Lymphatic fluid is squeezed through the vessels when we use our muscles

Lymphatic system is part of the immune system

  •  maintains fluid balance and plays a role in absorbing fats and fat-soluble nutrients
  • involves an extensive network of vessels that passes through almost all our tissues to allow for the movement of a fluid called lymph
  • lymph circulates through the body in a similar way to blood
How do you keep the lymph system healthy?
  1. Regular exercise
    can help to reduce the amount of tissue edema and swelling that the veins and lymph system need to clear.
  2. Treat lymph system damage early.  If you have swelling in an arm or leg from previous injury or cancer treatment, make sure you get treatment early. Reducing the length of time that the lymph system is over-taxed may decrease the long term damage. Kind of like a hernia – you should get it fixed sooner rather than later or it will just expand and get worse.
  3. Avoid tight fitting clothes.  If you have lymphatic issues, compressing the area with tight clothing will only make things worse.
  4. Physical therapy.  Some physical therapists (PTs) specialize in treating lymphedema. They have developed excellent massage techniques that can help to “milk” the lymph back to the blood circulation (called manual lymph drainage). They can also provide special wraps to reduce arm and leg swelling.

Lymphatic filariasis is a parasitic disease caused by three species of microscopic, thread-like worms. The adult worms only live in the human lymph system. The lymph system maintains the body’s fluid balance and fights infections. … People with theworms in their blood can give the infection to others through mosquitoes.

The filarial parasites specifically target the lymphatics and impair lymph flow, which is critical for the normal functions of the lymphatic system

Note: Women should not wear tight fitting clothes to allow the lymph to function and clean the blood.

LYMPHATIC CIRCULATION

The lymph is moved through the body in its own vessels making a one-way journey from the interstitial spaces to the subclavian veins at the base of the neck.

  • Since the lymphatic system does not have a heart to pump it, its upward movement depends on the motions of the muscle and joint pumps.
  • As it moves upward toward the neck the lymph passes through lymph nodes which filter it  to remove debris and pathogens.
  • The cleansed lymph continues to travel in only one direction, which is upward toward the neck.
  • At the base of the neck, the cleansed lymph flows into the subclavian veins on either side of the neck.

What can go wrong with the lymphatic system?

  1. Mechanical damage can disrupt the flow of lymph fluid, causing fluid back up and swelling.
    The lymph vessels are very delicate (almost like spider webs), and their walls are not as tough as arteries or veins. They are therefore quite prone to injury by mechanical and compressive forces. The most common causes of lymphatic system injury are surgery, radiation, and trauma. Luckily the lymphatic system is a complex web that can usually find flow work-arounds. However, if there is extensive damage in a specific area, it can be overwhelming and result in swelling to the nearby limb (for example) previously served by that part of the system.
  2. Cancer can plug up the system or cancer treatment can damage the lymphatics.
    When white blood cells divide out of control and become cancerous, it makes sense that they can damage the circulatory lymph system where they live. Lymphoma is a cancer of the lymph system that directly damages it. Sometimes cancer spreads through the lymph system and travels to other parts of the body. When cancer gets into the lymph nodes, physicians sometimes have to cut those nodes out (lymph node dissections are common in breast cancer treatment, for example) or use radiation to burn the cancer. This can lead to chronic swelling issues in the arms or legs, known as lymphedema.
  3. Parasites can block the lymphatic system.
    As discussed earlier, certain parasitic worms have an affinity for the lymph system and although they can be killed with medicines, the damage they do to the lymph vessels and nodes may be permanent.

There are about 600 lymph nodes in the body. These nodes swell in response to infection, due to a build-up of lymph fluid, bacteria, or other organisms and immune system cells.

A person with a throat infection, for example, may feel that their “glands” are swollen. Swollen glands can be felt especially under the jaw, in the armpits, or in the groin area. These are, in fact, not glands but lymph nodes.

They should see a doctor if swelling does not go away, if nodes are hard or rubbery and difficult to move, if there is a fever, unexplained weight-loss, or difficulty breathing or swallowing.

Source: https://www.medicalnewstoday.com/articles/303087.php

Fast facts about the lymphatic system

  • The lymphatic system plays a key role in the immune system, fluid balance, and absorption of fats and fat-soluble nutrients.
  • As lymph vessels drain fluid from body tissues, this enables foreign material to be delivered to the lymph nodes for assessment by immune system cells.
  • The lymph nodes swell in response to infection, due to a build-up of lymph fluid, bacteria, or other organisms and immune system cells.
  • Lymph nodes can also become infected, in a condition known as lymphadenitis.
  • If lymph nodes remain swollen, if they are hard and rubbery, and if there are other symptoms, you should see a doctor.

Definition

Lymph nodes, or

Lymph nodes, or “glands” may swell as the body responds to a threat.

The lymphatic system has three main functions:

  • It maintains the balance of fluid between the blood and tissues, known as fluid homeostasis.
  • It forms part of the body’s immune system and helps defend against bacteria and other intruders.
  • It facilitates absorption of fats and fat-soluble nutrients in the digestive system.

The system has special small vessels called lacteals. These enable it to absorb fats and fat-soluble nutrients from the gut.

They work with the blood capillaries in the folded surface membrane of the small intestine. The blood capillaries absorb other nutrients directly into the bloodstream.

Anatomy

The lymphatic system consists of lymph vessels, ducts, nodes, and other tissues.

Around 2 liters of fluid leak from the cardiovascular system into body tissues every day. The lymphatic system is a network of vessels that collect these fluids, or lymph. Lymph is a clear fluid that is derived from blood plasma.

The lymph vessels form a network of branches that reach most of the body’s tissues. They work in a similar way to the blood vessels. The lymph vessels work with the veins to return fluid from the tissues.

Unlike blood, the lymphatic fluid is not pumped but squeezed through the vessels when we use our muscles. The properties of the lymph vessel walls and the valves help control the movement of lymph. However, like veins, lymphatic vessels have valves inside them to stop fluid from flowing back in the wrong direction.

Lymph is drained progressively towards larger vessels until it reaches the two main channels, the lymphatic ducts in our trunk. From there, the filtered lymph fluid returns to the blood in the veins.

The vessels branch through junctions called lymph nodes. These are often referred to as glands, but they are not true glands as they do not form part of the endocrine system.

In the lymph nodes, immune cells assess for foreign material, such as bacteria, viruses, or fungus.

Lymph nodes are not the only lymphatic tissues in the body. The tonsils, spleen, and thymus gland are also lymphatic tissues.

What do the tonsils do?

In the back of the mouth, there are tonsils. These produce lymphocytes, a type of white blood cell, and antibodies.

They have a strategic position, hanging down from a ring forming the junction between the mouth and pharynx. This enables them to protect against inhaled and swallowed foreign bodies. The tonsils are the tissues affected by tonsillitis.

What is the spleen?

The spleen is not connected to the lymphatic system in the same way as lymph nodes, but it is lymphoid tissue. This means it plays a role in the production of white blood cells that form part of the immune system.

Its other major role is to filter the blood to remove microbes and old and damaged red blood cells and platelets.

The thymus gland

The thymus gland is a lymphatic organ and an endocrine gland that is found just behind the sternum. It secretes hormones and is crucial in the production, maturation, and differentiation of immune T cells.

It is active in developing the immune system from before birth and through childhood.

The bone marrow

Bone marrow is not lymphatic tissue, but it can be considered part of the lymphatic system because it is here that the B cell lymphocytes of the immune system mature.

Liver of a fetus

During gestation, the liver of a fetus is regarded as part of the lymphatic system as it plays a role in lymphocyte development.

Below is a 3-D model of the lymphatic system, which is fully interactive.

Explore the model using your mouse pad or touchscreen to understand more about the lymphatic system.

Function

The lymph system has three main functions.

Fluid balance

The lymphatic system helps maintain fluid balance. It returns excess fluid and proteins from the tissues that cannot be returned through the blood vessels.

The fluid is found in tissue spaces and cavities, in the tiny spaces surrounding cells, known as the interstitial spaces. These are reached by the smallest blood and lymph capillaries.

Around 90 percent of the plasma that reaches tissues from the arterial blood capillaries is returned by the venous capillaries and back along veins. The remaining 10 percent is drained back by the lymphatics.

Each day, around 2-3 liters is returned. This fluid includes proteins that are too large to be transported via the blood vessels.

Loss of the lymphatic system would be fatal within a day. Without the lymphatic system draining excess fluid, our tissues would swell, blood volume would be lost and pressure would increase.

Absorption

Most of the fats absorbed from the gastrointestinal tract are taken up in a part of the gut membrane in the small intestine that is specially adapted by the lymphatic system.

The lymphatic system has tiny lacteals in this part of the intestine that form part of the villi. These finger-like protruding structures are produced by the tiny folds in the absorptive surface of the gut.

Lacteals absorb fats and fat-soluble vitamins to form a milky white fluid called chyle.

This fluid contains lymph and emulsified fats, or free fatty acids. It delivers nutrients indirectly when it reaches the venous blood circulation. Blood capillaries take up other nutrients directly.

The immune system

The lymphatic system produces white blood cells, or lymphocytes that are crucial in fending off infections.

The lymphatic system produces white blood cells, or lymphocytes that are crucial in fending off infections.

The third function is to defend the body against unwanted organisms. Without it, we would die very soon from an infection.

Our bodies are constantly exposed to potentially hazardous micro-organisms, such as infections.

The body’s first line of defense involves:

  • physical barriers, such as the skin
  • toxic barriers, such as the acidic contents of the stomach
  • “friendly” bacteria in the body

However, pathogens often do succeed in entering the body despite these defenses. In this case, the lymphatic system enables our immune system to respond appropriately.

If the immune system is not able to fight off these micro-organisms, or pathogens, they can be harmful and even fatal.

A number of different immune cells and special molecules work together to fight off the unwanted pathogens.

How does the lymphatic system fight infection?

The lymphatic system produces white blood cells, known as lymphocytes. There are two types of lymphocyte, T cells and B cells. They both travel through the lymphatic system.

As they reach the lymph nodes, they are filtered and become activated by contact with viruses, bacteria, foreign particles, and so on in the lymph fluid. From this stage, the pathogens, or invaders, are known as antigens.

As the lymphocytes become activated, they form antibodies and start to defend the body. They can also produce antibodies from memory if they have already encountered the specific pathogen in the past.

Collections of lymph nodes are concentrated in the neck, armpits, and groin. We become aware of these on one or both sides of the neck when we develop so-called “swollen glands” in response to an illness.

It is in the lymph nodes that the lymphocytes first encounter the pathogens, communicate with each other, and set off their defensive response.

Activated lymphocytes then pass further up the lymphatic system so that they can reach the bloodstream. Now, they are equipped to spread the immune response throughout the body, through the blood circulation.

The lymphatic system and the action of lymphocytes, of which the body has trillions, form part of what immunologists call the “adaptive immune response.” These are highly specific and long-lasting responses to particular pathogens.

Diseases

The lymphatic system can stop working properly if nodes, ducts, vessels, or lymph tissues become blocked, infected, inflamed, or cancerous.

Lymphoma

Cancer that starts in the lymphatic system is known as lymphoma. It is the most serious lymphatic disease.

Hodgkin lymphoma affects a specific type of white blood cell known as Reed-Sternberg cells. Non-Hodgkin lymphoma refers to types that do not involve these cells.

Cancer that affects the lymphatic system is usually a secondary cancer. This means it has spread from a primary tumor, such as the breast, to nearby or regional lymph nodes.

Drainage areas

  • Damage disturbs the flow. When lymphatic tissues or lymph nodes have been damaged, destroyed or removed, lymph cannot drain normally from the affected area. When this happens excess lymph accumulates and results in the swelling that is characteristic of lymphedema.
  • Drainage areas. The treatment of lymphedema is based on the natural structures and the flow of lymph. The affected drainage area determines the pattern of the manual lymph drainage (MLD) and for self-massage. Although lymph does not normally cross from one area to another, MLD stimulates the flow from one area to another. It also encourages the formation of new lymph drainage pathways.
  • MLD treatment and self-massage begin by stimulating the area near the terminus and the larger lymphatic vessels. This stimulates the flow of lymph that is already in the system and frees space for the flow of the lymph that is going to enter the capillaries during the treatment.
  • MLD treatment continues as a gentle massage technique to stimulate the movement of the excess lymph in affected tissues. The rhythmic, light strokes of MLD provide just the right pressure to encourage this excess lymph to flow into the lymph capillaries.
  • The compression garments, aids, and/or bandages that are worn between treatments help control swelling by providing pressure that is needed to encourage the flow of lymph into the capillaries.
  • Exercise is important in the treatment of lymphedema because the movements of the muscles stimulate the flow of the lymph into the capillaries. Wearing a compression garment during exercise also provides resistance to further stimulate this flow.
  • Self-massage or simplified lympatic drainage, as prescribed by your therapist, is another way in which lymph is encouraged to flow into the capillaries. Each self-massage session begins at the terminus with strokes to stimulate the flow of lymph that is already in the system. This is followed by specialized strokes that encourage the flow of lymph into the capillaries and then upward to the terminus.

Other lymphatic system organs

The lymphatic system includes other organs, such as the spleen, thymus, tonsils and adenoids.

The spleen

The spleen is under your ribs, on the left side of your body. It has 2 main different types of tissue, red pulp and white pulp.

The red pulp filters worn out and damaged red blood cells from the blood and recycles them.

The white pulp contains many B lymphocytes and T lymphocytes. These are white blood cells that are very important for fighting infection. As blood passes through the spleen, these blood cells pick up on any sign of infection or illness and begin to fight it.

The thymus

The thymus is a small gland under your breast bone. It helps to produce white blood cells to fight infection. It is usually most active in teenagers and shrinks in adulthood.

The tonsils and adenoids

The tonsils are 2 glands in the back of your throat.

The adenoids are glands at the back of your nose, where it meets the back of your throat. The adenoids are also called the nasopharyngeal tonsils.

The tonsils and adenoids help to protect the entrance to the digestive system and the lungs from bacteria and viruses.

Exercises

https://www.google.com/search?q=exercises+for+the+lymphatic+system&rlz=1CAVNXA_enUS848&oq=exercises+for+the+lypm&aqs=chrome.1.69i57j0.8284j0j7&sourceid=chrome&ie=UTF-8

Massage

https://www.google.com/search?rlz=1CAVNXA_enUS848&ei=wu44XaKIMM680PEP3NissAE&q=massage+lymphatic+nodes&oq=massage+lymphatic+nodes&gs_l=psy-ab.3..0i22i30l10.4545.6438..6659…0.0..0.118.705.7j1……0….1..gws-wiz…….0i71j0i13j0i13i30j0.7JrbPFXh7KI&ved=0ahUKEwii8c7J387jAhVOHjQIHVwsCxYQ4dUDCAo&uact=5

 

Quickly assesses live tissue cellular antioxidant levels

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Quickly assesses live tissue cellular antioxidant levels in response to ROS

Complete labs have there place but a portable biophotonic scan measuring your anti-oxidant level can help you find what is missing in your body with whole foods, exercise, sleep, de-stressing and supplementation ( using AgeLOC and other nutrients). Get a reading of your anti-oxidant in the bay area. Call or text Connie at 408-854-1883 or motherhealth@gmail.com. Doctors and nurses are welcome to get this scanner to help your patients. Free training on Sept 14-15 in Utah. Connie will also provide health coaching training before then.

We work with Acupuncture professionals such as the Golden State Warriors team acupuncturists, Author, Dr. Steven Rosenblatt MD, Ph D, LAc etc. and functional medicine Doc’s. This does not replace other labs but quickly assesses live tissue cellular antioxidant levels in response to ROS.

Invented by NIH.


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 Rapamycin as immunosuppressive agent

mTOR signaling pathway in human cancer

Signaling pathway of mTOR

Many human tumors occur because of dysregulation of mTOR signaling, and can confer higher susceptibility to inhibitors of mTOR.[17] Deregulations of multiple elements of the mTOR pathway, like PI3K amplification/mutationPTEN loss of function, AKT overexpression, and S6K1, 4EBP1, and eIF4E overexpression have been related to many types of cancers. Therefore, mTOR is an interesting therapeutic target for treating multiple cancers, both the mTOR inhibitors themselves or in combination with inhibitors of other pathways.[1]

Upstream, PI3K/AKT signalling is deregulated through a variety of mechanisms, including overexpression or activation of growth factor receptors, such as HER-2 (human epidermal growth factor receptor 2) and IGFR (insulin-like growth factor receptor), mutations in PI3K and mutations/amplifications of AKT.[1] Tumor suppressor phosphatase and tensin homologuedeleted on chromosome 10 (PTEN) is a negative regulator of PI3K signaling. In many cancers the PTEN expression is decreased and may be downregulated through several mechanisms, including mutationsloss of heterozygositymethylation, and protein instability.[16]

Downstream, the mTOR effectors S6 kinase 1 (S6K1), eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and eukaryotic initiation factor 4E (eIF4E) are related to cellular transformation.[1] S6K1 is a key regulator of cell growth and also phosphorylates other important targets. Both eIF4E and S6K1 are included in cellular transformation and their overexpression has been linked to poor cancer prognosis.[16]

Development of mTOR inhibitors

Since the discovery of mTOR, much research has been done on the subject, using rapamycin and rapalogs to understand its biological functions.[15][18] The clinical results from targeting this pathway were not as straight forward as thought at first. Those results have changed the course of clinical research in this field.[15]

Initially, rapamycin was developed as an antifungal drug against Candida albicansAspergillus fumigatus and Cryptococcus neoformans.[5] Few years later its immunosuppressive properties were detected. Later studies led to the establishment of rapamycin as a major immunosuppressant against transplant rejection, along with cyclosporine A.[2] By using rapamycin in combination with cyclosporin A, it enhanced the rejection prevention in renal transplantation. Therefore, it was possible to use lower doses of cyclosporine which minimized toxicity of the drug.[5]

In the 1980s rapamycin was evaluated by the Developmental Therapeutic Branch of the National Cancer Institute (NCI). It was discovered that rapamycin had an anticancer activity and was a non-cytotoxic agent with cytostatic activity against several human cancer types.[5] However, due to unfavorable pharmacokinetic properties, the development of mTOR inhibitors for the treatment of cancer was not successful at that time.[3] Since then, rapamycin has also shown to be effective for preventing coronary artery re-stenosis and for the treatment of neurodegenerative diseases.[5]

First generation mTOR inhibitors

The development of rapamycin as an anticancer agent began again in the 1990s with the discovery of temsirolimus (CCI-779). This was a novel soluble rapamycin derivative that had a favorable toxicological profile in animals. More rapamycin derivatives with improved pharmacokinetics and reduced immunosuppressive effects have since then been developed for the treatment of cancer.[5] These rapalogs include temsirolimus (CCI-779), everolimus (RAD001), and ridaforolimus (AP-23573) which are being evaluated in cancer clinical trials.[19] Rapamycin analogs have similar therapeutic effects as rapamycin. However they have improved hydrophilicity and can be used for oral and intravenous administration.[4] In 2012 National Cancer Institute listed more than 200 clinical trials testing the anticancer activity of rapalogs both as monotherapy or as a part of combination therapy for many cancer types.[7]

Rapalogs, which are the first generation mTOR inhibitors, have proven effective in a range of preclinical models. However, the success in clinical trials is limited to only a few rare cancers.[20] Animal and clinical studies show that rapalogs are primarily cytostatic, and therefore effective as disease stabilizers rather than for regression.[21]The response rate in solid tumors where rapalogs have been used as a single-agent therapy have been modest. Due to partial mTOR inhibition as mentioned before, rapalogs are not sufficient for achieving a broad and robust anticancer effect, at least when used as monotherapy.[19][20][22]

Another reason for the limited success is that there is a feedback loop between mTORC1 and AKT in certain tumor cells. It seems that mTORC1 inhibition by rapalogs fails to repress a negative feedback loop that results in phosphorylation and activation of AKT.[18][23] These limitations have led to the development of the second generation of mTOR inhibitors.[7]

Rapamycin and rapalogs

Rapamycin and rapalogs (rapamycin derivatives) are small molecule inhibitors,[24] which have been evaluated as anticancer agents. The rapalogs have more favorable pharmacokinetic profile compared to rapamycin, the parent drug,[3] despite the same binding sites for mTOR and FKBP12.[5]

Chemical structures of sirolimus and temsirolimus

Sirolimus[edit]

The natural antibiotic, rapamycin or sirolimus,[6] a cytostatic agent, has been used in combination therapy with corticosteroids and cyclosporine in patients who received kidney transplantation to prevent organ rejection both in the US[25] and Europe,[26] due to its unsatisfying pharmacokinetic properties.[3] In 2003, the U.S. Food and Drug Administration approved sirolimus-eluting coronary stents, which are used in patients with narrowing of coronary arteries, or so-called atherosclerosis.[27]

Recently rapamycin has shown effective in the inhibition of growth of several human cancers and murine cell lines.[5] Rapamycin is the main mTOR inhibitor, but deforolimus (AP23573), everolimus (RAD001), and temsirolimus (CCI-779), are the newly developed rapamycin analogs.[2]

Temsirolimus

The rapamycin analog, temsirolimus (CCI-779)[2] is also a noncytotoxic agent which delays tumor proliferation.

Temsirolimus is pro-drug of rapamycin. It is approved by the U.S. Food and Drug Administration (FDA)[25] and the European Medicines Agency (EMA),[28] for the treatment of renal cell carcinoma (RCC). Temsirolimus has higher water solubility than rapamycin and is therefore administrated by intravenous injection.[3][6] It was approved in May 30, 2007, by FDA for the treatment of advanced RCC.[6]

Everolimus

Chemical structure of everolimus

Everolimus is the second novel Rapamycin analog.[2] From March 30, 2009 to May 5, 2011 the U.S. FDA approved everolimus for the treatment of advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenibsubependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS), and progressive neuroendocrine tumors of pancreatic origin(PNET).[29] In July and August 2012, two new indications were approved, for advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, and pediatric and adult patients with SEGA.[29] In 2009 and 2011, it was also approved throughout the European Union for advanced breast cancer, pancreatic neuroendocrine tumours, advanced renal cell carcinoma,[30] and SEGA in patients with tuberous sclerosis.[31]

Ridaforolimus

Chemical structure of ridaforolimus

Ridaforolimus (AP23573, MK-8669), or deforolimus, is the newest rapamycin analog and it is not a prodrug.[2] Like temsirolimus it can be administrated intravenously, and oral formulation is being estimated for treatment of sarcoma.[3] It was not on market in June 2012, since FDA wanted more human testing on it due to its effectiveness and safety.[32]

Second generation mTOR inhibitors

Action point of first and second generation mTOR inhibitors on PI3K/AKT/mTOR pathway

The second generation of mTOR inhibitors is known as ATP-competitive mTOR kinase inhibitors.[7] mTORC1/mTORC2 dual inhibitors are designed to compete with ATP in the catalytic site of mTOR. They inhibit all of the kinase-dependent functions of mTORC1 and mTORC2 and therefore, block the feedback activation of PI3K/AKT signaling, unlike rapalogs that only target mTORC1.[7][18] These types of inhibitors have been developed and several of them are being tested in clinical trials. Like rapalogs, they decrease protein translation, attenuate cell cycle progression, and inhibit angiogenesis in many cancer cell lines and also in human cancer. In fact they have been proven to be more potent than rapalogs.[7]

Theoretically, the most important advantages of these mTOR inhibitors is the considerable decrease of AKT phosphorylation on mTORC2 blockade and in addition to a better inhibition on mTORC1.[15] However, some drawbacks exist. Even though these compounds have been effective in rapamycin-insensitive cell lines, they have only shown limited success in KRAS driven tumors. This suggests that combinational therapy may by necessary for the treatment of these cancers. Another drawback is also their potential toxicity. These facts have raised concerns about the long term efficacy of these types of inhibitors.[7]

The close interaction of mTOR with the PI3K pathway has also led to the development of mTOR/PI3K dual inhibitors.[7]Compared with drugs that inhibit either mTORC1 or PI3K, these drugs have the benefit of inhibiting mTORC1, mTORC2, and all the catalytic isoforms of PI3K. Targeting both kinases at the same time reduces the upregulation of PI3K, which is typically produced with an inhibition on mTORC1.[15] The inhibition of the PI3K/mTOR pathway has been shown to potently block proliferation by inducing G1 arrest in different tumor cell lines. Strong induction of apoptosis and autophagy has also been seen. Despite good promising results, there are preclinical evidence that some types of cancers may be insensitive to this dual inhibition. The dual PI3K/mTOR inhibitors are also likely to have increased toxicity.[7]

Mechanism of action

The studies of rapamycin as immunosuppressive agent enabled us to understand its mechanism of action.[5] It inhibits T-cell proliferation and proliferative responses induced by several cytokines, including interleukin 1 (IL-1)IL-2IL-3IL-4IL-6IGFPDGF, and colony-stimulating factors (CSFs).[5] Rapamycin inhibitors and rapalogs can target tumor growth both directly and indirectly. Direct impact of them on cancer cells depend on the concentration of the drug and certain cellular characteristics. The indirect way, is based on interaction with processes required for tumor angiogenesis.[5]

Effects in cancer cells

Effects of Rapamycin and rapalogs in cancer cells

Rapamycin and rapalogs crosslink the immunophilin FK506 binding protein, tacrolimus or FKBP-12, through its methoxy group. The rapamycin-FKBP12 complex interferes with FRB domain of mTOR.[5][6] Molecular interaction between FKBP12, mTOR, and rapamycin can last for about three days (72 hours). The inhibition of mTOR blocks the binding of the accessory protein raptor (regulatory-associated protein of mTOR) to mTOR, but that is necessary for downstreamphosphorylation of S6K1 and 4EBP1.[5][22]

As a consequence, S6K1 dephosphorylates, which reduces protein synthesis and decreases cell motality and size. Rapamycin induces dephosphorylation of 4EBP1 as well, resulting in an increase in p27 and a decrease in cyclin D1 expression. That leads to late blockage of G1/S cell cycle. Rapamycin has shown to induce cancer cell death by stimulating autophagy or apoptosis, but the molecular mechanism of apoptosis in cancer cells has not yet been fully resolved. One suggestion of the relation between mTOR inhibition and apoptosis might be through the downstream target S6K1, which can phosphorylate BAD, a pro-apoptotic molecule, on Ser136.[5]That reaction breaks the binding of BAD to BCL-XL and BCL2, a mitochondrial death inhibitors, resulting in inactivation of BAD[5] and decreased cell survival.[6] Rapamycin has also shown to induce p53-independent apoptosis in certain types of cancer.[5]

Effects on tumor angiogenesis

Effects of Rapamycin and rapalogs on endothelial and tumor cells.

Tumor angiogenesis rely on interactions between endothelial vascular growth factors which can all activate the PI3K/AKT/mTOR in endothelial cells, pericytes, or cancer cells. Example of these growth factors are angiopoietin 1 (ANG1), ANG 2, basic fibroblast growth factor (bFGF)ephrin-B2vascular enothelial growth factor (VEGF), and members of the tumor growth factor-β (TGFβ) superfamily. One of the major stimuli of angiogenesis is hypoxia, resulting in activation of hypoxia-inducible transcription factors (HIFs) and expression of ANG2, bFGF, PDGF, VEGF, and VEGFR. Inhibition of HIF1α translation by preventing PDGF/PDGFR and VEGF/VEGFR can result from mTOR inhibition. A G0-G1 cell-cycle blockage can be the consequence of inactivation of mTOR in hypoxia-activated pericytes and endothelial cells.[5]

There are some evidence that extended therapy with rapamycin may have effect on AKT and mTORC2 as well.[2][33]

Training The Immune System To Fight Cancer Has 19th-Century Roots

Training The Immune System To Fight Cancer Has 19th-Century Roots

A novel immunotherapy drug is credited for successfully treating former President Jimmy Carter’s advanced melanoma. Instead of killing cancer cells, these drugs boost the patient’s immune system, which does the job instead.

Immunotherapy is cutting-edge cancer treatment, but the idea dates back more than 100 years, to a young surgeon who was willing to think outside the box.

Isabel Seliger for NPR

Isabel Seliger for NPR

His name was William Coley, and in the late summer of 1890 he was getting ready to examine a new patient at his practice in New York City. What he didn’t know was that the young woman waiting to see him would change his life and the future of cancer research.

Her name was Elizabeth Dashiell, also known as Bessie, says Dr. David Levine, director of archives at the Hospital for Special Surgery in New York. Bessie was 17 and showed up complaining of a problem with her hand. It seemed like a minor injury, just a small bump where she’d hurt it, but it wasn’t getting better, and she was in a lot of pain. She’d seen other doctors but nobody could diagnose the problem.

At first Coley thought Bessie must have an infection. But when he took a biopsy, it turned out to be a malignant, very advanced cancer called a sarcoma.

In those days there wasn’t very much anyone could do for Bessie. This was before radiation and chemotherapy, so Coley did the only thing he could — he amputated Bessie’s right arm just below the elbow in an attempt to stop the disease from spreading. Sadly, it didn’t work, and within a month, according to David Levine, the cancer had spread “to her lungs, to her liver and all over her body.”

Bessie’s final days were wrenching and painful. Coley was with her when she died on Jan. 23, 1891. Bessie’s death made a huge impression on the young surgeon. “It really shocked him,” says Stephen Hall, who wrote about Coley in his book A Commotion in the Blood: Life, Death and the Immune System.

Bessie’s death also spurred Coley into action. There wasn’t a lot known about cancer at the time, so Coley started digging through dozens upon dozens of old records at New York Hospital. He was looking for something that would help him understand this cruel and aggressive disease.

As a student, Coley had read Charles Darwin, and one of the lessons he took away from Darwin, Hall says, was to always pay attention when there’s a biological exception to the rule. “To ask yourself: Why this has happened?”

Coley discovered one of these biological exceptions. It was the case of a German immigrant named Fred Stein. Stein had been a patient in New York Hospital eight years earlier. He had a tumor on his neck that doctors tried to remove several times. Unfortunately for Stein, the tumor kept coming back and doctors expected him to die from the disease.

Then Stein contracted a serious infection of the skin caused by the strep bacteria. “It looked like Stein’s days were numbered,” Levine says. But Stein didn’t die. In fact, his tumor disappeared, and he was discharged. Coley wondered if all these years later, Stein could still be alive.

So in the winter of 1891, William Coley the surgeon became William Coley the detective. He headed for the tenements of the Lower East Side of Manhattan where the German immigrant community lived. He knocked on door after door asking for a man named Fred Stein who had a distinctive scar across his neck. After several weeks of searching, Coley found him alive and cancer-free.

Enlarge this image

A patient named Zola had a huge tumor on his neck. Coley treated Zola with bacteria that caused him to become violently ill. Within hours the tumor began to dissolve. He recovered completely.

Isabel Seliger for NPR

So why did Stein’s cancer go away and stay away after he got a bacterial infection? Coley speculated that the strep infection had reversed the cancer. and wondered what would happen if he tried to reproduce the effect by deliberately injecting cancer patients with bacteria.

He decided to test his idea on people who were the most seriously ill. His first subject was an Italian immigrant named Zola who, just like Bessie Dashiell, was suffering from sarcoma. Zola had tumors riddling his throat. He was so sick he could barely eat or speak or even breathe. For months Coley would try to make Zola sick from infection by creating little cuts and rubbing the strep bacteria into them, Hall says. There would be “a slight response but not too much.”

Then Coley got his hands on a much stronger strain of the bacteria. This time, Zola became violently ill with an infection that could easily have killed him. But within 24 hours, Zola’s orange-sized tumor began to liquefy and disintegrate. “This was a phenomenon that occurred rarely, but when you saw it you were utterly astonished,” Hall says.

Zola completely recovered. Coley knew he was on to something. He kept experimenting and refining his use of bacteria. Eventually, he named the treatment Coley’s toxins.

It was an exciting time. Coley was having tremendous success and his efforts were celebrated in America and abroad. But Bradley Coley Jr., William Coley’s grandson, says the American medical establishment at the time was skeptical. Nobody knew how Coley’s toxins worked, or why they worked sometimes and not others. Not even Coley could explain it.

That’s largely because the immune system was still a mystery and would remain so for decades to come.

When radiation therapy came along in the early 1900s, interest in Coley’s toxins was completely overshadowed by this new therapy. When his grandfather died, Bradley Coley says, “All interest in [Coley’s toxins] stopped.”

And quite possibly, that’s where Coley’s legacy would have ended except for this: After Coley’s death in 1936, his daughter, Helen Coley Nauts, started looking through her father’s papers while doing research for his biography. She found about 1,000 files of patients her father had treated with Coley’s toxins.

She spent years carefully analyzing these cases and could see that he had extraordinary rates of success in regressing some cancerous tumors. She couldn’t get anyone interested in studying her father’s work, so she decided to do it herself. With a small grant, in 1953 Helen Coley Nauts started the Cancer Research Institute, dedicated to understanding the immune system and its relationship to cancer.

In the more than 60 years since, researchers have expanded their understanding of the immune system dramatically and today, that understanding is paying off. Treatments that harness the power of the immune system are now available for a range of cancers such as stomach, lung, leukemia, melanoma and kidney.

Jedd Wolchok, chief of the melanoma and immunotherapeutics service at Memorial Sloan Kettering Cancer Center, says any treatment currently in use that exploits the power of the immune system to fight cancer has to “tip its hat” to the work William Coley began more than 100 years ago.

Immunoglobulin B cells from bone marrow and cytokines role during cancer expression

Antibody (or immunoglobulin) structure is made up of two heavy-chains and two light-chains. These chains are held together by disulfide bonds. The arrangement or processes that put together different parts of this antibody molecule play important role in antibody diversity and production of different subclasses or classes of antibodies. The organization and processes take place during the development and differentiation of B cells. That is, the controlled gene expression during transcription and translation coupled with the rearrangements of immunoglobulin gene segments result in the generation of antibody repertoire during development and maturation of B cells.

B-Cell Development

During the development of B cells, the immunoglobulin gene undergoes sequences of rearrangements that lead to formation of the antibody repertoire. For example, in the lymphoid cell, a partial rearrangement of the heavy-chain gene occurs which is followed by complete rearrangement of heavy-chain gene. Here at this stage, Pre-B cell, mμ heavy chain and surrogate light chain are formed. The final rearrangement of the light chain gene generates immature B cell and mIgM. The process explained here occurs only in the absence of the antigen. The mature B cell formed as RNA processing changes leaves the bone marrow and is stimulated by the antigen then differentiated into IgM -secreted plasma cells. Also at first, the mature B cell expresses membrane-bound IgD and IgM. These two classes could switch to secretory IgD and IgM during the processing of mRNAs.

Finally, further class switching follows as the cell keep dividing and differentiating. For instance, IgM switches to IgG which switches to IgA that eventually switches to IgE

The multigene organization of immunoglobulin genes

From studies and predictions such as Dreyer and Bennett’s, it shows that the light chains and heavy chains are encoded by separate multigene families on different chromosomes. They are referred to as gene segments and are separated by non-coding regions. The rearrangement and organization of these gene segments during the maturation of B cells produce functional proteins.The entire process of rearrangement and organization of these gene segments is the vital source where our body immune system gets its capabilities to recognize and respond to variety of antigens.

Light chain multigene family

The light chain gene has three gene segments. These include: the light chain variable region (V), joining region (J), and constant region (C) gene segments. The variable region of light is therefore encoded by the rearrangement of VJ segments. The light chain can be either kappa,κ or lambda,λ. This process takes place at the level of mRNAs processing. Random rearrangements and recombinations of the gene segments at DNA level to form one kappa or lambda light chain occurs in an orderly fashion. As a result, “a functional variable region gene of a light chain contains two coding segments that are separated by a non-coding DNA sequence in unrearranged germ-line DNA” (Barbara et al., 2007). Interestingly, the immunoglobulin lambda light chain locus contains protein-coding genes that can be lost with its rearrangement.[1] This is based on a physiological mechanism and is not pathogenetic for leukemias or lymphomas.[2] However,the rearrangement of several lambda variable subgenes can activate expression of an overlapping miRNA gene, which has consequences for gene expression regulation.[3]

Heavy-chain multigene family

Heavy chain contains similar gene segments such as VH, JH and CH, but also has another gene segment called D (diversity). Unlike the light chain multigene family, VDJ gene segments code for the variable region of the heavy chain. The rearrangement and reorganization of gene segments in this multigene family is more complex . The rearranging and joining of segments produced different end products because these are carried out by different RNA processes. The same reason is why the IgM and IgG are generates at the time.

Variable-Region Rearrangements

The variable region rearrangements happen in an orderly sequence in the bone marrow. Usually, the assortment of these gene segments occurs at B cell maturation.

Light chain DNA

The kappa and lambda light chains undergo rearrangements of the V and J gene segments. In this process, a functional Vlambda can combine with four functional Jλ –Cλ combinations. On the other hands, Vk gene segments can join with either one of the Jk functional gene segments. The overall rearrangements result in a gene segment order from 5 prime to 3 prime end. These are a short leader (L) exon, a noncoding sequence (intron), a joined VJ segment, a second intron, and the constant region. There is a promoter upstream from each leader gene segment. The leader exon is important in the transcription of light chain by the RNA polymerase. To remain with coding sequence only, the introns are removed during RNA- processing and repairing.[4] In summary,

Heavy chain DNA

The rearrangements of heavy-chains are different from the light chains because DNA undergoes rearrangements of V-D-J gene segments in the heavy chains. These reorganizations of gene segments produce gene sequence from 5 prime to 3 prime ends such as a short leader exon, an intron, a joined VDJ segment, a second intron and several gene segments. The final product of the rearrangement is transcribed when RNA polymerase

Mechanism of variable region rearrangements

It is understood that rearrangement occurs between specific sites on the DNA called recombination signal sequences (RSSs). The signal sequences are composed of a conserved palindromic heptamer and a conserved AT- rich nonamer. These signal sequences are separated by non-conserved spacers of 12 or 23 base pairs called one-turn and two-turn respectively. They are within the lambda chain, k-chain and The processes of rearrangement in these regions are catalyzed by two recombination-activating genes: RAG-1 and RAG-2 and other enzymes and proteins. The segments joined due to signals generated RSSs that flank each V, D, and J segments. Only genes flank by 12 -bp that join to the genes flank by 23-bp spacer during the rearrangements and combinations to maintain VL-JL and VH-DH-JH joining.

Generation of antibody diversity

Antibody diversity is produced by genetic rearrangement after shuffling and rejoining one of each of the various gene segments for the heavy and light chains. Due to mixing and random recombination of the gene segments errors can occur at the sites where gene segments join with each other. These errors are one of the sources of the antibody diversity that is commonly observed in both the light and heavy chains. Moreover, when B cells continue to proliferate, mutations accumulate at the variable regions through a process called somatic hypermutation. The high concentrations of these mutations at the variable region also produce high antibody diversity.

Class-switching

When the B cells get activated, class switching can occur. The class switching involves switch regions that made up of multiple copies of short repeatts(GAGCT and TGGGG). These switches occur at the level of rearrangements of the DNA because there is a looping event that chops off the constant regions for IgM and IgD and form the IgG mRNAs. Any continuous looping occurrence will produce IgE or IgA mRNAs.

In addition, cytokines are factors that have great effects on class switching of different classes of antibodies. Their interaction with B cells provides the appropriates signals needed for B cells differentiation and eventual class switching occurrence. For example, interleukin-4 induces the rearrangements of heavy chain immunoglobulin genes. That is IL- 4 induces the switching of Cμ to Cγ to Cκ.


Cytokines

Cytokines (cyto, from Greek “κύτταρο” kyttaro “cell” + kines, from Greek “κίνηση” kinisi “movement”) are a broad and loose category of small proteins (~5–20 kDa) that are important in cell signaling. Their release has an effect on the behavior of cells around them. It can be said that cytokines are involved in autocrine signalling, paracrine signalling and endocrine signalling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors but generally not hormones or growth factors (despite some overlap in the terminology). Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell.[1][2][3]

They act through receptors, and are especially important in the immune system; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways.[3]

They are different from hormones, which are also important cell signaling molecules, in that hormones circulate in less variable concentrations and hormones tend to be made by specific kinds of cells.

They are important in health and disease, specifically in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction.

When scientists saw the mouse heads glowing, they knew the discovery was big

May 21
Kari Alitalo had studied lymphatic vessels for more than two decades. So he knew that this network, which carries immune cells throughout the body and removes waste and toxins, didn’t extend into the brain: This had been accepted wisdom for more than 300 years. “Nobody questioned that it stopped at the brain,” says Alitalo, a scientist at the University of Helsinki in Finland.

Three years ago, Alitalo wanted to develop a more precise map of the lymphatic system. To do this, he used genetically modified mice whose lymphatic vessels glowed when illuminated by a particular wavelength of light. (The mice had been given a gene from a species of glowing jellyfish.)

When viewing the modified mice under the light, Aleksanteri Aspelund, a medical student in Alitalo’s laboratory, saw something unexpected: The heads of the mice glowed. At first, he suspected that there was something wrong — with the animals, the lighting or the measuring equipment. But when Alitalo and Aspelund repeated the experiment, they got the same result. It seemed that the lymphatic vessels extended to the brain after all.

This was surprising, to say the least: In the 21st century, major findings involving basic human anatomy are rare. “These days, you don’t make discoveries like this,” Alitalo says. “But every once in a while in science, you stumble on something really unexpected. You open a new door, to a whole new world.”

Alitalo is one of several scientists exploring this new world. Working independently, several other researchers, including Maiken Nedergaard of the University of Rochester and Jonathan Kipnis of the University of Virginia School of Medicine, have also shown that lymphatic vessels extend into the brain.

The discovery is much more than a historical footnote. It has major implications for a wide variety of brain diseases, including Alzheimer’s, multiple sclerosis, stroke and traumatic brain injury.

Researchers have identified two networks: the vessels that lead into and surround the brain, and those within the brain itself. The first is known as the lymphatic system for the brain, while the latter is called the glymphatic system. The “g” added to “lymphatic” refers to glia, the kind of neuron that makes up the lymphatic vessels in the brain. The glymphatic vessels carry cerebrospinal fluid and immune cells into the brain and remove cellular trash from it.

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Alitalo, Nedergaard, Kipnis and others have found evidence that when the systems malfunction, the brain can become clogged with toxins and suffused with inflammatory immune cells. Over decades, this process may play a key rolein Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and other neurodegenerative illnesses, research suggests. “This is a revolutionary finding,” Nedergaard says. “This system plays a huge role in the health of the brain.”

Nedergaard describes the glymphatic system as like a dishwasher for the brain. “The brain is very active,” she says, “and so it produces a lot of junk that needs to be cleaned out.”

In hindsight, she says, the system should have been noticed long ago. When the skull and head are dissected, the vessels are visible to the naked eye. But no one bothered to really look: “Usually the brain is seen only as a bunch of nerve cells. We have come to think of the brain as a computer. And it’s not. It’s a living organ.”

Nedergaard and Helene Benveniste, a scientist at Yale University, have found evidence linking problems in the lymphatic and glymphatic systems to Alzheimer’s. In a study on mice, they showed that glymphatic dysfunction contributes to the buildup in the brain of amyloid beta, a protein that plays a key role in the disease.

Last year, Jeff Iliff, a neuroscientist at Oregon Health & Science University, and several colleagues examined postmortem tissue from 79 human brains. They focused on aquaporin-4, a key protein in glymphatic vessels. In the brains of people with Alzheimer’s, this protein was jumbled; in those without the disease, the protein was well organized. This suggests that glymphatic breakdowns may play a role in the disease, Iliff says.

The vessels have also been implicated in autoimmune disease. Researchers knew that the immune system has limited access to the brain. But at the same time, the immune system kept tabs on the brain’s status; no one knew exactly how. Some researchers theorize that the glymphatic system could be the conduit and that in diseases such as multiple sclerosis — where the body’s immune system attacks certain brain cells — the communication may go awry.

The system may also play a role in symptoms of traumatic brain injury. Nedergaard has shown that in mice, the injuries can produce lasting damage to the glymphatic vessels, which are quite fragile. Mice are a good model, she says, because their glymphatic systems are very similar to humans’. She and Iliff found that even months after being injured, the animals’ brains were still not clearing waste efficiently, leading to a buildup of toxic compounds, including amyloid beta. Nedergaard returns to the dishwasher analogy. “It’s like if you only use a third of the water when you turn on the machine,” she says. “You won’t get clean dishes.”

Recent research has also found evidence that the glymphatic system may extend into the eye. For decades, scientists have noted that many people with Alzheimer’s disease also have glaucoma, in which damage to the optic nerve causes vision loss. But they struggled to find a common mechanism; the glymphatic system may be the link.

In January, Belgian and Swiss researchers identified a rich network of glymphatic vessels within the optic nerve. The scientists also found that when these vessels malfunction, they seem to leave behind deposits of amyloid beta as well as other neurotoxins that damage the optic nerve.

And in March, Harvard University researchers reported that glymphatic flow is significantly decreased in the period just before a migraine. The intense pain in these headaches is caused largely by inflamed nerves in the tissue that surrounds the brain. Neuroscientists Rami Burstein and Aaron Schain, the lead authors, theorize that faulty clearance of molecular waste from the brain could trigger inflammation in these pain fibers.

One key to glymphatic performance seems to be sleep. Nedergaard has shown that at least in mice, the system processes twice as much fluid during sleep as it does during wakefulness. She and her colleagues focused on amyloid beta; they found that the lymphatic system removed much more of the protein when the animals were asleep than when they were awake. She suggests that over time, sleep dysfunction may contribute to Alzheimer’s and perhaps other brain illnesses. “You only clean your brain when you’re sleeping,” she says. “This is probably an important reason that we sleep. You need time off from consciousness to do the housekeeping.”

Sleep position

Nedergaard and Benveniste have also found that sleep position is crucial. In an upright position — someone who is sitting or standing — waste is removed much less efficiently. Sleeping on your stomach is also not very effective; sleeping on your back is somewhat better, while lying on your side appears to produce the best results. The reason for these differences remains unclear, but Nedergaard suspects that it is probably related to the mechanical engineering of the lymphatic vessels and valves; she suggests that the healthiest approach may be to move periodically while you sleep.

Sleep is probably not the only way to improve glymphatic flow. For instance, a paper published in January by Chinese researchers reported that in mice, omega-3 fatty acidsimproved glymphatic functioning.

Benveniste is examining dexmedetomidine, an anesthetic that may have the ability to improve glymphatic flow. And in a small human study, other scientists have found that deep breathing significantly increases the glymphatic transport of cerebrospinal fluid into the brain.

Alitalo is experimenting with growth factors, compounds that can foster regrowth of the vessels in and around the brain. He has used this method to repair lymphatic vessels in pigs and is now testing the approach in the brains of mice that have a version of Alzheimer’s.

“Right now there are no clinical therapies in this area,” he says. “But give it a little time. This has only just been discovered.”


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