; neuroendocrine cancer (NEC) (synonymous with islet cell carcinoma) is more aggressive. Up to 60% of PanNETs are nonsecretory or nonfunctional, which either don’t secrete, or the quantity or type of products such as pancreatic polypeptide (PPoma), chromogranin A, and neurotensin do not cause a clinical syndrome, although blood levels may be elevated.[27] Functional tumors are often classified by the hormone most strongly secreted by the pancreatic neuroendocrine tumor, as discussed in that main article.

In addition to the two main categories of GEP-NET, there are rarer forms of neuroendocrine tumors that arise anywhere in the body, including within the lung, thymus and parathyroid. Bronchial carcinoid can cause airway obstruction, pneumonia, pleurisy, difficulty with breathing, cough, and hemoptysis, or may be associated with weakness, nausea, weight loss, night sweats, neuralgia, and Cushing’s syndrome. Some are asymptomatic.[citation needed]

Symptoms from secreted hormones may prompt measurement of the corresponding hormones in the blood or their associated urinary products, for initial diagnosis or to assess the interval change in the tumor. Secretory activity of the tumor cells is sometimes dissimilar to the tissue immunoreactivity to particular hormones.[55]

Given the diverse secretory activity of NETs there are many other potential markers, but a limited panel is usually sufficient for clinical purposes.[1] Aside from the hormones of secretory tumors, the most important markers are:

Newer markers include N-terminally truncated variant of Hsp70 is present in NETs but absent in normal pancreatic islets.[57] High levels of CDX2, a homeobox gene product essential for intestinal development and differentiation, are seen in intestinal NETs. Neuroendocrine secretory protein-55, a member of the chromogranin family, is seen in pancreatic endocrine tumors but not intestinal NETs.[57]

CT-scans, MRIs, sonography (ultrasound), and endoscopy (including endoscopic ultrasound) are common diagnostic tools. CT-scans using contrast medium can detect 95 percent of tumors over 3 cm in size, but generally not tumors under 1 cm.[3]

Advances in nuclear medicine imaging, also known as molecular imaging, has improved diagnostic and treatment paradigms in patients with neuroendocrine tumors. This is because of its ability to not only identify sites of disease but also characterize them. Neuronedocrine tumours express somatostatin receptors providing a unique target for imaging. Octreotide is a synthetic modifications of somatostatin with a longer half-life.[citation needed] OctreoScan, also called somatostatin receptor scintigraphy (SRS or SSRS), utilizes intravenously administered octreotide that is chemically bound to a radioactive substance, often indium-111, to detect larger lesions with tumor cells that are avid for octreotide.[citation needed]

Somatostatin receptor imaging can now be performed with positron emission tomography (PET) which offers higher resolution, three-dimensional and more rapid imaging. Gallium-68 receptor PET-CT is much more accurate than an OctreoScan.[58]

Imaging with fluorine-18 fluorodeoxyglucose (FDG) PET may be valuable to image some neuroendocrine tumors.[59] This scan is performed by injected radioactive sugar intravenously. Tumors that grow more quickly use more sugar. Using this scan, the aggressiveness of the tumor can be assessed.[citation needed]

The combination of somatostatin receptor and FDG PET imaging is able to quantify somatostatin receptor cell surface (SSTR) expression and glycolytic metabolism, respectively.[59] The ability to perform this as a whole body study is highlighting the limitations of relying on histopathology obtained from a single site. This is enabling better selection of the most appropriate therapy for an individual patient.[60]

NETs are often small, yellow or tan masses, often located in the submucosa or more deeply intramurally, and they can be very firm due to an accompanying intense desmoplastic reaction. The overlying mucosa may be either intact or ulcerated. Some GEP-NETs invade deeply to involve the mesentery.[citation needed] Histologically, NETs are an example of "small blue cell tumors," showing uniform cells which have a round to oval stippled nucleus and scant, pink granular cytoplasm. The cells may align variously in islands, glands or sheets. High power examination shows bland cytopathology. Electron microscopy can identify secretory granules. There is usually minimal pleomorphism but less commonly there can be anaplasia, mitotic activity, and necrosis.[citation needed]

Some neuroendocrine tumor cells possess especially strong hormonereceptors, such as somatostatin receptors and uptake hormones strongly. This avidity can assist in diagnosis and may make some tumors vulnerable to hormone targeted therapies.[citation needed]

NETs from a particular anatomical origin often show similar behavior as a group, such as the foregut (which conceptually includes pancreas, and even thymus, airway and lung NETs), midgut and hindgut; individual tumors within these sites can differ from these group benchmarks:

Foregut NETs are argentaffin negative. Despite low serotonin content, they often secrete 5-hydroxytryptophan (5-HTP), histamine, and several polypeptide hormones. There may be associated atypical carcinoid syndrome, acromegaly, Cushing disease, other endocrine disorders, telangiectasia, or hypertrophy of the skin in the face and upper neck.[62] These tumors can metastasize to bone.

Several issues help define appropriate treatment of a neuroendocrine tumor, including its location, invasiveness, hormone secretion, and metastasis. Treatments may be aimed at curing the disease or at relieving symptoms (palliation). Observation may be feasible for non-functioning low grade neuroendocrine tumors. If the tumor is locally advanced or has metastasized, but is nonetheless slowly growing, treatment that relieves symptoms may often be preferred over immediate challenging surgeries.[citation needed]

Intermediate and high grade tumors (noncarcinoids) are usually best treated by various early interventions (active therapy) rather than observation (wait-and-see approach).[63]

Treatments have improved over the past several decades, and outcomes are improving.[44] In malignant carcinoid tumors with carcinoid syndrome, the median survival has improved from two years to more than eight years.[64]

In secretory tumors, somatostatin analogs given subcutaneously or intramuscularly alleviate symptoms by blocking hormone release. A consensus review has reported on the use of somatostatin analogs for GEP-NETs.[72]

These medications may also anatomically stabilize or shrink tumors, as suggested by the PROMID study (Placebo-controlled prospective randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors): at least in this subset of NETs, average tumor stabilization was 14.3 months compared to 6 months for placebo.[73]

The CLARINET study (a randomized, double-blind, placebo-controlled study on the antiproliferative effects of lanreotide in patients with enteropancreatic neuroendocrine tumors) further demonstrated the antiproliferative potential of lanreotide, a somatostatin analog and recently approved FDA treatment for GEP-NETS. In this study, lanreotide showed a statistically significant improvement in progression-free survival, meeting its primary endpoint. The disease in sixty five percent of patients treated with lanreotide in the study had not progressed or caused death at 96 weeks, the same was true of 33% of patients on placebo. This represented a 53% reduction in risk of disease progression or death with lanreotide based on a hazard ratio of .47.[74]

Lanreotide is the first and only FDA approved antitumor therapy demonstrating a statistically significant progression-free survival benefit in a combined population of patients with GEP-NETS.[citation needed]

Interferon is sometimes used to treat GEP-NETs.[75] Its effectiveness is somewhat uncertain, but low doses can be titrated within each person, often considering the effect on the blood leukocyte count;[75] Interferon is often used in combination with other agents, especially somatostatin analogs such as octreotide.[citation needed]

Most gastrointestinal carcinoid tumors tend not to respond to chemotherapy agents,[47] showing 10 to 20% response rates that are typically less than 6 months. Combining chemotherapy medications has not usually been of significant improvement[47] showing 25 to 35% response rates that are typically less than 9 months.

Peptide receptor radionuclide therapy (PRRT) is a type of radioisotope therapy (RIT)[6] in which a peptide or hormone conjugated to a radionuclide or radioligand is given intravenously, the peptide or neuroamine hormone previously having shown good uptake of a tracer dose, using Somatostatin receptor imaging as detailed above. This type of radiotherapy is a systemic therapy and will impact somatostatin positive disease[76]. The peptide receptor may be bound to lutetium-177, yttrium-90, indium-111 and other isotopes including alpha emitters[77]. This is a highly targeted and effective therapy with minimal side effects in tumors with high levels of somatostatin cell surface expression, because the radiation is absorbed at the sites of the tumor, or excreted in the urine. The radioactively labelled hormones enter the tumor cells which, together with nearby cells, are damaged by the attached radiation. Not all cells are immediately killed; cell death can go on for up to two years.[citation needed]

PRRT was initially used for low grade NETs. It is also very useful in more aggressive NETs such as Grade 2 and 3 NETs[78][79] provided they demonstrate high uptake on SSTR imaging to suggest benefit.

Metastases to the liver can be treated by several types of hepatic artery treatments based on the observation that tumor cells get nearly all their nutrients from the hepatic artery, while the normal cells of the liver get about 70–80 percent of their nutrients and 50% their oxygen supply from the portal vein, and thus can survive with the hepatic artery effectively blocked.[44][80]

Hepatic artery embolization (HAE) occludes the blood flow to the tumors, achieving significant tumor shrinkage in over 80%.[46] In hepatic artery chemotherapy, the chemotherapy agents are given into the hepatic artery, often by steady infusion over hours or even days. Compared with systemic chemotherapy, a higher proportion of the chemotherapy agents are (in theory) delivered to the lesions in the liver.[80]

Hepatic artery chemoembolization (HACE), sometimes called transarterial chemoembolization (TACE), combines hepatic artery embolization with hepatic artery chemoinfusion: embospheres bound with chemotherapy agents, injected into the hepatic artery, lodge in downstream capillaries. The spheres not only block blood flow to the lesions, but by halting the chemotherapy agents in the neighborhood of the lesions, they provide a much better targeting leverage than chemoinfusion provides.[citation needed]

Selective internal radiation therapy (SIRT)[81] for neuroendocrine metastases to the liver[82] delivers radioactive microsphere therapy (RMT) by injection into the hepatic artery, lodging (as with HAE and HACE) in downstream capillaries. In contrast to hormone-delivered radiotherapy, the lesions need not overexpress peptide receptors. The mechanical targeting delivers the radiation from the yttrium-labeled microspheres selectively to the tumors without unduly affecting the normal liver.[83] This type of treatment is FDA approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, including neuroendocrine malignancies.[81]

Although estimates vary, the annual incidence of clinically significant neuroendocrine tumors is approximately 2.5–5 per 100,000;[87] two thirds are carcinoid tumors and one third are other NETs.

The prevalence has been estimated as 35 per 100,000,[87] and may be considerably higher if clinically silent tumors are included. An autopsy study of the pancreas in people who died from unrelated causes discovered a remarkably high incidence of tiny asymptomatic NETs. Routine microscopic study of three random sections of the pancreas found NETs in 1.6%, and multiple sections identified NETs in 10%.[88] As diagnostic imaging increases in sensitivity, such as endoscopicultrasonography, very small, clinically insignificant NETs may be coincidentally discovered; being unrelated to symptoms, such neoplasms may not require surgical excision.[citation needed]

Small intestinal neuroendocrine tumors were first distinguished from other tumors in 1907.[89][43] They were named carcinoid tumors because their slow growth was considered to be "cancer-like" rather than truly cancerous.[43]

However, in 1938 it was recognized that some of these small bowel tumors could be malignant.[89][43] Despite the differences between these two original categories, and further complexities due to subsequent inclusion of other NETs of pancreas and pulmonary origin, all NETs are sometimes (incorrectly) subsumed into the term "carcinoid".[citation needed]

Enterochromaffin cells, which give rise to carcinoid tumors, were identified in 1897 by Nikolai Kulchitsky and their secretion of serotonin was established in 1953[89] when the "flushing" effect of serotonin had become clinically recognized. Carcinoid heart disease was identified in 1952, and carcinoid fibrosis in 1961.[89]

Neuroendocrine tumors were sometimes called APUDomas because these cells often show amineprecursor (L-DOPA and 5-hydroxytryptophan) uptake and decarboxylation to produce biogenic amines such as catecholamines and serotonin. Although this behavior was also part of the disproven hypothesis that these cells might all embryologically arise from the neural crest,[54][63][64] neuroendocrine cells sometimes produce various types of hormones and amines,[64] and they can also have strong receptors for other hormones to which they respond.

There have been multiple nomenclature systems for these tumors,[2] and the differences between these schema have often been confusing. Nonetheless, these systems all distinguish between well-differentiated (low and intermediate-grade) and poorly differentiated (high-grade) NETs. Cellular proliferative rate is of considerable significance in this prognostic assessment.[2]

^ abcdPommier R. 2003. The role of surgery and chemoembolization in the management of carcinoid. California Carcinoid Fighters Conference. October 25, carcinoid.orgArchived 2015-09-15 at the Wayback Machine.

1.
Micrograph
–
A micrograph or photomicrograph is a photograph or digital image taken through a microscope or similar device to show a magnified image of an item. This is opposed to an image, which is at a scale that is visible to the naked eye. Micrography is the practice or art of using microscopes to make photographs, a micrograph contains extensive details that form the features of a microstructure. The neuropathologist Solomon C. Fuller designed and created the first photomicrograph in 1900, micrographs are widely used in all fields of microscopy. A light micrograph or photomicrograph is a micrograph prepared using an optical microscope, at a basic level, photomicroscopy may be performed simply by hooking up a regular camera to a microscope, thereby enabling the user to take photographs at reasonably high magnification. Roman Vishniac was a pioneer in the field of photomicroscopy, specializing in the photography of living creatures in full motion and he also made major developments in light-interruption photography and color photomicroscopy. An electron micrograph is a micrograph prepared using an electron microscope, however, the term electron micrograph is not used in electron microscopy. Digital micrography is a digital picture obtained either directly with a microscope or by scanning of a photomicrograph, digital micrographs are now commonly obtained using a USB microscope attached directly to a home computer or laptop. Today, an add-on three-in-one macro lens which has capability to take wide-angle, fish-eye and macro with 7x, 14x, micrographs usually have micron bars, or magnification ratios, or both. Magnification is a ratio between size of object on a picture and its real size, unfortunately, magnification is somewhat a misleading parameter. It depends on a size of a printed picture. Editors of journals and magazines routinely resize a figure to fit the page, a scale bar, or micron bar, is a bar of known length displayed on a picture. The bar can be used for measurements on a picture, when a picture is resized a bar is also resized. If a picture has a bar, the magnification can be easily calculated, ideally, all pictures destined for publication/presentation should be supplied with a scale bar, the magnification ratio is optional. All but one of the micrographs presented on this page do not have a bar, supplied magnification ratios are likely incorrect. The microscope has been used for scientific discovery. It has also linked to the arts since its invention in the 17th century. At first scientists used the microscope to view and draw objects not visible with the unaided eye, early adopters of the microscope, such as Robert Hooke and Antonie van Leeuwenhoek, were excellent illustrators

2.
H&E stain
–
Hematoxylin and eosin stain or haematoxylin and eosin stain is one of the principal stains in histology. A combination of hematoxylin and eosin, it produces blues, violets, the staining method involves application of hemalum, a complex formed from aluminum ions and hematein. Hemalum colors nuclei of cells blue, the nuclear staining is followed by counterstaining with an aqueous or alcoholic solution of eosin Y, which colors eosinophilic structures in various shades of red, pink and orange. The staining of nuclei by hemalum is ordinarily due to binding of the complex to DNA. The mechanism is different from that of nuclear staining by basic dyes such as thionine or toluidine blue, staining by basic dyes occurs only from solutions that are less acidic than hemalum, and it is prevented by prior chemical or enzymatic extraction of nucleic acids. The eosinophilic structures are composed of intracellular or extracellular protein. The Lewy bodies and Mallory bodies are examples of eosinophilic structures, most of the cytoplasm is eosinophilic. Red blood cells are stained intensely red, the structures do not have to be acidic or basic to be called basophilic and eosinophilic, the terminology is based on the affinity of cellular components for the dyes. Other colors, e. g. yellow and brown, can be present in the sample, they are caused by intrinsic pigments, some structures do not stain well. Basal laminae need to be stained by PAS stain or some silver stains, reticular fibers also require silver stain. Hydrophobic structures also tend to clear, these are usually rich in fats, e. g. adipocytes, myelin around neuron axons. Hematoxylin is a blue or violet stain that is basic/positive. DNA/RNA in the nucleus, and RNA in ribosomes in the endoplasmic reticulum are both acidic because the phosphate backbones of nucleic acids are negatively charged. The negatively charged backbones form salts with basic dyes containing positive charges, therefore, dyes like hematoxylin will bind to DNA and RNA and stain them violet. Eosin is a red or pink stain that is Acidic / Negative and it binds to acidophilic substances such as positively charged amino acid side chains. Most proteins in the cytoplasm of cells are basic because they are positively charged due to the arginine and lysine amino acid residues. These form salts with acid dyes containing negative charges, like eosin, therefore, eosin binds to these amino acids/proteins and stains them pink. This includes cytoplasmic filaments in muscle cells, intracellular membranes, kiernan JA Histological and Histochemical Methods, Theory and Practice

3.
Endocrine
–
The endocrine system is the collection of glands of an organism that secrete hormones directly into the circulatory system to be carried towards distant target organs. The phenomenon of biochemical processes serving to regulate distant tissues by means of directly into the circulatory system is called endocrine signaling. The major endocrine glands include the pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid gland, parathyroid gland, the endocrine system is in contrast to the exocrine system, which secretes its hormones to the outside of the body using ducts. The endocrine system is a signal system like the nervous system, yet its effects. The endocrine systems effects are slow to initiate, and prolonged in their response, the nervous system sends information very quickly, and responses are generally short lived. In vertebrates, the hypothalamus is the control center for all endocrine systems. The field of study dealing with the system and its disorders is endocrinology. Special features of endocrine glands are, in general, their ductless nature, their vascularity, in contrast, exocrine glands, such as salivary glands, sweat glands, and glands within the gastrointestinal tract, tend to be much less vascular and have ducts or a hollow lumen. For example, the kidney secretes endocrine hormones such as erythropoietin and renin, hormones can consist of either amino acid complexes, steroids, eicosanoids, leukotrienes, or prostaglandins. A number of glands that signal each other in sequence are referred to as an axis, for example. The word endocrine derives from the Greek words ἐνδο- endo- inside, within, the pituitary gland is an endocrine gland about the size of a pea and weighing 0.5 grams in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, the pituitary is functionally connected to the hypothalamus by the median eminence via a small tube called the infundibular stem or pituitary stalk. Oxytocin and anti-diuretic hormone are not secreted in the posterior lobe, the pancreas is a mixocrine gland and it secretes both enzymes and hormones. In 1998, skeletal muscle was identified as an organ due to its now well-established role in the secretion of myokines. The use of the term myokine to describe cytokines and other peptides produced by muscle as signalling molecules was proposed in 2003, signalling molecules released by adipose tissue are referred to as adipokines. The human endocrine system consists of several systems that operate via feedback loops, several important feedback systems are mediated via the hypothalamus and pituitary. Cortisol has major effects, and dopamine has immunomodulatory functions. On the other hand, cytokines produced during inflammation activate the HPA axis at all three levels, sensible to negative feedback, moreover, cytokines stimulate hepcidin release from the liver, which is eventually responsible for the anemia of chronic disease

4.
Hormonal
–
Hormones have diverse chemical structures, mainly of 3 classes, eicosanoids, steroids, and amino acid/protein derivatives. The glands that secrete hormones comprise the endocrine signaling system, the term hormone is sometimes extended to include chemicals produced by cells that affect the same cell or nearby cells. Hormones affect distant cells by binding to receptor proteins in the target cell resulting in a change in cell function. When a hormone binds to the receptor, it results in the activation of a signal transduction pathway, Hormone secretion may occur in many tissues. Endocrine glands are the example, but specialized cells in various other organs also secrete hormones. Hormone secretion occurs in response to specific biochemical signals from a range of regulatory systems. Upon secretion, certain hormones, including hormones and catecholamines, are water-soluble and are thus readily transported through the circulatory system. The endocrine system secretes hormones directly into the bloodstream typically into fenestrated capillaries, Hormones with paracrine function diffuse through the interstitial spaces to nearby target tissue. The reaction of the cells may then be recognized by the original hormone-producing cells. This is an example of a negative feedback loop. Hormone cells are typically of a cell type, residing within a particular endocrine gland, such as the thyroid gland, ovaries. Hormones exit their cell of origin via exocytosis or another means of membrane transport, the hierarchical model is an oversimplification of the hormonal signaling process. Different tissue types may also respond differently to the same hormonal signal, the rate of hormone biosynthesis and secretion is often regulated by a homeostatic negative feedback control mechanism. Such a mechanism depends on factors that influence the metabolism and excretion of hormones, thus, higher hormone concentration alone cannot trigger the negative feedback mechanism. Negative feedback must be triggered by overproduction of an effect of the hormone, for example, thyroid-stimulating hormone causes growth and increased activity of another endocrine gland, the thyroid, which increases output of thyroid hormones. To release active hormones quickly into the circulation, hormone biosynthetic cells may produce and these can then be quickly converted into their active hormone form in response to a particular stimulus. Eicosanoids are considered to act as local hormones and they are considered to be local because they possess specific effects on target cells close to their site of formation. They also have a rapid degradation cycle, making sure they do not reach distal sites within the body, most hormones initiate a cellular response by initially binding to either cell membrane associated or intracellular receptors

5.
Secretion
–
Secretion is the movement of material from one point to another, e. g. secreted chemical substance from a cell or gland. In contrast, excretion, is the removal of certain substances or waste products from a cell or organism, the classical mechanism of cell secretion is via secretory portals at the cell plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structure at the plasma membrane. Secretion in bacterial species means the transport or translocation of molecules for example, proteins. Secretion is an important mechanism in bacterial functioning and operation in their natural surrounding environment for adaptation. Eukaryotic cells, including human cells, have a highly evolved process of secretion, proteins targeted for the outside are synthesized by ribosomes docked to the rough endoplasmic reticulum. As they are synthesized, these proteins translocate into the ER lumen, where they are glycosylated, misfolded proteins are usually identified here and retrotranslocated by ER-associated degradation to the cytosol, where they are degraded by a proteasome. The vesicles containing the properly folded proteins then enter the Golgi apparatus, in the Golgi apparatus, the glycosylation of the proteins is modified and further posttranslational modifications, including cleavage and functionalization, may occur. The proteins are then moved into secretory vesicles which travel along the cytoskeleton to the edge of the cell, more modification can occur in the secretory vesicles. Eventually, there is vesicle fusion with the membrane at a structure called the porosome, in a process called exocytosis. Strict biochemical control is maintained over this sequence by usage of a pH gradient, the pH of the cytosol is 7.4, the ERs pH is 7.0, and the cis-golgi has a pH of 6.5. Secretory vesicles have pHs ranging between 5.0 and 6.0, some secretory vesicles evolve into lysosomes, which have a pH of 4.8, there are many proteins like FGF1, FGF2, interleukin-1 etc. which do not have a signal sequence. They do not use the classical ER-golgi pathway and these are secreted through various nonclassical pathways. At least four nonclassical protein secretion pathways have been described, many human cell types have the ability to be secretory cells. They have a well-developed endoplasmic reticulum and Golgi apparatus to fulfill their function, meibomian glands in the eyelid secrete sebum to lubricate and protect the eye. Secretion is not unique to eukaryotes alone, it is present in bacteria, ATP binding cassette type transporters are common to all the three domains of life. Some secreted proteins are translocated across the membrane by the Sec translocon. Others are translocated across the membrane by the twin-arginine translocation pathway

6.
Amine
–
In organic chemistry, amines are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group, important amines include amino acids, biogenic amines, trimethylamine, and aniline, see Category, Amines for a list of amines. Inorganic derivatives of ammonia are also called amines, such as chloramine, see Category, compounds with a nitrogen atom attached to a carbonyl group, thus having the structure R–CO–NR′R″, are called amides and have different chemical properties from amines. An aliphatic amine has no aromatic ring attached directly to the nitrogen atom, aromatic amines have the nitrogen atom connected to an aromatic ring as in the various anilines. The aromatic ring decreases the alkalinity of the amine, depending on its substituents, the presence of an amine group strongly increases the reactivity of the aromatic ring, due to an electron-donating effect. Amines are organized into four subcategories, Primary amines — Primary amines arise when one of three atoms in ammonia is replaced by an alkyl or aromatic. Important primary alkyl amines include, methylamine, most amino acids, Secondary amines — Secondary amines have two organic substituents bound to the nitrogen together with one hydrogen. Important representatives include dimethylamine, while an example of an aromatic amine would be diphenylamine, tertiary amines — In tertiary amines, nitrogen has three organic substituents. Examples include trimethylamine, which has a fishy smell. Cyclic amines — Cyclic amines are either secondary or tertiary amines, examples of cyclic amines include the 3-membered ring aziridine and the six-membered ring piperidine. N-methylpiperidine and N-phenylpiperidine are examples of tertiary amines. It is also possible to have four organic substituents on the nitrogen and these species are not amines but are quaternary ammonium cations and have a charged nitrogen center. Quaternary ammonium salts exist with many kinds of anions, Amines are named in several ways. Typically, the compound is given the prefix amino- or the suffix, the prefix N- shows substitution on the nitrogen atom. An organic compound with multiple amino groups is called a diamine, triamine, tetraamine, systematic names for some common amines, Hydrogen bonding significantly influences the properties of primary and secondary amines. Thus the melting point and boiling point of amines is higher than those of the corresponding phosphines, for example, methyl and ethyl amines are gases under standard conditions, whereas the corresponding methyl and ethyl alcohols are liquids. Amines possess a characteristic smell, liquid amines have a distinctive fishy smell. The nitrogen atom features a lone pair that can bind H+ to form an ammonium ion R3NH+

7.
Peptide
–
Peptides are biologically occurring short chains of amino acid monomers linked by peptide bonds. The covalent chemical bonds are formed when the group of one amino acid reacts with the amine group of another. The shortest peptides are dipeptides, consisting of 2 amino acids joined by a peptide bond, followed by tripeptides, tetrapeptides. A polypeptide is a long, continuous, and unbranched peptide chain, hence, peptides fall under the broad chemical classes of biological oligomers and polymers, alongside nucleic acids, oligosaccharides and polysaccharides, etc. Peptides are distinguished from proteins on the basis of size, all peptides except cyclic peptides have an N-terminal and C-terminal residue at the end of the peptide. Ribosomal peptides Ribosomal peptides are synthesized by translation of mRNA and they are often subjected to proteolysis to generate the mature form. These function, typically in higher organisms, as hormones and signaling molecules, some organisms produce peptides as antibiotics, such as microcins. Since they are translated, the amino acid residues involved are restricted to those utilized by the ribosome, however, these peptides frequently have posttranslational modifications such as phosphorylation, hydroxylation, sulfonation, palmitoylation, glycosylation and disulfide formation. In general, they are linear, although lariat structures have been observed, more exotic manipulations do occur, such as racemization of L-amino acids to D-amino acids in platypus venom. Nonribosomal peptides Nonribosomal peptides are assembled by enzymes that are specific to each peptide, the most common non-ribosomal peptide is glutathione, which is a component of the antioxidant defenses of most aerobic organisms. Other nonribosomal peptides are most common in organisms, plants. These complexes are often out in a similar fashion. These peptides are often cyclic and can have highly complex cyclic structures, since the system is closely related to the machinery for building fatty acids and polyketides, hybrid compounds are often found. The presence of oxazoles or thiazoles often indicates that the compound was synthesized in this fashion, Peptones See also Tryptone Peptones are derived from animal milk or meat digested by proteolysis. In addition to containing small peptides, the material includes fats, metals, salts, vitamins. Peptones are used in nutrient media for growing bacteria and fungi, Peptide fragments Peptide fragments refer to fragments of proteins that are used to identify or quantify the source protein. Peptides received prominence in molecular biology for several reasons, the first is that peptides allow the creation of peptide antibodies in animals without the need of purifying the protein of interest. This involves synthesizing antigenic peptides of sections of the protein of interest and these will then be used to make antibodies in a rabbit or mouse against the protein

8.
Hormone
–
Hormones have diverse chemical structures, mainly of 3 classes, eicosanoids, steroids, and amino acid/protein derivatives. The glands that secrete hormones comprise the endocrine signaling system, the term hormone is sometimes extended to include chemicals produced by cells that affect the same cell or nearby cells. Hormones affect distant cells by binding to receptor proteins in the target cell resulting in a change in cell function. When a hormone binds to the receptor, it results in the activation of a signal transduction pathway, Hormone secretion may occur in many tissues. Endocrine glands are the example, but specialized cells in various other organs also secrete hormones. Hormone secretion occurs in response to specific biochemical signals from a range of regulatory systems. Upon secretion, certain hormones, including hormones and catecholamines, are water-soluble and are thus readily transported through the circulatory system. The endocrine system secretes hormones directly into the bloodstream typically into fenestrated capillaries, Hormones with paracrine function diffuse through the interstitial spaces to nearby target tissue. The reaction of the cells may then be recognized by the original hormone-producing cells. This is an example of a negative feedback loop. Hormone cells are typically of a cell type, residing within a particular endocrine gland, such as the thyroid gland, ovaries. Hormones exit their cell of origin via exocytosis or another means of membrane transport, the hierarchical model is an oversimplification of the hormonal signaling process. Different tissue types may also respond differently to the same hormonal signal, the rate of hormone biosynthesis and secretion is often regulated by a homeostatic negative feedback control mechanism. Such a mechanism depends on factors that influence the metabolism and excretion of hormones, thus, higher hormone concentration alone cannot trigger the negative feedback mechanism. Negative feedback must be triggered by overproduction of an effect of the hormone, for example, thyroid-stimulating hormone causes growth and increased activity of another endocrine gland, the thyroid, which increases output of thyroid hormones. To release active hormones quickly into the circulation, hormone biosynthetic cells may produce and these can then be quickly converted into their active hormone form in response to a particular stimulus. Eicosanoids are considered to act as local hormones and they are considered to be local because they possess specific effects on target cells close to their site of formation. They also have a rapid degradation cycle, making sure they do not reach distal sites within the body, most hormones initiate a cellular response by initially binding to either cell membrane associated or intracellular receptors

9.
World Health Organization
–
The World Health Organization is a specialised agency of the United Nations that is concerned with international public health. It was established on 7 April 1948, headquartered in Geneva, the WHO is a member of the United Nations Development Group. Its predecessor, the Health Organization, was an agency of the League of Nations, the constitution of the World Health Organization had been signed by 61 countries on 22 July 1946, with the first meeting of the World Health Assembly finishing on 24 July 1948. It incorporated the Office international dhygiène publique and the League of Nations Health Organization, since its creation, it has played a leading role in the eradication of smallpox. The WHO is responsible for the World Health Report, an international publication on health, the worldwide World Health Survey. The head of WHO is Margaret Chan, the 2014/2015 proposed budget of the WHO is about US$4 billion. About US$930 million are to be provided by member states with a further US$3 billion to be from voluntary contributions, after failing to get a resolution passed on the subject, Alger Hiss, the Secretary General of the conference, recommended using a declaration to establish such an organisation. Dr. Sze and other delegates lobbied and a declaration passed calling for a conference on health. The use of the world, rather than international, emphasised the truly global nature of what the organisation was seeking to achieve. The constitution of the World Health Organization was signed by all 51 countries of the United Nations and it thus became the first specialised agency of the United Nations to which every member subscribed. Its constitution formally came into force on the first World Health Day on 7 April 1948, the first meeting of the World Health Assembly finished on 24 July 1948, having secured a budget of US$5 million for the 1949 year. Andrija Stampar was the Assemblys first president, and G. Brock Chisholm was appointed Director-General of WHO and its first priorities were to control the spread of malaria, tuberculosis and sexually transmitted infections, and to improve maternal and child health, nutrition and environmental hygiene. Its first legislative act was concerning the compilation of statistics on the spread. The logo of the World Health Organization features the Rod of Asclepius as a symbol for healing, in 1947 the WHO established an epidemiological information service via telex, and by 1950 a mass tuberculosis inoculation drive using the BCG vaccine was under way. In 1955, the eradication programme was launched, although it was later altered in objective. 1965 saw the first report on diabetes mellitus and the creation of the International Agency for Research on Cancer. In 1958, Viktor Zhdanov, Deputy Minister of Health for the USSR, called on the World Health Assembly to undertake an initiative to eradicate smallpox. At this point,2 million people were dying from smallpox every year, in 1966, WHO moved into its headquarters building

10.
Anatomy
–
Anatomy is the branch of biology concerned with the study of the structure of organisms and their parts. Anatomy is inherently tied to embryology, comparative anatomy, evolutionary biology, Human anatomy is one of the basic essential sciences of medicine. The discipline of anatomy is divided into macroscopic and microscopic anatomy, macroscopic anatomy, or gross anatomy, is the examination of an animals body parts using unaided eyesight. Gross anatomy also includes the branch of superficial anatomy, microscopic anatomy involves the use of optical instruments in the study of the tissues of various structures, known as histology, and also in the study of cells. The history of anatomy is characterized by an understanding of the functions of the organs. Anatomy and physiology, which study the structure and function of organisms and their parts, make a pair of related disciplines. Derived from the Greek ἀνατομή anatomē dissection, anatomy is the study of the structure of organisms including their systems, organs. It includes the appearance and position of the parts, the materials from which they are composed, their locations. Anatomy is quite distinct from physiology and biochemistry, which deal respectively with the functions of those parts, the discipline of anatomy can be subdivided into a number of branches including gross or macroscopic anatomy and microscopic anatomy. Gross anatomy is the study of large enough to be seen with the naked eye, and also includes superficial anatomy or surface anatomy. Microscopic anatomy is the study of structures on a scale, including histology. Anatomy can be studied using both invasive and non-invasive methods with the goal of obtaining information about the structure and organization of organs, angiography using X-rays or magnetic resonance angiography are methods to visualize blood vessels. The term anatomy is commonly taken to refer to human anatomy, however, substantially the same structures and tissues are found throughout the rest of the animal kingdom and the term also includes the anatomy of other animals. The term zootomy is also used to specifically refer to animals. The structure and tissues of plants are of a dissimilar nature, the kingdom Animalia or metazoa, contains multicellular organisms that are heterotrophic and motile. Most animals have bodies differentiated into separate tissues and these animals are known as eumetazoans. They have a digestive chamber, with one or two openings, the gametes are produced in multicellular sex organs, and the zygotes include a blastula stage in their embryonic development. Metazoans do not include the sponges, which have undifferentiated cells, unlike plant cells, animal cells have neither a cell wall nor chloroplasts

11.
Epithelium
–
Epithelial is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of blood vessels and organs throughout the body, there are three principal shapes of epithelial cell, squamous, columnar, and cuboidal. All glands are made up of epithelial cells, functions of epithelial cells include secretion, selective absorption, protection, transcellular transport, and sensing. Epithelial layers contain no blood vessels, so they must receive nourishment via diffusion of substances from the connective tissue. Cell junctions are well-employed in epithelial tissues, in general, epithelial tissues are classified by the number of their layers and by the shape and function of the cells. The three principal shapes associated with epithelial cells are—squamous, cuboidal and columnar, squamous epithelium has cells that are wider than their height. Cuboidal epithelium has cells whose height and width are approximately the same, columnar epithelium has cells taller than they are wide. However, when taller simple columnar epithelial cells are viewed in cross section showing several nuclei appearing at different heights and this kind of epithelium is therefore described as pseudostratified columnar epithelium. Transitional epithelium has cells that can change from squamous to cuboidal, Simple epithelium is a single layer of cells with every cell in direct contact with the basement membrane that separates it from the underlying connective tissue. In general, it is found where absorption and filtration occur, the thinness of the epithelial barrier facilitates these processes. In general, simple epithelial tissues are classified by the shape of their cells, the four major classes of simple epithelium are, simple squamous, simple cuboidal, simple columnar, pseudostratified. Simple squamous, which is found lining areas where passive diffusion of gases occur, E. g. skin, walls of capillaries, linings of the pericardial, pleural, and peritoneal cavities, as well as the linings of the alveoli of the lungs. Simple cuboidal, these cells may have secretory, absorptive, or excretory functions, examples include small collecting ducts of kidney, pancreas and salivary gland. Simple columnar, cells can be secretory, absorptive, or excretory, Simple columnar epithelium can be ciliated or non-ciliated, ciliated columnar is found in the reproductive tract. Non-ciliated epithelium can also possess microvilli, pseudostratified columnar epithelium, can be ciliated or non-ciliated. The ciliated type is called respiratory epithelium as it is almost exclusively confined to the larger respiratory airways of the nasal cavity, trachea. Stratified epithelium differs from simple epithelium in that it is multilayered and it is therefore found where body linings have to withstand mechanical or chemical insult such that layers can be abraded and lost without exposing subepithelial layers. Cells flatten as the layers become more apical, though in their most basal layers the cells can be squamous, stratified epithelia can have the following specializations, The basic cell types are squamous, cuboidal, and columnar classed by their shape

12.
Goblet cell carcinoid
–
They have a characteristic biphasic appearance which includes goblet cell-like cells, and neuroendocrine-type nuclear chromatin. GCCs have an aggressive course compared to other appendiceal neuroendocrine tumours

13.
Gastrointestinal tract
–
Gastrointestinal is an adjective meaning of or pertaining to the stomach and intestines. A tract is a collection of related anatomic structures or a series of connected body organs, the mouth, oesophagus, stomach, and intestines are part of the human alimentary canal. All bilaterians have a gastrointestinal tract, also called a gut or an alimentary canal and this is a tube that transfers food to the organs of digestion. In large bilaterians, the gastrointestinal tract generally also has an exit, some small bilaterians have no anus and dispose of solid wastes by other means. The gastrointestinal tract contains thousands of different bacteria in their gut flora, the human gastrointestinal tract consists of the esophagus, stomach, and intestines, and is divided into the upper and lower gastrointestinal tracts. In contrast, the digestive system comprises the gastrointestinal tract plus the accessory organs of digestion. The tract may also be divided into foregut, midgut, and hindgut, the whole human GI tract is about nine metres long at autopsy. The GI tract releases hormones from enzymes to help regulate the digestive process, the structure and function can be described both as gross anatomy and as microscopic anatomy or histology. The tract itself is divided into upper and lower tracts, the upper gastrointestinal tract consists of the buccal cavity, pharynx, esophagus, stomach, and duodenum. The exact demarcation between the upper and lower tracts is the muscle of the duodenum. Upon dissection, the duodenum may appear to be an organ, but it is divided into four segments based upon function, location. The four segments of the duodenum are as follows, bulb, descending, horizontal, the suspensory muscle attaches the superior border of the ascending duodenum to the diaphragm. The suspensory muscle is an important anatomical landmark which shows the division between the duodenum and the jejunum, the first and second parts of the small intestine. This is a muscle which is derived from the embryonic mesoderm. The lower gastrointestinal tract includes most of the intestine and all of the large intestine. In humans, the intestine is further subdivided into the duodenum, jejunum and ileum while the large intestine is subdivided into the cecum, colon, rectum. The small intestine begins at the duodenum, which receives food from the stomach and it is a tubular structure, usually between 6 and 7 m long. The area of the human, adult small intestinal mucosa is about 30 m2 and its main function is to absorb the products of digestion into the bloodstream

14.
Histology
–
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is commonly performed by examining cells and tissues under a microscope or electron microscope, the specimen having been sectioned, stained. Histological studies may be conducted using tissue culture, where human or animal cells are isolated and maintained in an artificial environment for various research projects. The ability to visualize or differentially identify microscopic structures is frequently enhanced through the use of histological stains, histology is an essential tool of biology and medicine. Trained physicians, frequently licensed pathologists, are the personnel who perform histopathological examination and their field of study is called histotechnology. In the 17th century, Italian Marcello Malpighi invented one of the first microscopes for studying tiny biological entities, Malpighi analysed several parts of the organs of bats, frogs and other animals under the microscope. Malpighi, while studying the structure of the lung, noticed its membranous alveoli and his discovery established how the oxygen we breathe enters the blood stream and serves the body. In the 19th century, histology was a discipline in its own right. The French anatomist Bichat introduced the concept of tissue in anatomy in 1801, the 1906 Nobel Prize in Physiology or Medicine was awarded to histologists Camillo Golgi and Santiago Ramon y Cajal. They had dueling interpretations of the structure of the brain based in differing interpretations of the same images. Cajal won the prize for his theory and Golgi for the staining technique he invented to make it possible. There are four types of animal tissues, muscle tissue, nervous tissue, connective tissue. All tissue types are subtypes of these four basic tissue types and their structure is very different from animal tissues. The most common fixative for light microscopy is 10% neutral buffered formalin, for electron microscopy, the most commonly used fixative is glutaraldehyde, usually as a 2. 5% solution in phosphate buffered saline. These fixatives preserve tissues or cells mainly by irreversibly cross-linking proteins and this can be detrimental to certain histological techniques. Further fixatives are often used for electron microscopy such as osmium tetroxide or uranyl acetate Formalin fixation leads to degradation of mRNA, miRNA and DNA in tissues, however, extraction, amplification and analysis of these nucleic acids from formalin-fixed, paraffin-embedded tissues is possible using appropriate protocols. Frozen section procedure is a way to fix and mount histology sections using a refrigeration device called a cryostat. It is often used after surgical removal of tumors to allow determination of margin

15.
Lymphovascular invasion
–
Lymphovascular invasion is spread of a cancer to the blood vessels and/or lymphatics. Lymph, A clear or white fluid that travels through vessels, moves within tissues, vascular, The bodys network of blood vessels. When cancer spreads to lymph and vascular system, it is termed as Lymphovascular Invasion. Lymphovascular invasion, especially in carcinomas, usually precedes spread to the nodes that drain the tissue in which the tumour arose. Conversely, cancers with lymph node spread, usually have lymphovascular invasion, lymph node metastases usually precede secondary tumours, i. e. distant metastases. The absence of LVI in the context of proven lymph node metastasis is thought to be due to sampling error. The predictive value and prevalence of lymphovascular invasion is strongly dependent on the type of cancer, in other words, LVI in one type of cancer may be much less important than LVI in another type of cancer. Generally speaking, it is associated with lymph node metastases which themselves are predictive of a poorer prognosis, in the context of proven lymph node metastases, LVI may have less prognostic significance or no prognostic significance. In breast cancer, LVI is not an independent risk factor for a poorer prognosis, in urothelial carcinoma, LVI is an independent predictor of a poorer prognosis that has more predictive power than tumour stage. In sporadic colorectal carcinoma, LVI of a poorer prognosis

16.
Mitosis
–
In cell biology, mitosis is a part of the cell cycle when replicated chromosomes are separated into two new nuclei. Mitosis and cytokinesis together define the phase of an animal cell cycle—the division of the mother cell into two daughter cells genetically identical to each other. The process of mitosis is divided into stages corresponding to the completion of one set of activities and these stages are prophase, prometaphase, metaphase, anaphase, and telophase. During mitosis, the chromosomes, which have already duplicated, condense, the result is two genetically identical daughter nuclei. The rest of the cell may then continue to divide by cytokinesis to produce two daughter cells, producing three or more daughter cells instead of normal two is a mitotic error called tripolar mitosis or multipolar mitosis. Other errors during mitosis can induce apoptosis or cause mutations, certain types of cancer can arise from such mutations. Mitosis occurs only in eukaryotic cells, prokaryotic cells, which lack a nucleus, divide by a different process called binary fission. Most animal cells undergo a change, known as mitotic cell rounding. Most human cells are produced by cell division. Important exceptions include the gametes – sperm and egg cells – which are produced by meiosis, german zoologist Otto Bütschli might have claimed the discovery of the process presently known as mitosis, a term coined by Walther Flemming in 1882. Mitosis was discovered in frog, rabbit, and cat cornea cells in 1873, the term is derived from the Greek word μίτος mitos warp thread. The primary result of mitosis and cytokinesis is the transfer of a parent cells genome into two daughter cells, the genome is composed of a number of chromosomes—complexes of tightly coiled DNA that contain genetic information vital for proper cell function. Because each resultant daughter cell should be identical to the parent cell. This occurs during the S phase of interphase, chromosome duplication results in two identical sister chromatids bound together by cohesin proteins at the centromere. When mitosis begins, the chromosomes condense and become visible, in some eukaryotes, for example animals, the nuclear envelope, which segregates the DNA from the cytoplasm, disintegrates into small vesicles. The nucleolus, which makes ribosomes in the cell, also disappears, microtubules project from opposite ends of the cell, attach to the centromeres, and align the chromosomes centrally within the cell. The microtubules then contract to pull the chromatids of each chromosome apart. Sister chromatids at this point are called daughter chromosomes, as the cell elongates, corresponding daughter chromosomes are pulled toward opposite ends of the cell and condense maximally in late anaphase

17.
Ki-67 (protein)
–
Antigen KI-67 also known as Ki-67 or MKI67 is a protein that in humans is encoded by the MKI67 gene. Antigen KI-67 is a protein that is associated with and may be necessary for cellular proliferation. Furthermore, it is associated with ribosomal RNA transcription, inactivation of antigen KI-67 leads to inhibition of ribosomal RNA synthesis. The Ki-67 protein is a marker for proliferation. It is strictly associated with cell proliferation, during interphase, the Ki-67 antigen can be exclusively detected within the cell nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. Ki-67 protein is present during all phases of the cell cycle. Ki-67 is an excellent marker to determine the fraction of a given cell population. The fraction of Ki-67-positive tumor cells is correlated with the clinical course of cancer. The best-studied examples in this context are carcinomas of the prostate, brain, for these types of tumors, the prognostic value for survival and tumor recurrence have repeatedly been proven in uni- and multivariate analysis. Ki-67 and MIB-1 monoclonal antibodies are directed against different epitopes of the same proliferation-related antigen, Ki-67 and MIB1 may be used on fixed sections. MIB-1 is used in applications to determine the Ki-67 labelling index. One of its advantages over the original Ki-67 antibody is that it can be used on formalin-fixed paraffin-embedded sections. The Ki-67 protein was originally defined by the monoclonal antibody Ki-67. The name is derived from the city of origin and the number of the clone in the 96-well plate. Ki-67 has been shown to interact with CBX3, PCNA - Proliferating Cell Nuclear Antigen, expressed during the DNA synthesis. Ki-67 Antigen at the US National Library of Medicine Medical Subject Headings http, //www. pathologyoutlines. com/topic/stainski67. html

18.
Endocrine gland
–
Endocrine glands are glands of the endocrine system that secrete their products, hormones, directly into the blood rather than through a duct. The major glands of the system include the pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid gland, parathyroid gland, hypothalamus. The hypothalamus and pituitary gland are neuroendocrine organs, the ability of a target cell to respond to a hormone depends on the presence of receptors, within the cell or on its plasma membrane, to which the hormone can bind. Changes in number and sensitivity of hormone receptors may occur in response to high or low levels of stimulating hormones, blood levels of hormones reflect a balance between secretion and degradation/excretion. The liver and kidneys are the organs that degrade hormones, breakdown products are excreted in urine. Hormone half-life and duration of activity are limited and vary from hormone to hormone, permissiveness is the situation in which a hormone cannot exert its full effects without the presence of another hormone. Synergism occurs when two or more hormones produce the effects in a target cell and their results are amplified. Antagonism occurs when a hormone opposes or reverses the effect of another hormone, the endocrine glands belong to the bodys control system. The hormones which they help to regulate the functions of cells. Endocrine organs are activated to release their hormones by humoral, neural or hormonal stimuli, negative feedback is important in regulating hormone levels in the blood. The nervous system, acting through hypothalamic controls, can in certain cases override or modulate hormonal effects, the pituitary gland hangs from the base of the brain by a stalk and is enclosed by bone. It consists of a glandular portion and a neural portion. The hypothalamus regulates the output of the anterior pituitary and synthesizes two hormones that it exports to the posterior pituitary for storage and later release. Four of the six anterior pituitary hormones are tropic hormones that regulate the function of other endocrine organs, most anterior pituitary hormones exhibit a diurnal rhythm of release, which is subject to modification by stimuli influencing the hypothalamus. Somatotropic hormone or Growth hormone is a hormone that stimulates growth of all body tissues but especially skeletal muscle. It may act directly, or indirectly via insulin-like growth factors, GH mobilizes fats, stimulates protein synthesis, and inhibits glucose uptake and metabolism. Secretion is regulated by growth hormone releasing hormone and growth hormone inhibiting hormone, hypersecretion causes gigantism in children and acromegaly in adults, hyposecretion in children causes pituitary dwarfism. Thyroid-stimulating hormone promotes normal development and activity of the thyroid gland, thyrotropin-releasing hormone stimulates its release, negative feedback of thyroid hormone inhibits it

19.
Pancreatic islets
–
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine cells, discovered in 1869 by German pathological anatomist Paul Langerhans. New studies show that the pancreatic islets constitute approximately 4. 5% of the pancreas volume, the islets of Langerhans are arranged in density routes throughout the healthy human pancreas. Islets of Langerhans can also form super structures called Islet clusters which are composed of small islets that surround large blood vessels, the roundness of islets along the pancreas has also been quantified through the Index of Sphericity method. Thus, the islets closest to the form are mainly found in the pancreas tail whereas the islets farthest from the spherical form are found in the pancreas neck. Hormones produced in the islets are secreted directly into the blood flow by five types of cells. It has turned out that the behavior of cells in intact islets differs significantly from the behavior of dispersed cells, the beta cells of the pancreatic islets secrete insulin, and so play a significant role in diabetes. It is thought that they are destroyed by immune assaults, however, there are also indications that beta cells have not been destroyed but have only become non-functional. Islet transplantation emerged as an option for the treatment of insulin requiring diabetes in the early 1970s with steady progress over the last three decades. Islet transplantation for type 1 diabetes currently requires potent immunosuppression to prevent host rejection of donor islets, an alternative source of beta cells, such insulin-producing cells derived from adult stem cells or progenitor cells would contribute to overcoming the shortage of donor organs for transplantation. The field of medicine is rapidly evolving and offers great hope for the nearest future. However, type 1 diabetes is the result of the destruction of beta cells in the pancreas. Therefore, a cure will require a sequential, integrated approach that combines adequate. Another potential source of cells may be xenotransplantation. The most likely source for xenogeneic islets for transplantation into human under evaluation is the pig pancreas, several studies in small and large animals models have shown that transplantation of islet cells across species is possible. However, several problems need to be overcome for porcine islet transplantation to become a viable clinical option, the immunogenicity of xenogeneic tissues may be different from and even stronger than allogeneic tissues. For instance, Galalpha1-3Galbeta1-4GlcNAc expressed on porcine cells represents a major barrier to xenotransplantation being the target of preformed antibodies present in human blood, remarkable progress has been recorded in the development of genetically modified pigs lacking or overexpressing molecules that may improve acceptance of transplanted tissues across into humans. Pigs lacking alpha-Gal or overexpressing human decay accelerating factor, amongst others, have been generated to study the impact on transplanted outcome in nonhuman primate models. Another possible antigenic target is the Hanganutziu-Deichter antigen, an acid found in pigs and not humans

20.
Parafollicular cell
–
Parafollicular cells are neuroendocrine cells in the thyroid which primary function is to secrete calcitonin. They are located adjacent to the follicles and reside in the connective tissue. These cells are large and have a pale stain compared with the cells or colloid. In teleost and avian species these cells occupy a structure outside the thyroid gland named the ultimobranchial body, parafollicular cells are pale-staining cells found in small number in the thyroid and are typically situated basally in the epithelium, without direct contact with the follicular lumen. They are always situated within the basement membrane, which surrounds the entire follicle, recent research has confirmed that parafollicular cells are derived from endoderm. This is in contrast to the held belief that they were neural crest derived. Until recently, parafollicular cells were believed to be derived from neural crest cells, embryologically, they associate with the ultimobranchial body, which is a ventral derivative of the fourth pharyngeal pouch. In a series of experiments, neural crest cells were transplanted from quail, with unique and easily identified nuclei, the presence of cells with quail nuclei populating the ultimobranchial body was demonstrated, which raised the conclusion that C cells migrate during embryologic development from the neural crest. Parafollicular cells secrete calcitonin, a hormone that participates in the regulation of calcium metabolism and it is important in fish and rodents, but its relevance in humans has not been demonstrated. Calcitonin lowers blood levels of calcium by inhibiting the resorption of bone by osteoclasts, parafollicular cells are also known to secrete in smaller quantities several neuroendocrine peptides such as serotonin, somatostatin or CGRP. They may also have a role in regulating thyroid hormones production locally, when parafollicular cells become cancerous, they lead to medullary carcinoma of the thyroid. Yoko Kameda Y and associatesshowed that C cells derive from pharyngeal endoderm along with thyroid, localization of immunoreactive calcitonin gene-related peptide in thyroid C dells from various mammalian species. Kameda, T. Nishimaki, M. Miura, S. X, mash1 regulates the development of C cells in mouse thyroid glands. Kameda, T. Nishimaki, O. Chisaka, S. Iseki, expression of the epithelial marker E-cadherin by thyroid C cells and their precursors during murine development. Kameda, M. Ito, T. Nishimaki, N. Gotoh, fRS2α is required for the separation, migration, and survival of pharyngeal-endoderm derived organs including thyroid, ultimobranchial body, parathyroid, and thymus. Cellular and molecular events on the development of mammalian thyroid C cells, cellular and molecular events on the development of mammalian C cells. Dev Dyn 245, 323-341 Baber EC, Contributions to the anatomy of the thyroid gland of the dog.287

21.
Foregut
–
The foregut is the anterior part of the alimentary canal, from the mouth to the duodenum at the entrance of the bile duct, and is attached to the abdominal walls by mesentery. The foregut develops from the primitive gut, and is developmentally distinct from the midgut and hindgut. Although the term “foregut” is typically used in reference to the section of the primitive gut. Pain in the region, just below the intersection of the ribs. In mammals, it is composed of number of interconnected ganglia that are arranged into two concentric rings embedded throughout the gut wall, beginning in the esophagus and ending in the anus. The main function of the ENS is to control the activity of the gastrointestinal glands. A large number of derived from the developing foregut also receive input from the vagus nerve. The foregut develops from a region of endoderm created after the initial cephalocaudal folding of the embryo. Simultaneously, the stomach begins to expand in width dorsally and ventrally in an asymmetric manner and this rotation positions the left vagus nerve anteriorly and right vagus nerve posteriorly. While the hindgut and midgut are only attached dorsally to the wall by a fold of peritoneum. Its two attachments are commonly referred to as the dorsal mesogastrium and the ventral mesogastrium, after this rotation the dorsal mesentery thins and forms the greater omentum, which is attached to the greater curvature of the stomach. The ventral mesentery forms the lesser omentum, and is attached to the developing liver, arterial supply to all these structures is from the celiac trunk, and venous drainage is by the portal venous system. Lymph from these organs is drained to the prevertebral celiac nodes at the origin of the artery from the aorta. In vertebrates, functional differentiation continues even after birth, with the transformation into the adult phenotype occurring through epithelial-mesenchymal transition, patterning events that determine tissue differentiation in vertebrates rely on several hox genes, the morphogen sonic hedgehog, and transcription factors such as sox2 and sox9. Esophageal atresia is a defect of the digestive system in which the continuity of the esophageal wall is interrupted. In most cases, the upper esophagus fails to connect with the lower esophagus, esophageal stricture is the narrowing of the esophagus resulting in swallowing difficulties. Pyloric stenosis is the thickening of the muscle forms the pyloric sphincter. Biliary atresia is a defect where the common bile duct

22.
Midgut
–
The midgut is the portion of the embryo from which most of the intestines develop. After it bends around the superior mesenteric artery, it is called the midgut loop and it comprises the portion of the alimentary canal from the end of the foregut at the opening of the bile duct to the hindgut, about two-thirds of the way through the transverse colon. During development, the midgut undergoes a rapid phase of growth in which the loop of midgut herniates outside of the abdominal cavity of the fetus. Later in development, the fetuss body catches up in relative to the midgut. The midgut loops slips back out of the cord and the physiological hernia ceases to exist. This change coincides with the termination of the sac and the counterclockwise rotation of the two limbs of the midgut loop around their combined central axis. Duodenum Jejunum Ileum Cecum Appendix Ascending colon Hepatic flexure of colon Transverse colon Arterial supply to the midgut is from the superior mesenteric artery, venous drainage is to the portal venous system. Lymph from the midgut drains to prevertebral superior mesenteric nodes located at the origin of the superior mesenteric artery from the aorta, portal drainage carries all non-lipid nutrients from digestion to the liver for processing and detoxification, while lymphatic drainage carries fatty chyle to the cisterna chyli. Autonomic innervation of the midgut is from the superior mesenteric plexus, malrotation of the midgut during development can lead to volvulus. Pain in the midgut is referred to the region around the belly button As stated, if this persists after birth it is called an omphalocele. In omphalocele, there is a defect in the development of the abdominal wall. Foregut Hindgut digest-020—Embryo Images at University of North Carolina radio/450 at eMedicine – Midgut Volvulus 00494 at CHORUS Umich. edu – development

23.
Hindgut
–
The hindgut is the posterior part of the alimentary canal. In mammals, it includes the third of the transverse colon and the splenic flexure. In zoology, the term refers also to the cecum. Arterial supply is by the Inferior mesenteric artery, and venous drainage is to the venous system. Lymphatic drainage is to the chyle cistern, the hindgut is innervated via the inferior mesenteric plexus. Sympathetic innervation is from the Lumbar splanchnic nerves, parasympathetic innervation is from S2-S4, hindgut fermentation digest-035—Embryo Images at University of North Carolina

24.
Peripheral nervous system
–
The peripheral nervous system is one of the two main parts of the nervous system, the other part is the central nervous system. The PNS consists of the nerves and ganglia outside of the brain, the main function of the PNS is to connect the CNS to the limbs and organs, essentially serving as a relay between the brain and spinal cord and the rest of the body. Unlike the CNS, the PNS is not protected by the column and skull, or by the blood–brain barrier. The peripheral nervous system is divided into the nervous system. In the somatic nervous system, the nerves are part of the PNS with the exception of the optic nerve. The second cranial nerve is not a peripheral nerve but a tract of the diencephalon. Cranial nerve ganglia originate in the CNS, however, the remaining ten cranial nerve axons extend beyond the brain and are therefore considered part of the PNS. The autonomic nervous system is a control of smooth muscle. The connection between CNS and organs allows the system to be in two different functional states, sympathetic and parasympathetic, the peripheral nervous system is divided into the somatic nervous system, and the autonomic nervous system. The somatic nervous system is under control, and transmits signals from the brain to end organs such as muscles. The sensory nervous system is part of the nervous system and transmits signals from senses such as taste and touch to the spinal cord. The autonomic nervous system is a system which influences the function of organs outside of voluntary control. The somatic system includes the sensory system and the somatosensory system and consists of sensory nerves and somatic nerves. In the head and neck, cranial nerves carry somatosensory data, there are twelve cranial nerves, ten of which originate from the brainstem, and mainly control the functions of the anatomic structures of the head with some exceptions. The nuclei of the nerve and the optic nerves lie in the forebrain and thalamus, respectively. One unique cranial nerve is the nerve, which receives sensory information from organs in the thorax. The accessory nerve is responsible for innervating the sternocleidomastoid and trapezius muscles, for the rest of the body, Spinal nerves are responsible for somatosensory information. These arise from the spinal cord, usually these arise as a web of interconnected nerves roots that arrange to form single nerves

The diagram shows the structural differences between rat islets (top) and humans islets (bottom) as well as the ventral part (left) and the dorsal part (right) of the pancreas. Different cell types are colour-coded. Rodent islets, unlike the human ones, show the characteristic insulin core.

The nervous system is the part of an animal that coordinates its actions by transmitting signals to and from different …

Horizontal section of the head of an adult female, showing skin, skull, and brain with grey matter (brown in this image) and underlying white matter

Major elements in synaptic transmission. An electrochemical wave called an action potential travels along the axon of a neuron. When the wave reaches a synapse, it provokes release of a small amount of neurotransmitter molecules, which bind to chemical receptor molecules located in the membrane of the target cell.

A heart valve normally allows blood to flow in only one direction through the heart. The four valves commonly …

This is further explanation of the echocardiogram above. MV: Mitral valve, TV: Tricuspid valve, AV: Aortic valve, Septum: Interventricular septum. Continuous lines demarcate septum and free wall seen in echocardiogram, dotted line is a suggestion of where the free wall of the right ventricle should be. The red line represents where the upper left loop in the echocardiogram transects the 3D-loop, the blue line represents the lower loop.

Illustration of the valves of the heart when the ventricles are contracting.

Structure of the heart valves

Wiggers diagram, showing various events during a cardiac cycle, with closures and openings of the aortic and mitral marked in the pressure curves.