Stem Cell Therapy: Helping the Body Heal Itself

Stem cells are natures own transformers. When the body is injured, stem cells travel the scene of the accident. Some come from the bone marrow, a modest number of others, from the heart itself. Additionally, theyre not all the same. There, they may help heal damaged tissue. They do this by secreting local hormones to rescue damaged heart cells and occasionally turning into heart muscle cells themselves. Stem cells do a fairly good job. But they could do better for some reason, the heart stops signaling for heart cells after only a week or so after the damage has occurred, leaving the repair job mostly undone. The partially repaired tissue becomes a burden to the heart, forcing it to work harder and less efficiently, leading to heart failure.

Initial research used a patients own stem cells, derived from the bone marrow, mainly because they were readily available and had worked in animal studies. Careful study revealed only a very modest benefit, so researchers have moved on to evaluate more promising approaches, including:

No matter what you may read, stem cell therapy for damaged hearts has yet to be proven fully safe and beneficial. It is important to know that many patients are not receiving the most current and optimal therapies available for their heart failure. If you have heart failure, and wondering about treatment options, an evaluation or a second opinion at a Center of Excellence can be worthwhile.

Randomized clinical trials evaluating these different approaches typically allow enrollment of only a few patients from each hospital, and hence what may be available at the Cleveland Clinic varies from time to time. To inquire about current trials, please call 866-289-6911 and speak to our Resource Nurses.

Cleveland Clinic is a large referral center for advanced heart disease and heart failure we offer a wide range of therapies including medications, devices and surgery. Patients will be evaluated for the treatments that best address their condition. Whether patients meet the criteria for stem cell therapy or not, they will be offered the most advanced array of treatment options.

Allogenic: from one person to another (for example: organ transplant)

Autogenic: use of one's own tissue

Myoblasts: immature muscle cells, may be able to change into functioning heart muscle cells

Stem Cells: cells that have the ability to reproduce, generate new cells, and send signals to promote healing

Transgenic: Use of tissue from another species. (for example: some heart valves from porcine or bovine tissue)

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Stem Cell Therapy for Heart Disease - Cleveland Clinic

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A transplant of the stem cells that form in bone marrow can help people recover from certain types of cancers and blood and bone marrow disorders, but having a bone marrow or stem cell transplant can require a donation from someone.

The bones of the body are hollow and in the centre especially in the flat bones such as the breastbone and pelvis can be found a soft tissue known as bone marrow. This sponge-like substance produces stem cells. These are immature cells that constantly divide to produce new cells, some of which grow into mature blood cells used by the body. These include:

Stem cells need to divide rapidly to make millions of blood cells every day. Without these stem cells it would be impossible to survive.

People who have a condition that damages bone marrow may not have enough stem cells to produce normal blood cells. This can occur if there is a type of bone marrow failure or a genetic blood or immune system disorder.

In other cases, treating people with certain types of cancer sometimes requires giving very high doses of chemotherapy to kill the cancer cells in the body. Whole body radiotherapy may also be used to kill off the cancer cells. However, these treatments can also kill healthy cells in the body, including the stem cells in bone marrow.

People who may need a bone marrow transplant include those with:

The collected stem cells are added to a solution that is put into the body by using a drip, similar to receiving a blood transfusion. These cells enter the bloodstream and then travel to the bones, where they can start producing blood cells again. In people who have cancer, this is performed the day after treatment with chemotherapy or radiotherapy ends.

Because having a transplant involves being given different medicines and blood transfusions as well as the transplant itself, the patient may be given a central line, or central venous catheter. An operation will be performed to insert a thin tube through the skin near the collarbone and into a large vein near the heart.

The transplant itself isn't painful, but the person will need to remain in hospital for between 5 to 6 weeks while their bone marrow recovers, allowing time for the donated stem cells to settle in and start producing new cells. Antibiotics are often given to limit the risk of infection, which is particularly high during this period and the reason why the person may be placed in isolation. Blood transfusions may also be necessary until the bone marrow is making enough new blood cells. The person will also be monitored to ensure the stem cells have been accepted.

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Bone marrow (stem cell) transplant and donation

Bone Marrow Stem Cells Comments Off on Bone marrow (stem cell) transplant and donation | August 30th, 2015

People usually volunteer to donate stem cells for an allogeneic transplant either because they have a loved one or friend who needs a match or because they want to help people. Some people give their stem cells so they can get them back later for an autologous transplant.

People who want to donate stem cells or join a volunteer registry can speak with their doctors or contact the National Marrow Donor Program to find the nearest donor center. Potential donors are asked questions to make sure they are healthy enough to donate and dont pose a risk of infection to the recipient. For more information about donor eligibility guidelines, contact the National Marrow Donor Program or the donor center in your area (see the To learn more section for contact information).

A simple blood test is done to learn the potential donors HLA type. There may be a one-time, tax-deductible fee of about $75 to $100 for this test. People who join a volunteer donor registry will most likely have their tissue type kept on file until they reach age 60.

Pregnant women who want to donate their babys cord blood should make arrangements for it early in the pregnancy, at least before the third trimester. Donation is safe, free, and does not affect the birth process. For more, see the section called How umbilical cord blood is collected.

If a possible stem cell donor is a good match for a recipient, steps are taken to teach the donor about the transplant process and make sure he or she is making an informed decision. If a person decides to donate, a consent form must be signed after the risks of donating are fully discussed. The donor is not pressured take part. Its always a choice.

If a person decides to donate, a medical exam and blood tests will be done to make sure the donor is in good health.

This process is often called bone marrow harvest, and its done in an operating room. The donor is put under general anesthesia (given medicine to put them into a deep sleep so they dont feel pain) while bone marrow is taken. The marrow cells are taken from the back of the pelvic (hip) bone. A large needle is put through the skin and into the back of the hip bone. Its pushed through the bone to the center and the thick, liquid marrow is pulled out through the needle. This is repeated several times until enough marrow has been taken out (harvested). The amount taken depends on the donors weight. Often, about 10% of the donors marrow, or about 2 pints, are collected. This takes about 1 to 2 hours. The body will replace these cells within 4 to 6 weeks. If blood was taken from the donor before the marrow donation, its often given back to the donor at this time.

After the bone marrow is harvested, the donor is taken to the recovery room while the anesthesia wears off. The donor may then be taken to a hospital room and watched until fully alert and able to eat and drink. In most cases, the donor is free to leave the hospital within a few hours or by the next morning.

The donor may have soreness, bruising, and aching at the back of the hips and lower back for a few days. Over-the-counter acetaminophen (Tylenol) or non-steroidal anti-inflammatory drugs (such as aspirin, ibuprofen, or naproxen) are helpful. Some people may feel tired or weak, and have trouble walking for a few days. The donor might be told to take iron supplements until the number of red blood cells returns to normal. Most donors are back to their usual schedule in 2 to 3 days. But it could take 2 or 3 weeks before they feel completely back to normal.

There are few risks for donors and serious complications are rare. But bone marrow donation is a surgical procedure. Rare complications could include anesthesia reactions, infection, transfusion reactions (if a blood transfusion of someone elses blood is needed this doesnt happen if you get your own blood), or injury at the needle insertion sites. Problems such as sore throat or nausea may be caused by anesthesia.

Allogeneic stem cell donors do not have to pay for the harvesting because the recipients insurance company usually covers the cost.

Once the cells are collected, they are filtered through fine mesh screens. This prevents bone or fat particles from being given to the recipient. For an allogeneic or syngeneic transplant, the cells may be given to the recipient through a vein soon after they are harvested. Sometimes they are frozen, such as when the donor lives far away from the recipient.

For several days before starting the donation process, the donor is given a daily injection (shot) of filgrastim (Neupogen). This is a growth-factor drug that causes the bone marrow to make and release stem cells into the blood. Filgrastim can cause some side effects, the most common being bone pain and headaches. These may be helped by over-the-counter acetaminophen (Tylenol) or nonsteroidal anti-inflammatory drugs (like aspirin or ibuprofen). Nausea, sleeping problems, low-grade (mild) fevers, and tiredness are other possible effects. These go away once the injections are finished and collection is completed.

Blood is removed through a catheter (a thin, flexible plastic tube) that is put in a large vein in the arm or chest. Its then cycled through a machine that separates the stem cells from the other blood cells. The stem cells are kept while the rest of the blood is returned to the donor through the same catheter. This process is called apheresis (a-fur-REE-sis). It takes about 2 to 4 hours and is done as an outpatient procedure. Often the process needs to be repeated daily for a few days, until enough stem cells have been collected.

Possible side effects of the catheter can include trouble placing the catheter in the vein, a collapsed lung from catheter placement, blockage of the catheter, or infection of the catheter or at the area where it enters the vein. Blood clots are another possible side effect. During the apheresis procedure donors may have problems caused by low calcium levels from the anti-coagulant drug used to keep the blood from clotting in the machine. These can include feeling lightheaded or tingly, and having chills or muscle cramps. These go away after donation is complete, but may be treated by giving the donor calcium supplements.

The process of donating cells for yourself (autologous stem cell donation) is pretty much the same as when someone donates them for someone else (allogeneic donation). Its just that in autologous stem cell donation the donor is also the recipient, giving stem cells for his or her own use later on. For some people, there are a few differences. For instance, sometimes chemotherapy (chemo) is given before the filgrastim is used to tell the body to make stem cells. Also, sometimes it can be hard to get enough stem cells from a person with cancer. Even after several days of apheresis, there may not be enough for the transplant. This is more likely to be a problem if the patient has had certain kinds of chemo in the past, or if they have an illness that affects their bone marrow.

Sometimes a second drug called plerixafor (Mozobil) is used along with filgrastim in people with non-Hodgkin lymphoma or multiple myeloma. This boosts the stem cell numbers in the blood, and helps reduce the number of apheresis sessions needed to get enough stem cells. It may cause nausea, diarrhea, and sometimes, vomiting. There are medicines to help if these symptoms become a problem. Rarely the spleen can enlarge and even rupture. This can cause severe internal bleeding and requires emergency medical care. The patient should tell the doctor right away if they have any pain in their left shoulder or under their left rib cage which can be symptoms of this emergency.

Parents can donate their newborns cord blood to volunteer or public cord blood banks at no cost. This process does not pose any health risk to the infant. Cord blood transplants use blood that would otherwise be thrown away.

After the umbilical cord is clamped and cut, the placenta and umbilical cord are cleaned. The cord blood is put into a sterile container, mixed with a preservative, and frozen until needed.

Remember that if you want to donate or bank (save) your childs cord blood, you will need to arrange it before the baby is born. Some banks require you to set it up before the 28th week of pregnancy, although others accept later setups. Among other things, you will be asked to answer health questions and sign a consent form.

Many hospitals collect cord blood for donation, which makes it easier for parents to donate. For more about donating your newborns cord blood, call 1-800-MARROW2 (1-800-627-7692) or visit Be the Match.

Privately storing a babys cord blood for future use is not the same as donating cord blood. Its covered in the section called Other transplant issues.

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Whats it like to donate stem cells?

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Renal cell carcinoma (RCC, also known as hypernephroma, Grawitz tumor, renal adenocarcinoma) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport waste molecules from the blood to the urine. RCC is the most common type of kidney cancer in adults, responsible for approximately 90-95% of cases.[1] Initial treatment is most commonly either partial or complete removal of the affected kidney(s) and remains the mainstay of curative treatment.[2] Where the cancer has not metastasised (spread to other organs) or burrowed deeper into the tissues of the kidney the 5-year survival rate is 65-90%,[3] but this is lowered considerably when the cancer has spread. It is relatively resistant to radiation therapy and chemotherapy, although some cases respond to targeted therapies such as sunitinib, temsirolimus, bevacizumab, interferon alfa and sorafenib which have improved the outlook for RCC.[4]

The body is remarkably good at hiding the symptoms and as a result people with RCC often have advanced disease by the time it is discovered.[5] The initial symptoms of RCC often include: blood in the urine (occurring in 40% of affected persons at the time they first seek medical attention), flank pain (40%), a mass in the abdomen or flank (25%), weight loss (33%), fever (20%), high blood pressure (20%), night sweats and generally feeling unwell.[1] RCC is also associated with a number of paraneoplastic syndromes (PNS) which are conditions caused by either the hormones produced by the tumour or by the body's attack on the tumour and are present in about 20% of those with RCC.[1] These syndromes most commonly affect tissues which have not been invaded by the cancer.[1] The most common PNSs seen in people with RCC are: anaemia (due to an underproduction of the hormone, erythropoietin), high blood calcium levels, polycythaemia (the opposite to anaemia, due to an overproduction of erythropoietin), thrombocytosis (too many platelets in the blood, leading to an increased tendency for blood clots and bleeds) and secondary amyloidosis.[6] When RCC metastasises it most commonly spreads to the lymph nodes, lungs, liver, adrenal glands, brain or bones.[6]

Historically, medical practitioners expected a person to present with three findings. This classic triad[7] is 1: haematuria, which is when there is blood present in the urine, 2: flank pain, which is pain on the side of the body between the hip and ribs, and 3: an abdominal mass, similar to bloating but larger. It is now known that this classic triad of symptoms only occurs in 10-15% of cases, and is usually indicative that the renal cell carcinoma (RCC) in an advanced stage.[7] Today, RCC is often asymptomatic (meaning little to no symptoms) and is generally detected incidentally when a person is being examined for other ailments.[8]

Other signs and symptom may include haematuria;[7] loin pain;[7] abdominal mass;[8]malaise, which is a general feeling of feeling unwell;[8] weight loss and/or loss of appetite;[9]anaemia resulting from depression of erythropoietin;[7]erythrocytosis (increased production of red blood cells) due to increased erythropoietin secretion;[7]varicocele, which is seen in males as an enlargement of the tissue at the testicle (more often the left testicle)[8]hypertension (high blood pressure) resulting from secretion of renin by the tumour;[10]hypercalcemia, which is elevation of calcium levels in the blood;[11] sleep disturbance or night sweats;[9] recurrent fevers;[9] and chronic fatigue.[12]

The greatest risk factors for RCC are lifestyle-related; smoking, obesity and hypertension (high blood pressure) have been estimated to account for up to 50% of cases.[13] Occupational exposure to some chemicals such as asbestos, cadmium, lead, chlorinated solvents, petrochemicals and PAH (polycyclic aromatic hydrocarbon) has been examined by multiple studies with inconclusive results.[14][15][16] Another suspected risk factor is the long term use of non-steroidal anti-inflammatory drugs (NSAIDS).[17]

Finally, studies have found that women who have had a hysterectomy are at more than double the risk of developing RCC than those who have not.[18] The reason for this remains unclear.

Hereditary factors have a minor impact on individual susceptibility with immediate relatives of people with RCC having a two to fourfold increased risk of developing the condition.[19] Other genetically linked conditions also increase the risk of RCC, including hereditary papillary renal carcinoma, hereditary leiomyomatosis, Birt-Hogg-Dube syndrome, hyperparathyroidism-jaw tumor syndrome, familial papillary thyroid carcinoma, von Hippel-Lindau disease[20] and sickle cell disease.[21]

The most significant disease affecting risk however is not genetically linked patients with acquired cystic disease of the kidney requiring dialysis are 30 times greater more likely than the general population to develop RCC.[22]

The tumour arises from the cells of the proximal renal tubular epithelium.[1] It is considered an adenocarcinoma.[6] There are two subtypes: sporadic (that is, non-hereditary) and hereditary.[1] Both such subtypes are associated with mutations in the short-arm of chromosome 3, with the implicated genes being either tumour suppressor genes (VHL and TSC) or oncogenes (like c-Met).[1]

The first steps taken to diagnose this condition are consideration of the signs and symptoms, and a medical history (the detailed medical review of past health state) to evaluate any risk factors. Based on the symptoms presented, a range of biochemical tests (using blood and/or urine samples) may also be considered as part of the screening process to provide sufficient quantitative analysis of any differences in electrolytes, renal and liver function, and blood clotting times.[21] Upon physical examination, palpation of the abdomen may reveal the presence of a mass or an organ enlargement.[23]

Although this disease lacks characterization in the early stages of tumor development, considerations based on diverse clinical manifestations, as well as resistance to radiation and chemotherapy are important. The main diagnostic tools for detecting renal cell carcinoma are ultrasound, computed tomography (CT) scanning and magnetic resonance imaging (MRI) of the kidneys.[24]

Renal cell carcinoma (RCC) is not a single entity, but rather a collection of different types of tumours, each derived from the various parts of the nephron (epithelium or renal tubules) and possessing distinct genetic characteristics, histological features, and, to some extent, clinical phenotypes.[21]

Clear Cell Renal Cell Carcinoma (CCRCC)

Array-based karyotyping can be used to identify characteristic chromosomal aberrations in renal tumors with challenging morphology.[28][29] Array-based karyotyping performs well on paraffin embedded tumours[30] and is amenable to routine clinical use. See also Virtual Karyotype for CLIA certified laboratories offering array-based karyotyping of solid tumours.

The 2004 World Health Organization (WHO) classification of genitourinary tumours recognizes over 40 subtypes of renal neoplasms. Since the publication of the latest iteration of the WHO classification in 2004, several novel renal tumour subtypes have been described:[31]

Laboratory tests are generally conducted when the patient presents with signs and symptoms that may be characteristic of kidney impairment. They are not primarily used to diagnose kidney cancer, due to its asymptomatic nature and are generally found incidentally during tests for other illnesses such as gallbladder disease.[33] In other words, these cancers are not detected usually because they do not cause pain or discomfort when they are discovered. Laboratory analysis can provide an assessment on the overall health of the patient and can provide information in determining the staging and degree of metastasis to other parts of the body (if a renal lesion has been identified) before treatment is given.

The presence of blood in urine is a common presumptive sign of renal cell carcinoma. The haemoglobin of the blood causes the urine to be rusty, brown or red in colour. Alternatively, urinalysis can test for sugar, protein and bacteria which can also serve as indicators for cancer. A complete blood cell count can also provide additional information regarding the severity and spreading of the cancer.[34]

The CBC provides a quantified measure of the different cells in the whole blood sample from the patient. Such cells examined for in this test include red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes). A common sign of renal cell carcinoma is anaemia whereby the patient exhibits deficiency in red blood cells.[35] CBC tests are vital as a screening tool for examination the health of patient prior to surgery. Inconsistencies with platelet counts are also common amongst these cancer patients and further coagulation tests, including Erythrocyte Sedimentation Rate (ESR), Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) should be considered.

Blood chemistry tests are conducted if renal cell carcinoma is suspected as cancer has the potential to elevate levels of particular chemicals in blood. For example, liver enzymes such as aspartate aminotransferase [AST] and alanine aminotransferase [ALT] are found to be at abnormally high levels.[36] The staging of the cancer can also be determined by abnormal elevated levels of calcium, which suggests that the cancer may have metastasised to the bones.[37] In this case, a doctor should be prompted for a CT scan. Blood chemistry tests also assess the overall function of the kidneys and can allow the doctor to decide upon further radiological tests.

The characteristic appearance of renal cell carcinoma (RCC) is a solid renal lesion which disturbs the renal contour. It will frequently have an irregular or lobulated margin and may be seen as a lump on the lower pelvic or abdomen region. Traditionally, 85 to 90% of solid renal masses will turn out to be RCC but cystic renal masses may also be due to RCC.[38] However, the advances of diagnostic modalities are able to incidentally diagnose a great proportion of patients with renal lesions that may appear to be small in size and of benign state. Ten percent of RCC will contain calcifications, and some contain macroscopic fat (likely due to invasion and encasement of the perirenal fat.[39] Deciding on the benign or malignant nature of the renal mass on the basis of its localized size is an issue as renal cell carcinoma may also be cystic. As there are several benign cystic renal lesions (simple renal cyst, haemorrhagic renal cyst, multilocular cystic nephroma, polycystic kidney disease), it may occasionally be difficult for the radiologist to differentiate a benign cystic lesion from a malignant one.[40] The Bosniak classification system for cystic renal lesions classifies them into groups that are benign and those that need surgical resection, based on specific imaging features.[41]

The main imaging tests performed in order to identify renal cell carcinoma are pelvic and abdominal CT scans, ultrasound tests of the kidneys (ultrasonography), MRI scans, intravenous pyelogram (IVP) or renal angiography.[42] Among these main diagnostic tests, other radiologic tests such as excretory urography, positron-emission tomography (PET) scanning, ultrasonography, arteriography, venography, and bone scanning can also be used to aid in the evaluation of staging renal masses and to differentiate non-malignant tumours from malignant tumours.

Contrast-enhanced Computed tomography (CT) scanning is a routinely used imaging procedure in determining the stage of the renal cell carcinoma in the abdominal and pelvic regions of the patient. CT scans have the potential to distinguish solid masses from cystic masses and may provide information on the localization, stage or spread of the cancer to other organs of the patient. Key parts of the human body which are examined for metastatic involvement of renal cell carcinoma may include the renal vein, lymph node and the involvement of the inferior vena cava.[43] According to a study conducted by Sauk et al., multidetector CT imaging characteristics have applications in diagnosing patients with clear renal cell carcinoma by depicting the differences of these cells at the cytogenic level.[44]

Ultrasonographic examination can be useful in evaluating questionable asymptomatic kidney tumours and cystic renal lesions if Computed Tomography imaging is inconclusive. This safe and non-invasive radiologic procedure uses high frequency sound waves to generate an interior image of the body on a computer monitor. The image generated by the ultrasound can help diagnose renal cell carcinoma based on the differences of sound reflections on the surface of organs and the abnormal tissue masses. Essentially, ultrasound tests can determine whether the composition of the kidney mass is mainly solid or filled with fluid.[42]

A Percutaneous biopsy can be performed by a radiologist using ultrasound or computed tomography to guide sampling of the tumour for the purpose of diagnosis by pathology. However this is not routinely performed because when the typical imaging features of renal cell carcinoma are present, the possibility of an incorrectly negative result together with the risk of a medical complication to the patient may make it unfavourable from a risk-benefit perspective.[11] However, biopsy tests for molecular analysis to distinguish benign from malignant renal tumours is of investigative interest.[11]

Magnetic Resonance Imaging (MRI) scans provide an image of the soft tissues in the body using radio waves and strong magnets. MRI can be used instead of CT if the patient exhibits an allergy to the contrast media administered for the test.[45][46] Sometimes prior to the MRI scan, an intravenous injection of a contrasting material called gadolinium is given to allow for a more detailed image. Patients on dialysis or those who have renal insufficiency should avoid this contrasting material as it may induce a rare, yet severe, side effect known as nephrogenic systemic fibrosis.[47] A bone scan or brain imaging is not routinely performed unless signs or symptoms suggest potential metastatic involvement of these areas. MRI scans should also be considered to evaluate tumour extension which has grown in major blood vessels, including the vena cava, in the abdomen. MRI can be used to observe the possible spread of cancer to the brain or spinal cord should the patient present symptoms that suggest this might be the case.

Intravenous pyelogram (IVP) is a useful procedure in detecting the presence of abnormal renal mass in the urinary tract. This procedure involves the injection of a contrasting dye into the arm of the patient. The dye travels from the blood stream and into the kidneys which in time, passes into the kidneys and bladder. This test is not necessary if a CT or MRI scan has been conducted.[48]

Renal angiography uses the same principle as IVP, as this type of X-ray also uses a contrasting dye. This radiologic test is important in diagnosing renal cell carcinoma as an aid for examining blood vessels in the kidneys. This diagnostic test relies on the contrasting agent which is injected in the renal artery to be absorbed by the cancerous cells.[49] The contrasting dye provides a clearer outline of abnormally-oriented blood vessels believed to be involved with the tumour. This is imperative for surgeons as it allows the patients blood vessels to be mapped prior to operation.[43]

The staging of renal cell carcinoma is the most important factor in predicting its prognosis.[50] Staging can follow the TNM staging system, where the size and extent of the tumour (T), involvement of lymph nodes (N) and metastases (M) are classified separately. Also, it can use overall stage grouping into stage I-IV, with the 1997 revision of AJCC described below:[50]

At diagnosis, 30% of renal cell carcinomas have spread to the ipsilateral renal vein, and 5-10% have continued into the inferior vena cava.[51]

The gross and microscopic appearance of renal cell carcinomas is highly variable. The renal cell carcinoma may present reddened areas where blood vessels have bled, and cysts containing watery fluids.[52] The body of the tumour shows large blood vessels that have walls composed of cancerous cells. Gross examination often shows a yellowish, multilobulated tumor in the renal cortex, which frequently contains zones of necrosis, haemorrhage and scarring. In a microscopic context, there are four major histologic subtypes of renal cell cancer: clear cell (conventional RCC, 75%), papillary (15%), chromophobic (5%), and collecting duct (2%). Sarcomatoid changes (morphology and patterns of IHC that mimic sarcoma, spindle cells) can be observed within any RCC subtype and are associated with more aggressive clinical course and worse prognosis. Under light microscopy, these tumour cells can exhibit papillae, tubules or nests, and are quite large, atypical, and polygonal.

Recent studies have brought attention to the close association of the type of cancerous cells to the aggressiveness of the condition. Some studies suggest that these cancerous cells accumulate glycogen and lipids, their cytoplasm appear "clear", the nuclei remain in the middle of the cells, and the cellular membrane is evident.[53] Some cells may be smaller, with eosinophilic cytoplasm, resembling normal tubular cells. The stroma is reduced, but well vascularised. The tumour compresses the surrounding parenchyma, producing a pseudocapsule.[54]

The most common cell type exhibited by renal cell carcinoma is the clear cell, which is named by the dissolving of the cells' high lipid content in the cytoplasm. The clear cells are thought to be the least likely to spread and usually respond more favourably to treatment. However, most of the tumours contain a mixture of cells. The most aggressive stage of renal cancer is believed to be the one in which the tumour is mixed, containing both clear and granular cells.[55]

The recommended histologic grading schema for RCC is the Fuhrman system (1982), which is an assessment based on the microscopic morphology of a neoplasm with haematoxylin and eosin (H&E staining). This system categorises renal cell carcinoma with grades 1, 2, 3, 4 based on nuclear characteristics. The details of the Fuhrman grading system for RCC are shown below:[56]

Nuclear grade is believed to be one of the most imperative prognostic factors in patients with renal cell carcinoma.[21] However, a study by Delahunt et al. (2007) has shown that the Fuhrman grading is ideal for clear cell carcinoma but may not be appropriate for chromophobe renal cell carcinomas and that the staging of cancer (accomplished by CT scan) is a more favourable predictor of the prognosis of this disease.[57] In relation to renal cancer staging, the Heidelberg classification system of renal tumours was introduced in 1976 as a means of more completely correlating the histopathological features with the identified genetic defects.[58]

The type of treatment depends on multiple factors and the individual, some of which include:[7][59]

Every form of treatment has both risks and benefits; a health care professional will provide the best options that suit the individual circumstances.

Active surveillance or "watchful waiting" is becoming more common as small renal masses or tumours are being detected and also within the older generation when surgery is not always suitable.[60] Active surveillance involves completing various diagnostic procedures, tests and imaging to monitor the progression of the RCC before embarking on a more high risk treatment option like surgery.[60] In the elderly, patients with co-morbidities, and in poor surgical candidates, this is especially useful.

Different procedures may be most appropriate, depending on circumstances.

Radical nephrectomy is the removal of the entire affected kidney including Gerota's fascia, the adrenal gland which is on the same side as the affected kidney, and the regional lymph nodes, all at the same time.[7] This method, although severe, is effective. But it is not always appropriate, as it is a major surgery that contains the risk of complication both during and after the surgery and can have a longer recovery time.[61] It is important to note that the other kidney must be fully functional, and this technique is most often used when there is a large tumour present in only one kidney.

Nephron-sparing partial nephrectomy is used when the tumor is small (less than 4cm in diameter) or when the patient has other medical concerns such as diabetes or hypertension.[7] The partial nephrectomy involves the removal of the affected tissue only, sparing the rest of the kidney, Gerota's fascia and the regional lymph nodes. This allows for more renal preservation as compared to the radical nephrectomy, and this can have positive long term health benefits.[62] Larger and more complex tumors can also be treated with partial nephrectomy by surgeons with a lot of kidney surgery experience.[63]

Laparoscopic nephrectomy uses laparoscopic surgery, with minimally invasive surgical techniques. Commonly referred to as key hole surgery, this surgery does not have the large incisions seen in a classically performed radical or partial nephrectomy, but still successfully removes either all or part of the kidney. Laparoscopic surgery is associated with shorter stays in the hospital and quicker recovery time but there are still risks associated with the surgical procedure.

Surgery for metastatic disease: If metastatic disease is present surgical treatment may still a viable option. Radical and partial nephrectomy can still occur, and in some cases if the metastasis is small this can also be surgically removed.[7] This depends on what stage of growth and how far the disease has spread.

Targeted ablative therapies are also known as percutaneous ablative therapies. Although the use of laparoscopic surgical techniques for complete nephrectomies has reduced some of the risks associated with surgery,[64] surgery of any sort in some cases will still not be feasible. For example, the elderly, people already suffering from severe renal dysfunction, or people who have several comorbidities, surgery of any sort is not warranted.[65] Instead there are targeted therapies which do not involve the removal of any organs or serious surgery. Rather, these therapies involve the ablation of the tumor or the affected area. Ablative treatments use imaging such as computed tomography (CT) or magnetic resonance imaging (MRI) to identify the location of the tumors, which ideally are smaller than 3.5cm and to guide the treatment. However there are some cases where ablation can be used on tumors that are larger.[65]

The two main types of ablation techniques that are used for renal cell carcinoma are radio frequency ablation and cryoablation.[65]

Radio frequency ablation uses an electrode probe which is inserted into the affected tissue, to send radio frequencies to the tissue to generate heat through the friction of water molecules. The heat destroys the tumor tissue.[7] Cell death will generally occur within minutes of being exposed to temperatures above 50C.

Cryoablation also involves the insertion of a probe into the affected area,[7] however, cold is used to kill the tumor instead of heat. The probe is cooled with chemical fluids which are very cold. The freezing temperatures cause the tumor cells to die by causing osmotic dehydration, which pulls the water out of the cell destroying the enzyme, organelles, cell membrane and freezing the cytoplasm.[65]

Immunotherapy is a method that activates the person's immune system and uses it to their own advantage. It was developed after observing that in some cases there was spontaneous regression.[66] That is, the renal cell carcinoma improved with no other therapies. Immunotherapy capitalises on this phenomenon and aims to build up a person's immune response to cancer cells.[66] Other medications target things such as growth factors that have been shown to promote the growth and spread of tumours.[67] They inhibit the growth factor in order to prevent tumours from forming.[68] There have been many different medications developed and most have only been approved in the last seven or so years.[69]

Some of the most recently developed treatments are listed below:[70]

Each of the treatments listed above is slightly different; some only work for a little while and others need to be used in conjunction with other therapies. There are also different side effects and risks associated with different forms of medication. As always, the advice of a health care professional should be sought if considering any of the therapies mentioned.

Chemotherapy and radiotherapy are not as successful in the case of RCC. RCC is resistant in most cases but there is about a 4-5% success rate sometimes, but this is often short lived with more tumours and growths developing later.[7]

Cancer vaccines are being developed but so far have been found to be effective for only certain forms of the RCC.[7] The vaccines are being designed to "prime" the immune system to provide tumour specific immunity.[66] They are still being developed but the present another treatment possibility.

Adjuvant therapy, which refers to therapy given after a primary surgery, has not been found to be beneficial in renal cell cancer.[72] Conversely, neoadjuvant therapy is administered before the intended primary or main treatment. In some cases neoadjuvant therapy has been shown to decrease the size and stage of the RCC to then allow it to be surgically removed.[68] This is a new form of treatment and the effectiveness of this approach is still being assessed in clinical trials.

Metastatic renal cell carcinoma (mRCC) is the spread of the primary renal cell carcinoma from the kidney to other organs. 25-30% of people have this metastatic spread by the time they are diagnosed with renal cell carcinoma.[73] This high proportion is explained by the fact that clinical signs are generally mild until the disease progresses to a more severe state.[74] The most common sites for metastasis are the lymph nodes, lung, bones, liver and brain.[8] How this spread affects the staging of the disease and hence prognosis is discussed in the Diagnosis and Prognosis section.

MRCC has a poor prognosis compared to other cancers although average survival times have increased in the last few years due to treatment advances. Average survival time in 2008 for the metastatic form of the disease was under a year[75] and by 2013 this improved to an average of 22 months.[76] Despite this improvement the 5 year survival rate for mRCC remains under 10%[77] and 20-25% of suffers remain unresponsive to all treatments and in these cases, the disease has a rapid progression.[76]

The available treatments for RCC discussed in the Treatment section are also relevant for the metastatic form of the disease. Options include interleukin-2 which is a standard therapy for advanced renal cell carcinoma.[72] In the past six years, seven new treatments have been approved specifically for mRCC (sunitinib, temsirolimus, bevacizumab, sorafenib, everolimus, pazopanib and axitinib).[4] These new treatments are based on the fact that renal cell carcinomas are very vascular tumors they contain a large number of blood vessels. The drugs aim to inhibit the growth of new blood vessels in the tumors, hence slowing growth and in some cases reducing the size of the tumors.[78] Side effects unfortunately are quite common with these treatments and include:[79]

Radiotherapy and chemotherapy are more commonly used in the metastatic form of RCC to target the secondary tumors in the bones, liver, brain and other organs. While not curative, these treatments do provide relief for suffers from symptoms associated with the spread of tumors.[76] Other potential treatments are still being developed, including tumor vaccines and small molecule inhibitors.[73]

The prognosis for renal cell carcinoma is largely influenced by a variety of factors, including tumour size, degree of invasion and metastasis, histologic type, and nuclear grade.[21] For metastatic renal cell carcinoma, factors which may present a poor prognosis include a low Karnofsky performance-status score (a standard way of measuring functional impairment in patients with cancer), a low haemoglobin level, a high level of serum lactate dehydrogenase, and a high corrected level of serum calcium.[80][81] For non-metastatic cases, the Leibovich scoring algorithm may be used to predict post-operative disease progression.[82]

Renal cell carcinoma is one of the cancers most strongly associated with paraneoplastic syndromes, most often due to ectopic hormone production by the tumour. The treatment for these complications of RCC is generally limited beyond treating the underlying cancer.

For those that have tumour recurrence after surgery, the prognosis is generally poor. Renal cell carcinoma does not generally respond to chemotherapy or radiation. Immunotherapy, which attempts to induce the body to attack the remaining cancer cells, has shown promise. Recent trials are testing newer agents, though the current complete remission rate with these approaches is still low, around 12-20% in most series. Most recently, treatment with tyrosine kinase inhibitors including nexavar, pazopanib, and rapamycin have shown promise in improving the prognosis for advanced RCC.[83]

The incidence of the disease varies according to geographic, demographic and, to a lesser extent, hereditary factors. There are some known risk factors, however the significance of other potential risk factors remains more controversial. The incidence of the cancer has been increasing in frequency worldwide at a rate of approximately 2-3% per decade[75] until the last few years where the number of new cases has stabilised.[14]

The incidence of RCC varies between sexes, ages, races and geographic location around the world. Men have a higher incidence than women (approximately 1.6:1)[72] and the vast majority are diagnosed after 65 years of age.[72] Asians reportedly have a significantly lower incidence of RCC than whites and while African countries have the lowest reported incidences, African Americans have the highest incidence of the population in the United States.[14] Developed countries have a higher incidence than developing countries, with the highest rates found in North America, Europe and Australia / New Zealand[84]

Daniel Sennert made the first reference suggesting a tumour arising in the kidney in his text Practicae Medicinae, first published in 1613.[85]

Miril published the earliest unequivocal case of renal carcinoma in 1810.[86] He described the case of Franoise Levelly, a 35 year old woman, who presented to Brest Civic Hospital on April 6, 1809, supposedly in the late stages of pregnancy.[85]

Koenig published the first classification of renal tumours based on macroscopic morphology in 1826. Koenig divided the tumors into scirrhous, steatomatous, fungoid and medullary forms.[87]

Following the classification of the tumour, researchers attempted to identify the tissue of origin for renal carcinoma.

The pathogenesis of renal epithelial tumours was debated for decades. The debate was initiated by Paul Grawitz when in 1883, he published his observations on the morphology of small, yellow renal tumours. Grawitz concluded that only alveolar tumours were of adrenal origin, whereas papillary tumours were derived from renal tissue.[85]

In 1893, Paul Sudeck challenged the theory postulated by Grawitz by publishing descriptions of renal tumours in which he identified atypical features within renal tubules and noted a gradation of these atypical features between the tubules and neighboring malignant tumour. In 1894, Otto Lubarsch, who supported the theory postulated by Grawitz coined the term hypernephroid tumor, which was amended tohypernephroma by Felix Victor Birch-Hirschfeld to describe these tumours.[88]

Vigorous criticism of Grawitz was provided by Oskar Stoerk in 1908, who considered the adrenal origin of renal tumours to be unproved. Despite the compelling arguments against the theory postulated by Grawitz, the term hypernephroma, with its associated adrenal connotation, persisted in the literature.[85]

Foot and Humphreys, and Foote et al. introduced the term Renal Celled Carcinoma to emphasize a renal tubular origin for these tumours. Their designation was slightly altered by Fetter to the now widely accepted term Renal Cell Carcinoma.[89]

Convincing evidence to settle the debate was offered by Oberling et al. in 1959 who studied the ultrastructure of clear cells from eight renal carcinomas. They found that the tumour cell cytoplasm contained numerous mitochondria and deposits of glycogen and fat. They identified cytoplasmic membranes inserted perpendicularly onto basement membrane with occasional cells containing microvilli along the free borders. They concluded that these features indicated that the tumours arose from the epithelial cells of the renal convoluted tubule, thus finally settling one of the most debated issues in tumour pathology.[85][90]

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Renal cell carcinoma - Wikipedia, the free encyclopedia

Uncategorized Comments Off on Renal cell carcinoma – Wikipedia, the free encyclopedia | August 21st, 2015

Published August 19, 2015

This image of the lab-grown brain is labeled to show identifiable structures: the cerebral hemisphere, the optic stalk and the cephalic flexure, a bend in the mid-brain region, all characteristic of the human fetal brain.(The Ohio State University)

Researchers at The Ohio State University were able to create a nearly complete human brain that matches the brain maturity of a 5-week-old fetus by using adult human skin cells.

The brain organoid is about the size of a pencil eraser and has an identifiable structure containing 99 percent of the genes present in the human fetal brain, according to a news release. Scientists say its the most complete human brain model yet developed.

It not only looks like the developing brain, its diverse cell types express nearly all genes like a brain, Rene Anand, a professor of biological chemistry and pharmacology at Ohio State, said in a news release. Weve struggled for a long time trying to solve complex brain disease problems that cause tremendous pain and suffering. The power of this brain model bodes very well for human health because it gives us better and more relevant options to test and develop therapeutics other than rodents.

Anand, who began his quest four years ago, studies the association between nicotinic receptors and central nervous system disorders. Hes hopeful that the lab-grown brain will provide ethical and more rapid and accurate testing of experimental drugs before the clinical trial stage.

In central nervous system diseases, this will enable studies of either underlying genetic susceptibility or purely environmental influences, or a combination, Anand said in the news release. Genomic science infers there are up to 600 genes that give rise to autism, but we are stuck there. Mathematical correlations and statistical methods are insufficient to in themselves identify causation. You need an experimental system you need a human brain.

Anand and his team built the model system in 15 weeks, using techniques to convert adult skin cells into pluripotent cells, which are immature cells that can be programmed to become any tissue in the body. They worked to differentiate pluripotent stem cells into cells that are designed to become neural tissue, according to the news release.

While the model lacks a vascular system, it does contain a spinal cord, all major regions of the brain, multiple cell types, signaling circuitry and a retina, according to the news release.

Anand reported on his research at the 2015 Military Health System Research Symposium.

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Researchers create lab-grown brain using human skin cells ...

Skin Stem Cells Comments Off on Researchers create lab-grown brain using human skin cells … | August 20th, 2015

This is an achievement: Scientists have used skin cells to build a rudimentary human brain. (These were induced pluripotent stem cells.) From The Guardian story:

Though not conscious the miniature brain, which resembles that of a five-week-old foetus, could potentially be useful for scientists who want to study the progression of developmental diseases. It could also be used to test drugs for conditions such as Alzheimers and Parkinsons, since the regions they affect are in place during an early stage of brain development.

The brain, which is about the size of a pencil eraser, is engineered from adult human skin cells and is the most complete human brain model yet developed, claimed Rene Anand of Ohio State University, Columbus, who presented the work today at the Military Health System Research Symposium in Fort Lauderdale, Florida.

May it be so.

Lets analyze what this breakthrough could portend:

1. No need for unethical human cloning to derive cells for use in research and drug testing.

2. No need for fetal farming for experimentation and organ transplants.

3. No need for Planned Parenthood dismemberments of fetuses killed in a less crunchy way in abortion.

Remember when embryonic stem cells were OUR ONLY HOPE?

And that those of us who said that particular meme wasnt true were anti science? Pshaw.

#applause

Continued here:
ETHICAL Stem Cells Grow Human Brain | National Review Online

Skin Stem Cells Comments Off on ETHICAL Stem Cells Grow Human Brain | National Review Online | August 20th, 2015

Find your glossary term by first letter:

a form of complementary and alternative medicine that involves inserting thin needles thorugh the skin at specific points on the body to control pain and other symptoms.

a form of complementary and alternative medicine that involves inserting thin needles thorugh the skin at specific points on the body to control pain and other symptoms.

written instructions letting others know the type of care you want if you are seriously ill or dying. These include a living will and health care power of attorney.

written instructions letting others know the type of care you want if you are seriously ill or dying. These include a living will and health care power of attorney.

disorders that involve an immune response in the body. Allergies are reactions to allergens such as plant pollen, other grasses and weeds, certain foods, rubber latex, insect bites, or certain drugs.

tiny glands in the breast that produce milk.

a brain disease that cripples the brain's nerve cells over time and destroys memory and learning. It usually starts in late middle age or old age and gets worse over time. Symptoms include loss of memory, confusion, problems in thinking, and changes in language, behavior, and personality.

clear, slightly yellowish liquid that surrounds the unborn baby (fetus) during pregnancy. It is contained in the amniotic sac.

when the amount of red blood cells or hemoglobin (the substance in the blood that carries oxygen to organs) becomes reduced, causing fatigue that can be severe.

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Glossary Index | womenshealth.gov

Uncategorized Comments Off on Glossary Index | womenshealth.gov | August 3rd, 2015

Ankylosing Spondilytis, is a kind of inflammatory, autoimmune disorder of unknown etiology primarily affecting the spine, axial skeleton and large proximal joints of the body, this may inturn lead to eventual fusion of the spine.It can rage from mild to progressively degenerating diseases.

Although autoimmune, 90% of the patients suffering from the condition have proved to express the presence of HLA-B27 geneotype, confirming the genetic association of the disorder. Estimates may vary but it is observed that young men between the age group 20-40 are affected. The characterization of AS is done various symptoms, three of them occur most generally and they are pain, stiffness,excessive fatigue etc. Although the symptoms are very generalized there are some telltale conditions such as severe back pain.

The current treatments include severe physiotherapy, medication and other rehabilitation approach. However with these treatment regimen the pathophysiology of the disease is not reversed neither the further progression is stopped. On the contrary, the cutting edge stem cell treatment can offer the solution for the condition. Stem cells are the original, naive cells capable of forming any cells of the same or different lineage.

Ankylosing Spondilytis is a kind of arthritis mainly affecting the spine, but sometimes other organs are also involved.

Mentioned below is case analysis of a patient who had been suffering from Ankylosing Spondilytis. And at a young age of 25 years, he was unable to walk. Now after stem cells treatment he has started walking and his quality of life has improved.

Case Study

Name of the patient:- Rahul (name is changed for privacy reasons)

Disease: Ankylosing Spondilytis

Rahul was suffering from Ankylosing Spondilytis since past 14 years. Painful joints, restricted movements and stiffness in the body was his way of life. Although Rahul doesn't have any family history of joint diseases.

Rahul's symptoms started with sudden onset of the back pain, which went on to be severe with the whole body aches, upto the extent that he could hardly walk or if he could, he started walking like an old man. Although the initial X ray analysis showed nothing, may be because practically it take several years to show changes associated with the spine. Consequently Rahul had to visit rheumatologists, who confirmed after almost 3 years that he is suffering from AS. His treatment regimen involved diet plan, some oral medications and restricted sports activities.

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Spinal Cord Injury Treatment, Stem Cell Therapy For Spinal ...

Spinal Cord Stem Cells Comments Off on Spinal Cord Injury Treatment, Stem Cell Therapy For Spinal … | August 1st, 2015

A new method for delivering stem cells to damaged heart muscle has shown early promise in treating severe heart failure, researchers report.

In a preliminary study, they found the tactic was safe and feasible for the 48 heart failure patients they treated. And after a year, the patients showed a modest improvement in the heart's pumping ability, on average.

It's not clear yet whether those improvements could be meaningful, said lead researcher Dr. Amit Patel, director of cardiovascular regenerative medicine at the University of Utah.

He said larger clinical trials are underway to see whether the approach could be an option for advanced heart failure.

Other experts stressed the bigger picture: Researchers have long studied stem cells as a potential therapy for heart failure -- with limited success so far.

"There's been a lot of promise, but not much of a clinical benefit yet," said Dr. Lee Goldberg, who specializes in treating heart failure at the University of Pennsylvania.

Researchers are still sorting through complicated questions, including how to best get stem cells to damaged heart muscle, said Goldberg, who was not involved in the new study.

What's "novel" in this research, he said, is the technique Patel's team used to deliver stem cells to the heart. They took stem cells from patients' bone marrow and infused them into the heart through a large vein called the coronary sinus.

Patel agreed that the technique is the advance.

"Most other techniques have infused stem cells through the arteries," Patel explained. One obstacle, he said, is that people with heart failure generally have hardened, narrowed coronary arteries, and the infused stem cells "don't always go to where they should."

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Stem Cells Show Promise in Heart Failure Treatment

Cardiac Stem Cells Comments Off on Stem Cells Show Promise in Heart Failure Treatment | August 1st, 2015

Clara's Story

Clara had a severe heart attack in 2004. Before contacting us she had received adult stem cells from a company in Thailand - a process requiring at least a one week stay.

When she contacted Stemaid, she had just had an echocardiogram showing that her overall left ventricular ejection fraction was estimated to be 30 to 35%. She opted to receive one injection of 5 million Embryonic Stem Cells by Stemaid in November 2010. She arrived at 1pm and was done by 3pm the same day.

We received the following email from her in April 2011: I had an EKO last week and rate is 44%, up from the 33/35% it was before I received Stemaid's stem cells! . Are the stem cells still available and still as good?

The heart contains a small amount of stem cells, the cardiac stem cells, that are produced when there is a need for production of more heart cells or for an active replacement of damaged ones. These cardiac cells are produced in high quantity for about one week following an infarction, actively repairing the damaged areas of the heart.

However this high production stops after a week and the repair stops as well.

Initial studies showed that by introducing embryonic stem cells, the heart starts to repair again within minutes of their injection. More recent studies showed that the injection of embryonic stem cells actually triggers the production of cardiac stem cells for one week. Another week of active repair is offered each time that one receives embryonic stem cells.

If you have suffered from an infarction, we suggest a minimum of 3 injections of esc over the course of 3 weeks to get significant repair.

Some of the patients who have received Stemaid Embryonic Stem-Cells have agreed to be mentioned on our website so that we may illustrate the benefits of them.

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Heart Disease - Stemaid : Embryonic Stem-cells

Cardiac Stem Cells Comments Off on Heart Disease – Stemaid : Embryonic Stem-cells | August 1st, 2015

Date: 01 Aug 2015

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Tanshinone IIA (TSA) is a lipophilic diterpene purified from the Chinese herb Danshen, which exhibits potent antioxidant and anti-inflammatory properties. Effect of TSA remains largely uninvestigated on the osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs), which are widely used in cell-based therapy of bone diseases. In the present study, both ALP activity at day 7 and calcium content at day 24 were upregulated during the osteogenesis of mouse BM-MSCs treated with TSA (1 and 5M), demonstrating that it promoted the osteogenesis at both early and late stages. We found that TSA promoted osteogenesis and inhibited osteoclastogenesis, evident by RT-PCR analysis of osteogenic marker gene expressions. However, osteogenesis was inhibited by TSA at 20M. We further revealed that TSA (1 and 5M) upregulated BMP and Wnt signaling. Co-treatment with Wnt inhibitor DKK-1 or BMP inhibitor noggin significantly decreased the TSA-promoted osteogenesis, indicating that upregulation of BMP and Wnt signaling plays a significant role and contributes to the TSA-promoted osteogenesis. Of clinical interest, our study suggests TSA as a promising therapeutic strategy during implantation of BM-MSCs for a more effective treatment of bone diseases.

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Effects of Tanshinone IIA on osteogenic differentiation of ...

Bone Marrow Stem Cells Comments Off on Effects of Tanshinone IIA on osteogenic differentiation of … | August 1st, 2015

Our skin has the amazing capability to renew itself throughout our adult life. Also, our hair follicle goes through a cycle of growth and degeneration. This happens all the time in our skin even though we are not aware of it. However, even though skin renews itself we still have to help it a little bit to get better results. Stem cells play an important role in this process of skin renewal or hair growth and the purpose of this article is to discuss and provide additional information about these tiny cells that play a big part in our life.

Skin stem cell is defined as multipotent adult skin cells which are able to self-renew or differentiate into various cell lineages of the skin. These cells are active throughout our life via skin renewal process or during skin repair after injuries. These cells reside in the epidermis and hair follicle and one of their purposes is to ensure the maintenance of adult skin and hair regeneration.

The truth is, without these little cells, our skin wouldnt be able to cope with various environmental influences. Our skin is exposed to different influences 24/7, for example, washing your face with soap, going out during summer or cold winter days etc. All these factors have a big impact on our skin and it constantly has to renew itself to stay in a good condition. This is where skin stem cells step in. They make sure your skin survives the influence of constant stress, heat, cold, even makeup, soap, etc.

Our skin is quite sensitive and due to its constant exposure to different influences throughout the day, it can get easily damage. Damage to skin cells can be caused by pretty much everything, from soap to cigarette smoke. One of the most frequent skin cell damages are the result of:

Skin stem cells are still subjected to scientific projects where researchers are trying to discover as much as possible about them. So far, they have identified several types of these cells, and they are:

Also, some scientists suggest that there is another type of stem cells mesenchymal stem cells which can be found in dermis (layer situated below the epidermis) and hypodermis (innermost and the thickest layer of the skin). However, this claim has been branded controversial and is a subject of many arguments and disputes between scientists. It is needed to conduct more experiments to find out whether this statement really is true.

Stem cells are found in many organs and tissues, besides skin. For example, scientists have discovered stem sells in brain, heart, bone marrow, peripheral blood, skeletal muscle, teeth, liver, gut etc. Stem cells reside in a specific area of each tissue or organ and that area is called stem cell niche. The same case is with the skin as well.

The ability of stem cells to regenerate and form almost any cell type in the body inspired scientists to work on various skin products that contain stem cells. Also, they decided to investigate the effect of plant stem cells on human skin. They discovered that plant stem cells are, actually, very similar to human skin stem cells and they function in a similar way as well. This discovery made scientists turn to plants as the source of stem cells and are trying to include them into the skin products due to their effectiveness in supporting skins cellular turnover. Another similarity between plant stem cells and human skin stem cells is their ability to develop according to their environment.

Fun Fact: The inspiration to use plant stem cells in skin care came from an unusual place almost extinct apple tree from Switzerland.

The benefits of plant stem cells on human skin are versatile. They offer possibility to treat some skin conditions, heal wounds, and repair the skin after some injury faster than it would usually take. Also, they bring back elasticity to the skin, reduce the appearance of wrinkles and slow down the aging process.

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Skin Stem Cells: Benefits, Types, Medical Applications and ...

Skin Stem Cells Comments Off on Skin Stem Cells: Benefits, Types, Medical Applications and … | August 1st, 2015

You will have a low white blood cell count after your treatment. This means you are more at risk of getting an infection. You are likely to get an infection from the normally harmless bacteria we all have in our digestive systems and on our skin.

To stop this from happening your nurse may give you tablets called gut sterilisers (antibiotics) and mouthwashes. And they will encourage you to have a shower each day.

You are also at risk of infection from food. The nurses on the ward will tell you and your relatives about the food you can and can't eat. The rules vary from hospital to hospital but you may be told that

Your room will be thoroughly cleaned every day. Your visitors will be asked to wash their hands before they come into your room. They may also have to wear disposable gloves and aprons. Visitors with coughs and colds are not allowed. Some hospitals don't allow you to have plants or flowers in your room because bacteria and fungi can grow in the soil or water, and may cause infection.

Even with all these precautions, most people do get an infection at some point and need to have antibiotics. You can help yourself by trying to do your mouth care properly and getting up to shower and have your bed changed even on the days you don't feel too good.

After a transplant you will have lost immunity to diseases you were vaccinated against as a child. The team caring for you will advise you about the immunisations you need and when. You should only have inactivated immunisations and not live ones. To lower the risk of you getting any of these infections it is important that all your family have the flu vaccine and any children have all their immunisations.

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Side effects of bone marrow and stem cell transplants ...

Bone Marrow Stem Cells Comments Off on Side effects of bone marrow and stem cell transplants … | July 23rd, 2015

Hair follicle lineage and niche signals regulate hair follicle stem cells. (a) HFSCs can exist in two states. Quiescent bulge stem cells (Bu-SCs) are located in the outer layer of this niche and contribute to the generation of the outer root sheath. Primed stem cells reside in the hair germ, sandwiched between the bulge and a specialized dermal cluster known as the dermal papilla. They are responsible for generating the transit amplifying cell (TAC) matrix, which then gives rise to the hair shaft and its inner root sheath (IRS) channel. Although matrix and IRS are destroyed during catagen, many of the outer root sheath (ORS) cells are spared and generate a new bulge right next to the original one at the end of catagen. The upper ORS contributes to the outer layer of the new bulge, and the middle ORS contributes to the hair germ. Some of the lower ORS cells become the differentiated inner keratin 6+ (K6+) bulge cells, which provide inhibitory signals to Bu-SCs, raising their activation threshold for the next hair cycle. (b) During telogen, K6+ bulge cells produce BMP6 and FGF-18, dermal fibroblasts (DFs) produce BMP4 and subcutaneous adipocytes express BMP2. Together, these factors maintain Bu-SCs and hair germ in quiescence. At the transition to anagen, BMP2 and BMP4 are downregulated, whereas the expression of activation factors including noggin (NOG), FGF-7, FGF-10 and TGF-2 from dermal papillae and PDGF- from adipocyte precursor cells (APCs) is elevated. This, in turn, stimulates hair germ proliferation, and a new hair cycle is launched. Bu-SCs maintain their quiescent state until TAC matrix is generated and starts producing SHH.

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Emerging interactions between skin stem cells and their ...

Skin Stem Cells Comments Off on Emerging interactions between skin stem cells and their … | July 23rd, 2015

Recently, Ive written about transition from iPS cell research to iPS cell large-scale manufacturing and automation. Ive described iPS cell process development in Cellular Dynamics International and New York Stem Cell Foundation Research Institute. Today, Id like to share presentations of 2 more players in the field Lonza and Roslin Cells. Both presentations were recorded at Stem Cell Meeting on the Mesa, held on October 14-16, 2013.

What was especially interesting to see a cost comparison between research and clinical-grade GMP-produced iPS cell lines:

(Screenshot from Lonza presentation at Stem Cell Meeting on the Mesa, 2013)

Interestingly, the major cost contributor in GMP-grade iPS cell production is a facility cost. I think, this is a first estimation of cost difference, presented for public.

The framework for establishing clinical-grade iPS cell manufacturing, nicely outlined in the recent article. Id also recommend you to read the following open access articles:

Tagged as: cost, iPS, manufacturing

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Clinical GMP-grade iPS cell production - Stem Cell Assays

IPS Cell Therapy Comments Off on Clinical GMP-grade iPS cell production – Stem Cell Assays | July 23rd, 2015

The stem cell controversy is the consideration of the ethics of research involving the development, usage, and destruction of human embryos. Most commonly, this controversy focuses on embryonic stem cells. Not all stem cell research involves the creation, usage and destruction of human embryos. For example, adult stem cells, amniotic stem cells and induced pluripotent stem cells do not involve creating, using or destroying human embryos and thus are minimally, if at all, controversial.

The use of stem cells has been happening for decades. In 1998, scientists discovered how to extract stem cells from human embryos. This discovery led to moral ethics questions concerning research involving embryo cells, such as what restrictions should be made on studies using these types of cells? At what point does one consider life to begin? Is it just to destroy an embryo cell if it has the potential to cure countless numbers of patients? Political leaders are debating how to regulate and fund research studies that involve the techniques used to remove the embryo cells. No clear consensus has emerged. Other recent discoveries may extinguish the need for embryonic stem cells.[1]

Since stem cells have the ability to differentiate into any type of cell, they offer something in the development of medical treatments for a wide range of conditions. Treatments that have been proposed include treatment for physical trauma, degenerative conditions, and genetic diseases (in combination with gene therapy). Yet further treatments using stem cells could potentially be developed thanks to their ability to repair extensive tissue damage.[2]

Great levels of success and potential have been shown from research using adult stem cells. In early 2009, the FDA approved the first human clinical trials using embryonic stem cells. Embryonic stem cells can become all cell types of the body which is called totipotent. Adult stem cells are generally limited to differentiating into different cell types of their tissue of origin. However, some evidence suggests that adult stem cell plasticity may exist, increasing the number of cell types a given adult stem cell can become. In addition, embryonic stem cells are considered more useful for nervous system therapies, because researchers have struggled to identify and isolate neural progenitors from adult tissues[citation needed]. Embryonic stem cells, however, might be rejected by the immune system - a problem which wouldn't occur if the patient received his or her own stem cells.

Some stem cell researchers are working to develop techniques of isolating stem cells that are as potent as embryonic stem cells, but do not require a human embryo.

Some believe that human skin cells can be coaxed to "de-differentiate" and revert to an embryonic state. Researchers at Harvard University, led by Kevin Eggan, have attempted to transfer the nucleus of a somatic cell into an existing embryonic stem cell, thus creating a new stem cell line.[3] Another study published in August 2006 also indicates that differentiated cells can be reprogrammed to an embryonic-like state by introducing four specific factors, resulting in induced pluripotent stem cells.[4]

Researchers at Advanced Cell Technology, led by Robert Lanza, reported the successful derivation of a stem cell line using a process similar to preimplantation genetic diagnosis, in which a single blastomere is extracted from a blastocyst.[5] At the 2007 meeting of the International Society for Stem Cell Research (ISSCR),[6] Lanza announced that his team had succeeded in producing three new stem cell lines without destroying the parent embryos. "These are the first human embryonic cell lines in existence that didn't result from the destruction of an embryo." Lanza is currently in discussions with the National Institutes of Health (NIH) to determine whether the new technique sidesteps U.S. restrictions on federal funding for ES cell research.[7]

Anthony Atala of Wake Forest University says that the fluid surrounding the fetus has been found to contain stem cells that, when utilized correctly, "can be differentiated towards cell types such as fat, bone, muscle, blood vessel, nerve and liver cells". The extraction of this fluid is not thought to harm the fetus in any way. He hopes "that these cells will provide a valuable resource for tissue repair and for engineered organs as well".[8]

The status of the human embryo and human embryonic stem cell research is a controversial issue as, with the present state of technology, the creation of a human embryonic stem cell line requires the destruction of a human embryo. Stem cell debates have motivated and reinvigorated the pro-life movement, whose members are concerned with the rights and status of the embryo as an early-aged human life. They believe that embryonic stem cell research instrumentalizes and violates the sanctity of life and is tantamount to murder.[9] The fundamental assertion of those who oppose embryonic stem cell research is the belief that human life is inviolable, combined with the belief that human life begins when a sperm cell fertilizes an egg cell to form a single cell.

A portion of stem cell researchers use embryos that were created but not used in in vitro fertility treatments to derive new stem cell lines. Most of these embryos are to be destroyed, or stored for long periods of time, long past their viable storage life. In the United States alone, there have been estimates of at least 400,000 such embryos.[10] This has led some opponents of abortion, such as Senator Orrin Hatch, to support human embryonic stem cell research.[11] See Also Embryo donation.

Original post:
Stem cell controversy - Wikipedia, the free encyclopedia

Uncategorized Comments Off on Stem cell controversy – Wikipedia, the free encyclopedia | July 20th, 2015

Understanding Cancer -- Diagnosis and Treatment How Is Cancer Diagnosed?

The earlier cancer is diagnosed and treated, the better the chance of its being cured. Some types of cancer -- such as those of the skin, breast, mouth, testicles, prostate, and rectum -- may be detected by routine self-exam or other screening measures before the symptoms become serious. Most cases of cancer are detected and diagnosed after a tumor can be felt or when other symptoms develop. In a few cases, cancer is diagnosed incidentally as a result of evaluating or treating other medical conditions.

Cancer diagnosis begins with a thorough physical exam and a complete medical history. Laboratory studies of blood, urine, and stool can detect abnormalities that may indicate cancer. When a tumor is suspected, imaging tests such as X-rays, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and fiber-optic endoscopy examinations help doctors determine the cancer's location and size. To confirm the diagnosis of most cancers , a biopsy needs to be performed in which a tissue sample is removed from the suspected tumor and studied under a microscope to check for cancer cells.

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Cancer Center: Types, Symptoms, Causes, Tests, and ...

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Characterization of isolated human SHEDs and DPSCs for use in transplantation studies. Flow cytometry analysis showed that the SHEDs and DPSCs expressed a set of mesenchymal stem cell (MSC) markers (i.e., CD90, CD73, and CD105), but not endothelial/hematopoietic markers (i.e., CD34, CD45, CD11b/c, and HLA-DR) (Table 1). Like human BMSCs, both the SHEDs and DPSCs exhibited adipogenic, chondrogenic, and osteogenic differentiation as described previously (refs. 16, 17, and data not shown). The majority of SHEDs and DPSCs coexpressed several neural lineage markers: nestin (neural stem cells), doublecortin (DCX; neuronal progenitor cells), III-tubulin (early neuronal cells), NeuN (mature neurons), GFAP (neural stem cells and astrocytes), S-100 (Schwann cells), and A2B5 and CNPase (oligodendrocyte progenitor cells), but not adenomatous polyposis coli (APC) or myelin basic protein (MBP) (mature oligodendrocytes) (Figure 1A and Table 1). This expression profile was confirmed by immunohistochemical analyses (Figure 1B).

Characterization of the SHEDs and DPSCs used for transplantation. (A) Flow cytometry analysis of the neural cell lineage markers expressed in SHEDs. Note that most of the SHEDs and DPSCs coexpressed neural stem and multiple progenitor markers, but not mature oligodendrocytes (APC and MBP). (B) Confocal images showing SHEDs coexpressed nestin, GFAP, and DCX. SHEDs also expressed markers for oligodendrocyte progenitor cells (A2B5 and CNPase), but not for mature oligodendrocytes (APC and MBP). Scale bar: 10 m. (C) Real-time RT-PCR analysis of the expression of neurotrophic factors. Results are expressed as fold increase compared with the level expressed in skin fibroblasts. Data represent the average measurements for each cell type from 3 independent donors. This set of experiments was repeated twice and yielded similar results. Data represent the mean SEM. *P < 0.01 compared with BMSCs and fibroblasts (Fbs).

Flow cytometry of stem cells from humans

Next, we examined the expression of representative neurotrophic factors by real-time PCR. Both the SHEDs and DPSCs expressed glial cellderived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) at more than 3 to 5 times the levels expressed by skin-derived fibroblasts or BMSCs (Figure 1C).

We further characterized the transcriptomes of SHEDs and BMSCs by cDNA microarray analysis. This gene expression analysis revealed a 2.0-fold difference in the expression of 3,318 of 41,078 genes between SHEDs and BMSCs. Of these, 1,718 genes were expressed at higher levels in the SHEDs and 1,593 genes were expressed at lower levels (data not shown). The top 30 genes showing higher expression in the SHEDs were in the following ontology categories: extracellular and cell surface region, cell proliferation, and tissue/embryonic development (Table 2).

Functional gene classification in SHEDs versus BMSCs

SHEDs and DPSCs promoted locomotor recovery after SCI. To compare the neuroregenerative activities of human SHEDs and DPSCs with those of human BMSCs and human skin fibroblasts, we transplanted the cells into the completely transected SCs, as described in Methods, and evaluated locomotion recovery using the Basso, Beattie, Bresnahan locomotor rating scale (BBB scale) (24). Remarkably, the animals that received SHEDs or DPSCs exhibited a significantly higher BBB score during the entire observation period, compared with BMSC-transplanted, fibroblast-transplanted, or PBS-injected control rats (Figure 2A). Importantly, their superior recoveries were evident soon after the operation, during the acute phase of SCI. After the recovery period (5 weeks after the operation), the rats that had received SHEDs were able to move 3 joints of hind limb coordinately and walk without weight support (P < 0.01; Supplemental Videos 1 and 2), while the BMSC- or fibroblast-transplanted rats exhibited only subtle movements of 12 joints. These results demonstrate that the transplantation of SHEDs or DPSCs during the acute phase of SCI significantly improved the recovery of hind limb locomotor function. Since the level of recovery was similar in the SHED- and DPSC-transplanted rats, we focused on the phenotypical examination of SHED-transplanted rats to elucidate how tooth-derived stem cells promoted the regeneration of the completely transected rat SC.

Engrafted SHEDs promote functional recovery of the completely transected SC. (A) Time course of functional recovery of hind limbs after complete transection of the SC. A total of 1 106 SHEDs, DPSCs, BMSCs, or fibroblasts were transplanted into the SCI immediately after transection. Data represent the mean SEM. **P < 0.001, *P < 0.01 compared with SCI models injected with PBS. (BD) Representative images (B and C) and quantification (D) of NF-Mpositive nerve fibers in sagittal sections of a completely transected SC, at 8 weeks after SCI. Dashed lines outline the SC. Insets are magnified images of boxed areas in B and C. (D) Nerve fiber quantification, representing the average of 3 experiments performed under the same conditions. The x axis indicates specific locations along the rostrocaudal axis of the SC (3 mm rostral and caudal to the epicenter), and y axis indicates the percentage of NF-Mpositive fibers compared with that of the sham-operated SCs at the ninth thoracic spinal vertebrate (Th9) level. Data represent the mean SEM. *P < 0.05 compared with SCI models injected with PBS. Scale bars: 100 m and inset 20 m (B) and 50 m (C). Asterisks in B and C indicate the epicenter of the lesion.

SHEDs regenerated the transected corticospinal tract and raphespinal serotonergic axons. To examine whether engrafted SHEDs affect the preservation of neurofilaments, we performed immunohistochemical analyses with an antineurofilament M (NF-M) mAb, 8 weeks after transection. Compared with the PBS-treated control SCs, the SHED-transplanted SCs exhibited greater preservation of NF-positive axons from 3 mm rostral to 3 mm caudal to the transected lesion site (Figure 2, B and C; asterisk indicates epicenter). The percentages of NF-positive axons in the epicenter of the SHED-transplanted and control SCs were 35.8% 13.0% and 8.7% 3.4%, respectively, relative to sham-treated SCs (Figure 2D).

Regeneration of both the corticospinal tract (CST) and the descending serotonergic raphespinal axons is important for the recovery of hind limb locomotor function in rat SCI. We therefore examined whether these axons had extended beyond the epicenter in the SHED-transplanted SCs. The CST axons were traced with the anterograde tracer biotinylated dextran amine (BDA), which was injected into the sensorimotor cortex. The serotonergic raphespinal axons were immunohistochemically detected by a mAb that specifically reacts with serotonin (5-hydroxytryptamine [5-HT]), which is synthesized within the brain stem. We found that both BDA- and 5-HTpositive fibers extended as far as 3 mm caudal to the epicenter in the SHED-transplanted but not the control group (Figures 3 and 4). Furthermore, some BDA- and 5-HTpositive boutons could be seen apposed to neurons in the caudal stump (Figure 3D and Figure 4C), suggesting that the regenerated axons had established new neural connections. Notably, although the number of descending axons extending beyond the epicenter was small, we observed many of them penetrating the scar tissue of the rostral stump (Figure 3A and Figure 4A). The percentages of 5-HTpositive axons of the SHED-transplanted SCs at 1 and 3 mm rostral to the epicenter were 58.9% 3.9% and 78.3% 7.4% relative to sham-treated SC, respectively (Figure 4D). These results demonstrate that the engrafted SHEDs promoted the recovery of hind limb locomotion via the preservation and regeneration of transected axons, even in the microenvironment of the damaged CNS.

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High levels of active TGF- in the bone marrow and abnormalities in bone remodeling are associated with multiple skeletal disorders. Genetic mutations in the TGF- signaling pathway cause premature activation of matrix latent TGF- and may manifest with various skeletal defects. There are additional diseases that result in high levels of active TGF-, which may contribute to the pathology. Here, we discuss how abnormal TGF- signaling results in uncoupled bone remodeling, mainly by loss of site-directed recruitment of MSCs that causes aberrant bone formation. Direct or indirect inhibition of TGF- signaling may provide potential therapeutic options for these disorders.

Genetic disorders. The critical role of TGF-1 in the reversal phase of bone remodeling is demonstrated by the range of skeletal disorders resulting from mutations in genes involved in TGF-1 signaling. Camurati-Engelmann disease (CED), characterized by a fusiform thickening of the diaphysis of the long bones and skull, is caused by mutations in TGFB1 that result in premature activation of TGF-1 (7174). Approximately 11 different TGFB1 mutations have been identified from families affected by CED (75, 76). All of the mutations are located in the region encoding LAP, either destabilizing LAP disulfide bridging or affecting secretion of the protein, both of which increase TGF-1 signaling, as confirmed by in vitro cell cultures and mouse models. Bone histology sections from patients with CED show decreased trabecular connectivity despite normal bone histomorphometric parameters with respect to osteoblast and osteoclast numbers (76, 77), suggestive of uncoupled bone remodeling. In vitro, the ratio of active to total TGF-1 in conditioned medium from cells expressing the CED mutant TGF-1 is significantly higher and enhances MSC migration (18). Targeted recruitment of MSCs to the bone-remodeling site is likely disrupted, secondary to loss of a TGF- gradient.

Elevations in TGF- signaling have also been observed in many genetic connective tissue disorders with craniofacial, skeletal, skin, and cardiovascular manifestations, including Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS). MFS is caused by mutations in fibrillin and often results in aortic dilation, myopia, bone overgrowth, and joint laxity. Fibrillin is deposited in the ECM and normally binds TGF-, rendering it inactive. In MFS, the decreased level of fibrillin enhances TGF- activity (78). LDS is caused by inactivating mutations in genes encoding TRI and TRII (79). Physical manifestations include arterial aneurysms, hypertelorism, bifid uvula/cleft palate, and bone overgrowth resulting in arachnodactyly, joint laxity, and scoliosis. Pathologic analyses of affected tissue suggest chronically elevated TGF- signaling, despite the inactivating mutation (79). The mechanism of enhanced TGF- signaling remains under investigation. SGS is caused by mutations in the v-ski avian sarcoma viral oncogene homolog (SKI; refs. 80, 81) and causes physical features similar to those of MFS plus craniosynostosis. SKI negatively regulates SMAD-dependent TGF- signaling by impeding SMAD2 and SMAD3 activation, preventing nuclear translocation of the SMAD4 complex, and inhibiting TGF- target gene output by competing with p300/CBP for SMAD binding and recruiting transcriptional repressor proteins, such as mSin3A and HDACs (8284).

The neurocutaneous syndrome neurofibromatosis type 1 (NF1) has been noted to have skeletal features similar to those of CED, MFS, and LDS, including kyphoscoliosis, osteoporosis, and tibial pseudoarthrosis. Hyperactive TGF-1 signaling has been implicated as the primary factor underlying the pathophysiology of the osseous defects in Nf1fl/Col2.3Cre mice, a model of NF1 that closely recapitulates the skeletal abnormalities found in human disease (85). The exact mechanisms mediating mutant neurofibrominassociated enhancement of TGF- production and signaling remain unknown.

Osteoarthritis. While genetic disorders are rare, they have provided critical insight into the pathophysiology of more common disorders. Uncoupled bone remodeling accompanies the onset of osteoarthritis. TGF-1 is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis (86). High levels of active TGF-1 induced formation of nestin+ MSC clusters via activation of ALK5-SMAD2/3. MSCs underwent osteoblast differentiation in these clusters, leading to formation of marrow osteoid islets. Transgenic expression of active TGF-1 in osteoblastic cells alone was sufficient to induce osteoarthritis, whereas direct inhibition of TGF- activity in subchondral bone attenuated the degeneration of articular cartilage. Knockout of Tgfbr2 in nestin+ MSCs reduced osteoarthritis development after ACLT compared with wild-type mice, which confirmed that MSCs are the target cell population of TGF- signaling. High levels of active TGF-1 in subchondral bone likely disrupt the TGF- gradient and interfere with targeted migration of MSCs. Furthermore, mutations of ECM proteins that bind to latent TGF-s, such as small leucine-rich proteoglycans (87) and fibrillin (88), or mutations in genes involved in activation of TGF-, such as in CED (76) and LDS (89), are associated with high osteoarthritis incidence. Osteoblast differentiation of MSCs in aberrant locations appears histologically as subchondral bone osteoid islets and alters the thickness of the subchondral plate and calcified cartilage zone, changes known to be associated with osteoarthritis (90, 91). A computer-simulated model found that a minor increase in the size of the subchondral bone (1%2%) causes significant changes in the mechanical load properties on articular cartilage, which likely leads to degeneration (86). Importantly, inhibition of the TGF- signaling pathway delayed the development of osteoarthritis in both mouse and rat models (86).

MSCs in bone loss. Aging leads to deterioration of tissue and organ function. Skeletal aging is especially dramatic: bone loss in both women and men begins as early as the third decade, immediately after peak bone mass. Aging bone loss occurs when bone formation does not adequately compensate for osteoclast bone resorption during remodeling. Age-associated osteoporosis was previously believed to be due to a decline in survival and function of osteoblasts and osteoprogenitors; however, recent work by Park and colleagues found that mature osteoblasts and osteoprogenitors are actually nonreplicative cells and require constant replenishment from bone marrow MSCs (92). When MSCs fail to migrate to bone-resorptive sites or are unable to commit and differentiate into osteoblasts, new bone formation is impaired. Therefore, insufficient recruitment of MSCs, or their differentiation to osteoblasts, at the bone remodeling surface may contribute to the decline in bone formation in the elderly.

There are multiple hypotheses regarding the decreased osteogenic potential of MSCs during aging. For example, during aging, the bone marrow environment has an increased concentration of ROS and lipid oxidation that may decrease osteoblast differentiation, yet increase osteoclast activity (93, 94). MSCs also undergo senescence, which decreases proliferative capacity and contributes to decreased bone formation (95, 96). Cellular senescence involves the secretion of a plethora of factors, including TGF-, which induces expression of cyclin-dependent kinase inhibitors 2A and 2B (p16INK4A and p15INK4B, respectively; refs. 97).

Microgravity experienced by astronauts during spaceflight causes severe physiological alterations in the human body, including a 1%2% loss of bone mass every month during spaceflight (98). Several studies have shown decreases in osteoblastic markers of bone formation and increases in bone resorption (99101). The underlying molecular mechanisms responsible for the apparent concurrent decrease in bone formation and increase in bone resorption remain under investigation. Work by the McDonald group suggests that bone remodeling may become uncoupled under zero-gravity conditions secondary to decreased RhoA activity and resultant changes in actin stress fiber formation (102). In modeled microgravity, cultured human MSCs exhibit disruption of F-actin stress fibers within three hours of initiation of microgravity; the fibers are completely absent after seven days. RhoA activity is significantly reduced, and introduction of an adenoviral construct expressing constitutively active RhoA can reverse the elimination of stress fibers, significantly increasing markers of osteoblast differentiation (102). Under zero-gravity conditions, RhoA is unable to bind to its receptor, and a sufficient number of MSCs may not be able to migrate correctly to the bone-resorptive site for osteoblast differentiation, ultimately leading to bone loss with every cycle of remodeling.

Bone metastases are a frequent complication of cancer and often have both osteolytic and osteoblastic features, indicative of dysregulated bone remodeling. The importance of the bone marrow microenvironment contributing to the spread of cancer was first described in 1889 (103), postulating that tumor cells can grow only if they are in a conducive environment. Activation of matrix TGF- during bone remodeling plays a central role in the initiation of bone metastases and tumor expansion by regulating osteolytic and prometastatic factors (reviewed in refs. 104110). For example, TGF- can induce osteoclastic bone destruction by upregulating tumor cell expression of PTHrP and IL-11. Additionally, upregulation of CXCR4 by TGF- may home cancer cells to bones.

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JCI - Bone marrow mesenchymal stem cells and TGF- ...

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General Information About Adult Non-Hodgkin Lymphoma (NHL)

The NHLs are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment.[1]

Like Hodgkin lymphoma, NHL usually originates in lymphoid tissues and can spread to other organs. NHL, however, is much less predictable than Hodgkin lymphoma and has a far greater predilection to disseminate to extranodal sites. The prognosis depends on the histologic type, stage, and treatment.

Estimated new cases and deaths from NHL in the United States in 2015:[2]

NHL usually originates in lymphoid tissues.

Anatomy of the lymph system.

The NHLs can be divided into two prognostic groups: the indolent lymphomas and the aggressive lymphomas.

Indolent NHL types have a relatively good prognosis with a median survival as long as 20 years, but they usually are not curable in advanced clinical stages.[3] Early-stage (stage I and stage II) indolent NHL can be effectively treated with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology.

The aggressive type of NHL has a shorter natural history, but a significant number of these patients can be cured with intensive combination chemotherapy regimens.

In general, with modern treatment of patients with NHL, overall survival at 5 years is over 60%. Of patients with aggressive NHL, more than 50% can be cured. The vast majority of relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients who manifest both indolent and aggressive histologies.[4]

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Adult Non-Hodgkin Lymphoma Treatment - National Cancer ...

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