They used to call August the silly season when politicians and journalists went away on holiday. The newspapers were stuck with stories of cats stuck up trees. Not so this August. These are the current stories: 1. Riots in the UK; 2. Famine in the horn of Africa; 3. America's credit rating degraded; 4. The Euro collapsing; 5 War in Libya; 6. War in Afghanistan; 7. Atrocities in Syria; 8. The aftermath of the Norway Massacre; 9. The aftermath of Levi-Strauss; 10. England walloping India in the Test Match.
It's not a day when Sports News makes the front pages, but it might be a good day to bury bad news.
This is the day that a major new treatment for CLL was announced. I will cover it maturely when I have all the background, but I have blogged about this approach in the past with some enthusiasm since I heard about its proposed use in ALL at GTAC. Mind, I can't find where I put it, so perhaps it was a comment rather than an entry. Never mind I shall definitely write an article about it.
Thursday, August 11, 2011
Anemia of chronic disorders: Hepcidin levels
Hepcidin assays
The central role played by hepcidin in the pathogenesis of ACD suggests that measurement of hepcidin levels might be a useful diagnostic tool in the evaluation of possible ACD. The first measurements of hepcidin relied on extraction from urine, and were laborious, but more recently mass spectrometric and immunological methods to measure levels in urine and serum have been developed with potential for clinical use, and some are now commercially available.
Elevated serum hepcidin levels have been observed in a variety of inflammatory diseases, including rheumatological conditions, inflammatory bowel disease, infections, multiple myeloma, non-Hodgkin lymphoma and critical illness. However, whilst hepcidin levels will usually be elevated in these inflammatory anaemias, levels may not be elevated in patients who have co-existent ACD and iron deficiency as the inflammation-induced increase in hepcidin production will be opposed by the effects of iron deficiency: indeed the long-term effects of hepcidin may to be produce iron deficiency through reduced intestinal iron absorption, so the use of hepcidin levels to diagnose ACD will need to be evaluated carefully. Hepcidin levels may therefore be more useful in distinguishing patients with pure ACD from those with combined ACD and iron deficiency and this may be of therapeutic value. Further standardization and investigation is probably required before hepcidin levels come into routine and widespread clinical use however.
Whether the anaemia observed in some elderly patients has the same pathogenesis as ACD has been a subject of considerable debate. In a large study of patients aged 65 years and over, the relationships between urinary hepcidin, iron status, anaemia and inflammatory markers were investigated: surprisingly, urinary hepcidin levels were closely associated with markers of iron status but not with inflammatory markers, raising the possibility that hepcidin-independent pathways may contribute to hypoferraemia and anaemia in ACD, or that hepcidin levels may only be elevated in settings of overt inflammation.
Growth differentiation factor 15
Growth differentiation factor 15 (GDF15) is an erythropoiesis-derived hormone that is markedly increased in β-thalassaemia and congenital dyserythropoietic anaemia, and inhibits hepcidin expression, contributing to the iron overload seen in these anaemias. Levels of GDF15 have been studied in patients with ACD, ACD/IDA and IDA. Subjects with both ACD and ACD/IDA showed significantly higher levels of GDF15 than patients with IDA, and GDF15 concentrations correlated with interleukin-1β, suggesting that inflammation induces GDF15 expression, although the pathophysiological relevance of this is unclear.
The central role played by hepcidin in the pathogenesis of ACD suggests that measurement of hepcidin levels might be a useful diagnostic tool in the evaluation of possible ACD. The first measurements of hepcidin relied on extraction from urine, and were laborious, but more recently mass spectrometric and immunological methods to measure levels in urine and serum have been developed with potential for clinical use, and some are now commercially available.
Elevated serum hepcidin levels have been observed in a variety of inflammatory diseases, including rheumatological conditions, inflammatory bowel disease, infections, multiple myeloma, non-Hodgkin lymphoma and critical illness. However, whilst hepcidin levels will usually be elevated in these inflammatory anaemias, levels may not be elevated in patients who have co-existent ACD and iron deficiency as the inflammation-induced increase in hepcidin production will be opposed by the effects of iron deficiency: indeed the long-term effects of hepcidin may to be produce iron deficiency through reduced intestinal iron absorption, so the use of hepcidin levels to diagnose ACD will need to be evaluated carefully. Hepcidin levels may therefore be more useful in distinguishing patients with pure ACD from those with combined ACD and iron deficiency and this may be of therapeutic value. Further standardization and investigation is probably required before hepcidin levels come into routine and widespread clinical use however.
Whether the anaemia observed in some elderly patients has the same pathogenesis as ACD has been a subject of considerable debate. In a large study of patients aged 65 years and over, the relationships between urinary hepcidin, iron status, anaemia and inflammatory markers were investigated: surprisingly, urinary hepcidin levels were closely associated with markers of iron status but not with inflammatory markers, raising the possibility that hepcidin-independent pathways may contribute to hypoferraemia and anaemia in ACD, or that hepcidin levels may only be elevated in settings of overt inflammation.
Growth differentiation factor 15
Growth differentiation factor 15 (GDF15) is an erythropoiesis-derived hormone that is markedly increased in β-thalassaemia and congenital dyserythropoietic anaemia, and inhibits hepcidin expression, contributing to the iron overload seen in these anaemias. Levels of GDF15 have been studied in patients with ACD, ACD/IDA and IDA. Subjects with both ACD and ACD/IDA showed significantly higher levels of GDF15 than patients with IDA, and GDF15 concentrations correlated with interleukin-1β, suggesting that inflammation induces GDF15 expression, although the pathophysiological relevance of this is unclear.
Wednesday, August 10, 2011
Health check. Nordic Walking
This morning I went for my check with my exercise monitor. I am half way through my exercises program for cancer sufferers. It has not been as easy as I had hoped because of my great tiredness. I hope I am back on schedule with increased steroids and a diuretic to prevent peripheral edema from the water retention. My blood tests today were good with a normal Hb, WBC and platelets, fasting blood glucose and lipids though low plasma cortisol, and normal electrolytes and liver function tests apart from a borderline ALT which I have had for a very long time. My calcium was a bit high but I knew about that. My BP was 130/80 which is fine for my age.
Laura, who is supervising my exercise program, is training people in Nordic walking. This looks like the ideal exercise for people with cancer and those with bad backs.
Laura, who is supervising my exercise program, is training people in Nordic walking. This looks like the ideal exercise for people with cancer and those with bad backs.
John 6:32-33: The Bread of life
Jesus said to them, "I tell you the truth, it is not Moses who has given you the bread from heaven, but it is my Father who gives you the true bread from heaven. For the bread of God is he who comes down from heaven and gives life to the world.
People often want to murder the messenger but here we have evidence that the Jews of the time regarded the messenger, Moses, too highly. God was regarded so highly that they could not even say his name (YHWH). Consequently Moses was thought of as more than God's messenger.
We are apt to fall into the same trap. How many earthly preachers are lauded beyond their due?
We have already heard mention of the water of eternal life and now the bread of eternal life. These are metaphors!. It is the death of Jesus in full recompence for our sins that is the source of eternal life. Not just for our individual sins but for our sinful attitude, our tendency to go on sinning.
People often want to murder the messenger but here we have evidence that the Jews of the time regarded the messenger, Moses, too highly. God was regarded so highly that they could not even say his name (YHWH). Consequently Moses was thought of as more than God's messenger.
We are apt to fall into the same trap. How many earthly preachers are lauded beyond their due?
We have already heard mention of the water of eternal life and now the bread of eternal life. These are metaphors!. It is the death of Jesus in full recompence for our sins that is the source of eternal life. Not just for our individual sins but for our sinful attitude, our tendency to go on sinning.
Riots in the UK, continued
London was quiet last night but copycat rioting spread to other parts of the country including Manchester, Birmingham, Liverpool, Nottingham and Bristol. A pattern seems to be emerging. The initial incident was triggered by the arrest of a career criminal of mixed race in Tottenham. It appears that although carrying a handgun, he did not discharge it, but something in the arrest caused a police officer to shoot his gun. The bullet from this ricocheted from the criminal's arm into the police radio of another office who thought he was being shot at and he unceremoniously shot the criminal.
The relatives of the shot man could not believe the original police story that he had shot at the police and organized a peaceful protest, but this was quickly hijacked by non-residents who became confrontational with police. The riot was summoned by anarchists using Blackberry Instant Messenger (which is encrypted). Most of those assembling were black teenage gangs, but white, left-wing anarchists were often among the ring leaders.
The police were taken unawares and really had no idea where the next riot would break out. London is a huge city, really a string of towns with high street shopping streets within a circular diameter of 30 miles. Enfield to Croydon, two towns within London where violence occurred are more than 25 miles apart. By the fourth night 16000 police had been drafted in from around the country, especially from the south and west where there is no large ethnic population, and these numbers contained the violence.
In Manchester the police acted much more robustly than in London. This may be because it wasn't in front of the 'liberal' media or because they were learning from the experience of London. The reaction of the public in London is for citizens to deploy to guard their own shops and businesses, but we have seen murders and muggings by the rioters of the defenders. The reaction to these riots has been one of disgust. Several of the people I have spoken have called for many extreme measures including bring the army back from Afghanistan, using tear gas and water cannon on the streets and rubber or even lead bullets.
So far this is being treated as a criminal matter. There have been over 1100 arrests, mostly of young people who have been caught in the act of looting or captured on CCTV. I doubt we shall hear many more calls for the removal of CCTV cameras. Where to put all these youngsters if they receive stiff prison sentences, is another matter.
These children were brought up under socialism and so the idea of something for nothing is current with them. They are used to getting subsidized housing if they have a child at 15 as an unmarried mother; they are used to fathering children with no come-back; they are used to be mollycoddled by social workers; they are used to youth detention centers with flat-screen TVs and play stations; they are used to a soft life with no responsibilities. Having seen the Coalition's plans for them, no wonder they are grabbing all they can while they can. But retribution is coming.
London's police was called 'institutionally racist' by the MacPhereson report. It is not. The problem faced by London is largely confined to people of foreign origin. The importation of West Indian immigrants in the 1950s has not been solved. A culture where fathers do not stay with families leaving young men without cultural support, coupled with connexions with Jamaican crime syndicates bringing in drugs and guns has led to criminal gangs like we saw in Baltimore in The Wire.
To add to the mix, we have had waves of immigration from the Indian subcontinent. Much of this has been beneficial to our economy, with Hindus, in particular settling in west London and becoming high achievers in education and business. The same can be said for some Muslim communities. However the influence of hard-line Islamists and brutal Somali gangs cannot be over-emphasized.
Finally, we have seen East Europeans added to the plot, bringing people traficking for prostitution to the story. 80% of the gun and knife violence in London is black on black. three quartes of the rest is black on Eastern European or vice wersa.
ACD: differential diagnosis especially from iron deficiency
The diagnosis of ACD is not easy and the differential diagnosis is wide including hemoglobinopathies, nutritional deficiencies, bleeding or hemolysis, medications, recurrent phlebotomy, and bone marrow infection or infiltration. Typically the anemia is mild to moderate, and the textbooks say normochromic and normocytic (although anemia may become microcytic as disease progresses). I think this is wrong and put about by academics who haven't spent thousands of hours looking at blood films of medical patients as I have. In my experience the anemia is often hypochromic and microcytic, reflecting the unavailability of perfectly adequate irons stores, though I conceed that concomitant iron deficiency may also be present (these patients are often treated with NSAIDS that cause gastrointestinal bleeding).
The reticulocyte count is low, reflecting the hypoproliferative nature of the anemia. Inflammation may be inferred from other features of the blood count, such as neutrophilia, monocytosis or thrombocytosis, and through measurement of non-specific inflammatory markers, such as C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR).
Exclusion of iron deficiency anemia is very important in the work-up of patients with ACD, although the two conditions frequently co-exist. Typically, serum iron and transferrin saturation are both decreased in ACD, indicating limited iron supply to the red cells, but transferrin levels are increased in IDA, whereas in ACD they are normal or decreased. Measurement of serum ferritin is frequently of little value, as ferritin is an acute phase protein as well as an indicator of iron stores, and levels will be increased in the presence of inflammation. The gold standard for assessment of iron stores remains a Perl’s stained bone marrow aspirate, but a bone marrow biopsy is otherwise of limited value in the diagnosis of ACD, so other non-invasive tools for measurement of iron supply are needed.
Serum transferrin receptor (sTFR) and sTFR/ferritin ratio
The measurement of sTFR, the truncated fragment of the membrane receptor, has been suggested as a possible tool for differentiating between ACD and IDA. The transferrin receptor is found on virtually all cells in the body, but is present at high levels on erythroid progenitors. sTFR levels increase in IDA as the availability of iron for erythropoiesis decreases, whereas in ACD levels may not differ from steady state because transferrin receptor expression is negatively affected by inflammatory cytokines. However, in practice interpretation of this assay in differentiating IDA from ACD has proved more difficult, and the assay has not been standardized. In CLL sTFR gives false values and is not used.
The ratio of sTFR to the log of the serum ferritin has been proposed to be a useful tool in the diagnosis of ACD, and particularly in differentiating ACD from IDA. A ratio <1 makes ACD likely, whereas ratios >2 suggest that iron stores are deficient, with or without ACD.
Red cell indices
Many modern haematology analysers are capable of calculating new red cell indices that may be useful in the evaluation of different forms of anaemia. Two of these, the reticulocyte haemoglobin content (CHr) and the percentage hypochromic red cells (%HYPO) (reported by Bayer Advia 120 haematology analyser) can provide information about iron supply to the erythron, and may be useful in guiding the management of ACD. CHr is a measure of haemoglobin in the most recently formed erythrocytes, while the %HYPO indicates the percentage of cells with haemoglobin content of <280 g/l. The former gives a relatively acute evaluation (48 h) of recent bone marrow activity, whereas the latter gives a time-averaged picture (20–120 d). Similar indices can be reported by the Sysmex XE-2100 analyser), which derives RET-Y (equivalent to CHr) and RBC-Y (equivalent to HYPO%). CHr has been shown to be a useful tool in the detection of early iron deficiency, as well as in monitoring early response to iron therapy.
A study has been made of the relationship between CHr, %HYPO and sTFR/ferritin ratio to evaluate anaemia in 442 patients with disease-specific anaemias and 154 non-anaemic subjects. A simple plot of CHr against sTFR/ferritin divided anaemic samples into four functional quadrants: (i) iron replete, normal eythropoiesis; (ii) reduced iron supply but not yet iron-deficient erythropoiesis; (iii) iron depleted with iron-deficient erythropoiesis; (iv) iron replete but with functional iron deficiency leading to decreased haemoglobinization. This may help in deciding whether iron supplementation may improve haemoglobin levels in individual patients. It is not known whether this will be valid in CLL patients.
The reticulocyte count is low, reflecting the hypoproliferative nature of the anemia. Inflammation may be inferred from other features of the blood count, such as neutrophilia, monocytosis or thrombocytosis, and through measurement of non-specific inflammatory markers, such as C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR).
Exclusion of iron deficiency anemia is very important in the work-up of patients with ACD, although the two conditions frequently co-exist. Typically, serum iron and transferrin saturation are both decreased in ACD, indicating limited iron supply to the red cells, but transferrin levels are increased in IDA, whereas in ACD they are normal or decreased. Measurement of serum ferritin is frequently of little value, as ferritin is an acute phase protein as well as an indicator of iron stores, and levels will be increased in the presence of inflammation. The gold standard for assessment of iron stores remains a Perl’s stained bone marrow aspirate, but a bone marrow biopsy is otherwise of limited value in the diagnosis of ACD, so other non-invasive tools for measurement of iron supply are needed.
Serum transferrin receptor (sTFR) and sTFR/ferritin ratio
The measurement of sTFR, the truncated fragment of the membrane receptor, has been suggested as a possible tool for differentiating between ACD and IDA. The transferrin receptor is found on virtually all cells in the body, but is present at high levels on erythroid progenitors. sTFR levels increase in IDA as the availability of iron for erythropoiesis decreases, whereas in ACD levels may not differ from steady state because transferrin receptor expression is negatively affected by inflammatory cytokines. However, in practice interpretation of this assay in differentiating IDA from ACD has proved more difficult, and the assay has not been standardized. In CLL sTFR gives false values and is not used.
The ratio of sTFR to the log of the serum ferritin has been proposed to be a useful tool in the diagnosis of ACD, and particularly in differentiating ACD from IDA. A ratio <1 makes ACD likely, whereas ratios >2 suggest that iron stores are deficient, with or without ACD.
Red cell indices
Many modern haematology analysers are capable of calculating new red cell indices that may be useful in the evaluation of different forms of anaemia. Two of these, the reticulocyte haemoglobin content (CHr) and the percentage hypochromic red cells (%HYPO) (reported by Bayer Advia 120 haematology analyser) can provide information about iron supply to the erythron, and may be useful in guiding the management of ACD. CHr is a measure of haemoglobin in the most recently formed erythrocytes, while the %HYPO indicates the percentage of cells with haemoglobin content of <280 g/l. The former gives a relatively acute evaluation (48 h) of recent bone marrow activity, whereas the latter gives a time-averaged picture (20–120 d). Similar indices can be reported by the Sysmex XE-2100 analyser), which derives RET-Y (equivalent to CHr) and RBC-Y (equivalent to HYPO%). CHr has been shown to be a useful tool in the detection of early iron deficiency, as well as in monitoring early response to iron therapy.
A study has been made of the relationship between CHr, %HYPO and sTFR/ferritin ratio to evaluate anaemia in 442 patients with disease-specific anaemias and 154 non-anaemic subjects. A simple plot of CHr against sTFR/ferritin divided anaemic samples into four functional quadrants: (i) iron replete, normal eythropoiesis; (ii) reduced iron supply but not yet iron-deficient erythropoiesis; (iii) iron depleted with iron-deficient erythropoiesis; (iv) iron replete but with functional iron deficiency leading to decreased haemoglobinization. This may help in deciding whether iron supplementation may improve haemoglobin levels in individual patients. It is not known whether this will be valid in CLL patients.
Anemia of chronic disorders: is red cell lifespan shortened?
Reduced red cell survival
Early studies (from 1966) suggested that red cell survival is shortened in ACD and more recent research using breath carbon monoxide levels to assess red cell survival confirms that red cell survival is modestly shortened in patients with rheumatoid arthritis and anemic hospital inpatients. This may be a contributory factor in ACD, but there have been no direct studies of the mechanisms involved. These might include increased erythrophagocytosis induced by inflammatory cytokines or oxidative damage to erythrocytes, causing reduced survival.
Early studies (from 1966) suggested that red cell survival is shortened in ACD and more recent research using breath carbon monoxide levels to assess red cell survival confirms that red cell survival is modestly shortened in patients with rheumatoid arthritis and anemic hospital inpatients. This may be a contributory factor in ACD, but there have been no direct studies of the mechanisms involved. These might include increased erythrophagocytosis induced by inflammatory cytokines or oxidative damage to erythrocytes, causing reduced survival.
Tuesday, August 09, 2011
John 6:30-31. A 'type' of Moses.
So they asked him, "What miraculous sign then will you give that we may see it and believe you? What will you do? Our forefathers ate the manna in the desert; as it is written: 'He gave them bread from heaven to eat' "
Here is their objection to the feeding of the 5000. They'd seen it all before. Moses had fed them with 'magic' bread, not just once but for 40 years. They were determined not to be impressed by Jesus even though Moses was 1200 years in their past. They were as oppressed as a nation by the Romans as the Hebrews had been by the Egyptians and they were looking for a similar solution, but they failed to see Moses as a 'type' of Christ. They were looking for a savior who was a 'type' of Moses.
Here is their objection to the feeding of the 5000. They'd seen it all before. Moses had fed them with 'magic' bread, not just once but for 40 years. They were determined not to be impressed by Jesus even though Moses was 1200 years in their past. They were as oppressed as a nation by the Romans as the Hebrews had been by the Egyptians and they were looking for a similar solution, but they failed to see Moses as a 'type' of Christ. They were looking for a savior who was a 'type' of Moses.
We need the innovations of young men
One of the faults in the police response to the London riots, pointed out by the newspapers today, has been the lack of initiative by sergeants and inspectors on the ground; they have found it safer to wait for instructions from Commanders and Superintendents at the back.
This is a problem in many walks of life including health care and education. One of the reasons that I was so excited by the football match on Sunday was the fact that Manchester United, being 2-0 behind at half time, threw on their young men as substitutes so that the average age of the players on their side for most of the second half was only 22. They played with flair and a lack of fear. Especially pleasing was the role of Tom Cleverly.
In the UK it is not usual for young people to go to College and University on Sports Scholarships. Academic prowess of high quality is still needed for 'proper' Universities. Although he has been known to Manchester United for several years, Tom would not commit to being a footballer, instead, opting to continue his education and take up a University place. It is a fact that in the days when Liverpool were the top British team, they had two University graduates, Steve Heighway and Brian Hall in their first team. It seems to me that the best teams at most sports don't just possess a David Beckham or Wayne Rooney with an educated right foot, but also someone with an educated brain.
In Medicine we have been stultified by protocols and control by the multi-disciplinary team. No-one can take a decision unless it is rubber stamped by 'higher' authority and no-one can try anything new because it isn't in the protocol. I can remember the thrill of making my own decisions. One a protocol driven radiotherapist accused me of being a 'cowboy oncologist'. I replied by naming my next regimen for bladder cancer, 'Blazing Saddles'.
Over the years my innovations included monoclonal antibody therapy and peripheral blood derived stem cell transplants as well as DNA vaccines and the use of IGHV gene mutations for prognostic testing. Not bad for a maverick.
This is a problem in many walks of life including health care and education. One of the reasons that I was so excited by the football match on Sunday was the fact that Manchester United, being 2-0 behind at half time, threw on their young men as substitutes so that the average age of the players on their side for most of the second half was only 22. They played with flair and a lack of fear. Especially pleasing was the role of Tom Cleverly.
In the UK it is not usual for young people to go to College and University on Sports Scholarships. Academic prowess of high quality is still needed for 'proper' Universities. Although he has been known to Manchester United for several years, Tom would not commit to being a footballer, instead, opting to continue his education and take up a University place. It is a fact that in the days when Liverpool were the top British team, they had two University graduates, Steve Heighway and Brian Hall in their first team. It seems to me that the best teams at most sports don't just possess a David Beckham or Wayne Rooney with an educated right foot, but also someone with an educated brain.
In Medicine we have been stultified by protocols and control by the multi-disciplinary team. No-one can take a decision unless it is rubber stamped by 'higher' authority and no-one can try anything new because it isn't in the protocol. I can remember the thrill of making my own decisions. One a protocol driven radiotherapist accused me of being a 'cowboy oncologist'. I replied by naming my next regimen for bladder cancer, 'Blazing Saddles'.
Over the years my innovations included monoclonal antibody therapy and peripheral blood derived stem cell transplants as well as DNA vaccines and the use of IGHV gene mutations for prognostic testing. Not bad for a maverick.
What to do when the money has all gone.
The financial markets are in melt down. Standard and Poor's decision to degrade America's credit-worthiness and the high interest rate for borrowing Spanish and Italian bonds have sent a message that those with free cash are less willing to lend to sovereign nations for fear of not getting their money back.
Who are those with money to lend? Above all, China, but also the Arab states with oil reserves, and Germany, with a successful manufacturing economy. The Arab states have money from an accident of history; they were primitive nomadic tribes that happened to wander over land under which the Western powers found oil at a time when the Western powers built an oil-based economy. There is no merit to their hegemony over oil and they can be seen as parasites on the back of the American and European beast. Were the American model to collapse, the parasites would die with it.
So much of Chinese industry is also parasitical on the West. It depends on raising its standard of living by selling to the West, even though it is getting paid in depreciating dollars. China is a country with 300 million middle class people and a billion peasants. There will be a clamor for all 1.3 billion to become relatively rich; a clamor fueled by the Internet. This is why the Chinese government keeps an oppressive lid on dissent and why, whatever snide remarks it makes, it is content to accept the barbs about human rights, swallow the dollar as a reserve currency and still keep lending to the USA and Europe. Meanwhile it counterfeits Western technology and brand names with impunity.
That is not to say there is no genuine technological advancement in China. There is an improving standard in its science and education. More people speak English in China than do so in Europe or in America. I have been impressed by the improvement in quality of scientific articles that I get sent from China now to Leukemia Research. To be sure we are still rejecting two thirds, but we were rejecting over 95%.
Meanwhile, for once, the UK economy is not in trouble. This is entirely due to the Coalition government's decision on taking office to reduce borrowing over a 5-year term. This was opposed by the outgoing socialist government which had spent its way to penury. The insultingly blind Mr Balls still persists in advocating spending his way out of trouble, but the point is you can't spend other people's money if they won't lend it to you and if you try and confiscate it by higher taxes, they take the money and run.
Mrs Thatcher was derided for trying to run a nation's economy like a housewife, but she had a good principle. Don't buy things that you can't afford! We have always run our household like this and deliberately avoided the temptations that neighbors and the crowd force upon us. Even then there are things that we own that we could well do without. I remember a book by Ron Sider, called Rich Christians in an Age of Hunger. I called out one Christian who was intent on buying a Prius to save the planet. In fact, it would do much less damage to the planet to buy and run an old clunker until it dropped. The cost of manufacturing a Prius would never be redeemed by the lower cost of running it. It follows that we really don't need 'growth' to keep our economies going. Be content with what we have and learn to share our prosperity. Communication has been eased by electronics; use them for that purpose rather than for mindless games. Skype is OK but I remember taking evidence from America from a witness by a professional communications set-up. It was as good as being in the same room and saved a huge amount of jet fuel.
China is buying up mountains in Africa and Australia full of rare earths for future technology. Are we doing the same or can we rely on secondary markets of recycling? I despair when I see people scuttling to the Indian Ocean for holidays; is there nowhere closer? Is it just because it is exotic?
The book of Ecclesiastes teaches us about the futility of modern life. It is like trying to confine the wind in a sheep pen. Step off the travelator and watch the world go by. It will all come round again next week and nothing much will have changed.
Who are those with money to lend? Above all, China, but also the Arab states with oil reserves, and Germany, with a successful manufacturing economy. The Arab states have money from an accident of history; they were primitive nomadic tribes that happened to wander over land under which the Western powers found oil at a time when the Western powers built an oil-based economy. There is no merit to their hegemony over oil and they can be seen as parasites on the back of the American and European beast. Were the American model to collapse, the parasites would die with it.
So much of Chinese industry is also parasitical on the West. It depends on raising its standard of living by selling to the West, even though it is getting paid in depreciating dollars. China is a country with 300 million middle class people and a billion peasants. There will be a clamor for all 1.3 billion to become relatively rich; a clamor fueled by the Internet. This is why the Chinese government keeps an oppressive lid on dissent and why, whatever snide remarks it makes, it is content to accept the barbs about human rights, swallow the dollar as a reserve currency and still keep lending to the USA and Europe. Meanwhile it counterfeits Western technology and brand names with impunity.
That is not to say there is no genuine technological advancement in China. There is an improving standard in its science and education. More people speak English in China than do so in Europe or in America. I have been impressed by the improvement in quality of scientific articles that I get sent from China now to Leukemia Research. To be sure we are still rejecting two thirds, but we were rejecting over 95%.
Meanwhile, for once, the UK economy is not in trouble. This is entirely due to the Coalition government's decision on taking office to reduce borrowing over a 5-year term. This was opposed by the outgoing socialist government which had spent its way to penury. The insultingly blind Mr Balls still persists in advocating spending his way out of trouble, but the point is you can't spend other people's money if they won't lend it to you and if you try and confiscate it by higher taxes, they take the money and run.
Mrs Thatcher was derided for trying to run a nation's economy like a housewife, but she had a good principle. Don't buy things that you can't afford! We have always run our household like this and deliberately avoided the temptations that neighbors and the crowd force upon us. Even then there are things that we own that we could well do without. I remember a book by Ron Sider, called Rich Christians in an Age of Hunger. I called out one Christian who was intent on buying a Prius to save the planet. In fact, it would do much less damage to the planet to buy and run an old clunker until it dropped. The cost of manufacturing a Prius would never be redeemed by the lower cost of running it. It follows that we really don't need 'growth' to keep our economies going. Be content with what we have and learn to share our prosperity. Communication has been eased by electronics; use them for that purpose rather than for mindless games. Skype is OK but I remember taking evidence from America from a witness by a professional communications set-up. It was as good as being in the same room and saved a huge amount of jet fuel.
China is buying up mountains in Africa and Australia full of rare earths for future technology. Are we doing the same or can we rely on secondary markets of recycling? I despair when I see people scuttling to the Indian Ocean for holidays; is there nowhere closer? Is it just because it is exotic?
The book of Ecclesiastes teaches us about the futility of modern life. It is like trying to confine the wind in a sheep pen. Step off the travelator and watch the world go by. It will all come round again next week and nothing much will have changed.
London riots
For a third night there has been rioting by anarchists in London. It has now spread to Birmingham, Bristol and Liverpool. The ostensible cause was the shooting of a man in Tottenham who allegedly had shot at a policeman, the policeman only escaping death because the bullet lodged in his police radio. However, the family of the shot man have condemned the violence and it is clear that the so called cause is only an excuse.
Millions of pounds worth of damage have been done and most of the perpetrators as well as the victims are black. This black on black crime is nothing new. Most of those killed and killing with guns and knives in our great cities are black. Most unemployment, most failure of education, most gang warfare is among the young black male community. These young men are brought up by unmarried or deserted women, for whom the state supplies social housing. The only male role models are criminals. The police have been intimidated by liberal intellectuals into a PC attitude and been called institutionally racists. Yet the victims are themselves black and David Lamy the local black MP has described the actions of the rioters as 'sheer criminality'.
Unfortunately, the Labour Party leadership has blamed the rioting on the austerity cuts. People whose livelihood has been threatened by 'cuts' might be stealing food or money, but not designer sports clothes of flat screen televisions.
In truth, the numbers involved are not great. In Hackney last night there were 50 rioters and 250 police, who soon (3 hours) had the situation controled. The Anarchists are using the social networking sites to conspire to group in set places so that they can inflict the greatest damage with small numbers. It looks to me that a criminal charge of conspiracy might stand up in Law. Under-cover policing might work. What we don't want to see is weak punishment by the courts when these people are prosecuted. Is it time to bring in the army? Perhaps. Water cannon with indelible dye might be another option.
Millions of pounds worth of damage have been done and most of the perpetrators as well as the victims are black. This black on black crime is nothing new. Most of those killed and killing with guns and knives in our great cities are black. Most unemployment, most failure of education, most gang warfare is among the young black male community. These young men are brought up by unmarried or deserted women, for whom the state supplies social housing. The only male role models are criminals. The police have been intimidated by liberal intellectuals into a PC attitude and been called institutionally racists. Yet the victims are themselves black and David Lamy the local black MP has described the actions of the rioters as 'sheer criminality'.
Unfortunately, the Labour Party leadership has blamed the rioting on the austerity cuts. People whose livelihood has been threatened by 'cuts' might be stealing food or money, but not designer sports clothes of flat screen televisions.
In truth, the numbers involved are not great. In Hackney last night there were 50 rioters and 250 police, who soon (3 hours) had the situation controled. The Anarchists are using the social networking sites to conspire to group in set places so that they can inflict the greatest damage with small numbers. It looks to me that a criminal charge of conspiracy might stand up in Law. Under-cover policing might work. What we don't want to see is weak punishment by the courts when these people are prosecuted. Is it time to bring in the army? Perhaps. Water cannon with indelible dye might be another option.
Anemia of chronic disorders: the effect of EPO
Reduced EPO production
Under normal physiological conditions, levels of EPO are inversely correlated with hemoglobin levels and tissue oxygenation, but in chronic inflammatory conditions the EPO response is blunted, leading to inadequate levels of EPO for the degree of anemia, and this is thought to be mediated via inflammatory cytokines such as IL-1 and TNF-alpha, though not all studies confirm this.
Reduced erythroid responsiveness
In ACD, the proliferation and differentiation of erythroid progenitor cells is reduced. Early studies showed that macrophages from patients with ACD could suppress erythroid colony formation in vitro. Subsequent studies showed this effect to be due to inhibitory effects of inflammatory cytokines, especially interferon-gamma, on growth of BFU-E and CFU-E, and that this effect could be overcome by addition of high concentrations of EPO to the culture systems. Hepcidin itself has an inhibitory effect on erythropoiesis in vitro at low EPO concentrations.
It has been demonstrated that bone marrow cultures from patients with active rheumatoid arthritis showed defective growth when compared to normal controls, and that there was an inverse correlation between colony growth and levels of TNF-alpha in the culture supernatant. Moreover, these effects were reversed both in vitro and in vivo following treatment with infliximab, an antibody against TNF-alpha.
Under normal physiological conditions, levels of EPO are inversely correlated with hemoglobin levels and tissue oxygenation, but in chronic inflammatory conditions the EPO response is blunted, leading to inadequate levels of EPO for the degree of anemia, and this is thought to be mediated via inflammatory cytokines such as IL-1 and TNF-alpha, though not all studies confirm this.
Reduced erythroid responsiveness
In ACD, the proliferation and differentiation of erythroid progenitor cells is reduced. Early studies showed that macrophages from patients with ACD could suppress erythroid colony formation in vitro. Subsequent studies showed this effect to be due to inhibitory effects of inflammatory cytokines, especially interferon-gamma, on growth of BFU-E and CFU-E, and that this effect could be overcome by addition of high concentrations of EPO to the culture systems. Hepcidin itself has an inhibitory effect on erythropoiesis in vitro at low EPO concentrations.
It has been demonstrated that bone marrow cultures from patients with active rheumatoid arthritis showed defective growth when compared to normal controls, and that there was an inverse correlation between colony growth and levels of TNF-alpha in the culture supernatant. Moreover, these effects were reversed both in vitro and in vivo following treatment with infliximab, an antibody against TNF-alpha.
Monday, August 08, 2011
Football season begins
The Charity Shield is a pre-season football match between the League Champions and the FA cup winners, which is usually used as a last training run before the season opens. It is seldom a proper match, but yesterday's event was more than that. For one thing it was a grudge match between the two Manchester Clubs, City who have been taken over by an Arab who owned one fifth of the Word's oil reserves and United who are the most successful British Club ever.
City have bought established players from around the world while United have bought young British players. The result was an injury time 3-2 win for United. What made the game exceptional was a wonder goal conjured up by the new boy, Tom Cleverly, together with old (but only 25) stagers Rooney and Nani. Man Utd policy of training up very young players and retaining them as long as they are happy seems to pay off. In their squad are seven strikers: Rooney, Berbatov, Owen, Wellbeck, Diouf, Macheda and Hernandez as well as Young and Giggs who have played there. Midfielders now include Giggs, Fletcher, Anderson, Carrick, Nani, Cleverly, Young, Park, Gibson and Valencia and defenders include the two Da Silva twins, Smalling, Evans, Vidic, Jones, Ferdinand and Evra and there are three goalkeepers in DeGea, Kurszczak and Lindegaard. There are a few who may be on their way out like Obertan and Bebe, but 9 other youngsters are signed up for the 1st team squad.
I can't see that spending £32 million and breaking the wage structure for Wesley Sneijder from Inter is a good idea. With this squad they should see off both Chelsea and Man City for the foreseeable future.
The season starts anew next weekend.
City have bought established players from around the world while United have bought young British players. The result was an injury time 3-2 win for United. What made the game exceptional was a wonder goal conjured up by the new boy, Tom Cleverly, together with old (but only 25) stagers Rooney and Nani. Man Utd policy of training up very young players and retaining them as long as they are happy seems to pay off. In their squad are seven strikers: Rooney, Berbatov, Owen, Wellbeck, Diouf, Macheda and Hernandez as well as Young and Giggs who have played there. Midfielders now include Giggs, Fletcher, Anderson, Carrick, Nani, Cleverly, Young, Park, Gibson and Valencia and defenders include the two Da Silva twins, Smalling, Evans, Vidic, Jones, Ferdinand and Evra and there are three goalkeepers in DeGea, Kurszczak and Lindegaard. There are a few who may be on their way out like Obertan and Bebe, but 9 other youngsters are signed up for the 1st team squad.
I can't see that spending £32 million and breaking the wage structure for Wesley Sneijder from Inter is a good idea. With this squad they should see off both Chelsea and Man City for the foreseeable future.
The season starts anew next weekend.
John 6:28-29; The work that God requires.
Then they asked him, "What must we do to do the works that God requires?"
Perhaps they had this passage from the Old Testament in mind "Whoever loves money never has enough; Whoever loves wealth is never satisfied with their income. This too is meaningless. As goods increase, so do those who consume them. And what benefit are they to the owners except to feast their eyes on them? The sleep of a laborer is sweet, whether they eat little or much, but as for the rich, their abundance permits them no sleep."
But they misunderstand the meaning of 'work'. Jesus replies, "The work of God is this: to believe the one he has sent."
Over and over we are told that the greatest sin is unbelief. To believe we need humility. It takes a lot for modern man to put away his pride in his own ability and to surrender to God. Look at the story of Job. It took a demonstration of God's creativity for him to stop justifying himself. Today most people no longer believe in a Creator God; foolishly they put it down to evolution. Instead we must point to the wickedness of the world and demonstrate the solution that Jesus has brought. We must still believe in the miraculous, though.
Perhaps they had this passage from the Old Testament in mind "Whoever loves money never has enough; Whoever loves wealth is never satisfied with their income. This too is meaningless. As goods increase, so do those who consume them. And what benefit are they to the owners except to feast their eyes on them? The sleep of a laborer is sweet, whether they eat little or much, but as for the rich, their abundance permits them no sleep."
But they misunderstand the meaning of 'work'. Jesus replies, "The work of God is this: to believe the one he has sent."
Over and over we are told that the greatest sin is unbelief. To believe we need humility. It takes a lot for modern man to put away his pride in his own ability and to surrender to God. Look at the story of Job. It took a demonstration of God's creativity for him to stop justifying himself. Today most people no longer believe in a Creator God; foolishly they put it down to evolution. Instead we must point to the wickedness of the world and demonstrate the solution that Jesus has brought. We must still believe in the miraculous, though.
Anemia of chronic disorders: Hepcidin
Altered iron homeostasis
Low serum iron levels are a common feature of ACD: mice injected with pro-inflammatory cytokines, IL-1 and TNF-alpha developed low serum irons and anemia and in human volunteers, injection of IL-6 caused reduction in serum iron levels and transferrin saturation, This effect is now known to be mediated via a 25 amino acid polypeptide hormone known as hepcidin.
Hepcidin is produced by liver cells (and to a lesser extent fat cells and macrophages) and plays a key role in the regulation of iron balance and transport. The hormone’s actions work through its binding to ferroportin, the major protein for removing iron from cells, resulting in the blockade of iron export from body iron stores in macrophages and liver cells; Also inhibition of iron absorption by the duodenum occurs, although recent evidence suggests that this may be caused by downregulation of another transport protein, divalent metal transporter-1 (DMT-1) rather than ferroportin. The combined effect is to restrict iron availability for erythropoiesis, sometimes referred to as a state of ‘functional iron deficiency’, (which is why ACD is often microcytic rather than normocytic as most of the text books assert, and to result in iron accumulation in tissue macrophages. Hepcidin overexpression in transgenic mice reproduces many of the features of ACD and hepcidin levels are raised in a variety of inflammatory disorders. Once bound to ferroportin, the ligand-receptor complex is internalized and degraded, and cellular iron export ceases.
Normally, regulation of hepcidin production occurs through recognition of iron levels and erythropoietic activity. Thus iron excess stimulates hepcidin production, leading to reduced iron absorption and switching off iron release from tissue stores. Conversely, in iron deficiency, hepcidin production is suppressed, enabling increased iron absorption and release of storage iron: similar changes occur when erythroid activity increases.
In inflammatory conditions, hepcidin production is increased, and IL-6 has been shown to be a potent inducer of hepcidin via STAT-3signaling. There is also evidence of a role for other inflammatory cytokines, including IL-1 and bone morphogenetic proteins (BMPs) 2, 4, 6 and 9.
Parallel processes can be seen in malignant conditions. For example, in patients with Hodgkin lymphoma, hepcidin levels were closely correlated with levels of IL-6, rather than other cytokines whereas a recent study suggests that BMP-2, rather than IL-6, is the key inducer of hepcidin in patients with multiple myeloma: hepcidin levels in patients with myeloma inversely correlate with hemoglobin levels, and anti-BMP-2 antibodies blocked the hepcidin-inducing activity of sera from patients with myeloma more consistently than anti-IL-6.
That the erythropoietic and inflammatory pathways regulating hepcidin production may be separate was suggested by a recent study: using a rat model of ACD, it demonstrated that animals with ACD rendered iron-deficient by phlebotomy had lower hepcidin levels than animals with ACD alone. Similar findings were noted in patients with ACD/IDA when compared to individuals with ACD, and the former were able to absorb dietary iron and mobilize iron from macrophage stores. This is an important observation if hepcidin levels are to be incorporated into the diagnostic pathway for patients with ACD.
Low serum iron levels are a common feature of ACD: mice injected with pro-inflammatory cytokines, IL-1 and TNF-alpha developed low serum irons and anemia and in human volunteers, injection of IL-6 caused reduction in serum iron levels and transferrin saturation, This effect is now known to be mediated via a 25 amino acid polypeptide hormone known as hepcidin.
Hepcidin is produced by liver cells (and to a lesser extent fat cells and macrophages) and plays a key role in the regulation of iron balance and transport. The hormone’s actions work through its binding to ferroportin, the major protein for removing iron from cells, resulting in the blockade of iron export from body iron stores in macrophages and liver cells; Also inhibition of iron absorption by the duodenum occurs, although recent evidence suggests that this may be caused by downregulation of another transport protein, divalent metal transporter-1 (DMT-1) rather than ferroportin. The combined effect is to restrict iron availability for erythropoiesis, sometimes referred to as a state of ‘functional iron deficiency’, (which is why ACD is often microcytic rather than normocytic as most of the text books assert, and to result in iron accumulation in tissue macrophages. Hepcidin overexpression in transgenic mice reproduces many of the features of ACD and hepcidin levels are raised in a variety of inflammatory disorders. Once bound to ferroportin, the ligand-receptor complex is internalized and degraded, and cellular iron export ceases.
Normally, regulation of hepcidin production occurs through recognition of iron levels and erythropoietic activity. Thus iron excess stimulates hepcidin production, leading to reduced iron absorption and switching off iron release from tissue stores. Conversely, in iron deficiency, hepcidin production is suppressed, enabling increased iron absorption and release of storage iron: similar changes occur when erythroid activity increases.
In inflammatory conditions, hepcidin production is increased, and IL-6 has been shown to be a potent inducer of hepcidin via STAT-3signaling. There is also evidence of a role for other inflammatory cytokines, including IL-1 and bone morphogenetic proteins (BMPs) 2, 4, 6 and 9.
Parallel processes can be seen in malignant conditions. For example, in patients with Hodgkin lymphoma, hepcidin levels were closely correlated with levels of IL-6, rather than other cytokines whereas a recent study suggests that BMP-2, rather than IL-6, is the key inducer of hepcidin in patients with multiple myeloma: hepcidin levels in patients with myeloma inversely correlate with hemoglobin levels, and anti-BMP-2 antibodies blocked the hepcidin-inducing activity of sera from patients with myeloma more consistently than anti-IL-6.
That the erythropoietic and inflammatory pathways regulating hepcidin production may be separate was suggested by a recent study: using a rat model of ACD, it demonstrated that animals with ACD rendered iron-deficient by phlebotomy had lower hepcidin levels than animals with ACD alone. Similar findings were noted in patients with ACD/IDA when compared to individuals with ACD, and the former were able to absorb dietary iron and mobilize iron from macrophage stores. This is an important observation if hepcidin levels are to be incorporated into the diagnostic pathway for patients with ACD.
Sunday, August 07, 2011
The anemia of chronic disorders
When I was working at Bournemouth, one of my Wessex colleagues was Salisbury consultant haematologist Jonathan Cullis. He was an ex registrar from the Hammersmith hospital who had been there with my buddy, David Oscier. He has produced an excellent review of the anemia of chronic disease, which is obviously relevant for CLL sufferers so I am going to review this paper, step by step as a service to them.
Anemia of chronic disease (ACD), or anemia of inflammation, is the term used to describe the anemia with reduced red cell production seen in response to systemic illness or inflammation. It is the second most prevalent form of anemia after iron deficiency anemia (IDA) and the most common amongst patients with chronic illnesses. It is seen in a variety of conditions, including infections, cancer and autoimmune conditions. The anemia of chronic renal failure, although sometimes referred to as ACD, should not be included and will only be discussed to throw insights into other forms of ACD can be derived from relevant papers. ACD is typically normochromic and normocytic (but often microcytic), characterized by low serum iron, decreased transferrin saturation, decreased bone marrow sideroblasts and increased reticuloendothelial iron. The mechanisms that produce the anemia include impaired production of erythropoietin (EPO), blunted marrow erythroid response to EPO, iron-restricted erythropoiesis, and a diminished pool of EPO-responsive cells.
Among the conditions associated with ACD are viral, bacterial, parasitic and fungal infections, hematological and solid tumor malignancies, autoimmune conditions like rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, vasculitis, polymyalgia, systemic sclerosis, polymyositis, sarcoidosis and inflammatory bowel disease, and some cardiac diseases such as chronic heart failure.
Anemia of chronic disease (ACD), or anemia of inflammation, is the term used to describe the anemia with reduced red cell production seen in response to systemic illness or inflammation. It is the second most prevalent form of anemia after iron deficiency anemia (IDA) and the most common amongst patients with chronic illnesses. It is seen in a variety of conditions, including infections, cancer and autoimmune conditions. The anemia of chronic renal failure, although sometimes referred to as ACD, should not be included and will only be discussed to throw insights into other forms of ACD can be derived from relevant papers. ACD is typically normochromic and normocytic (but often microcytic), characterized by low serum iron, decreased transferrin saturation, decreased bone marrow sideroblasts and increased reticuloendothelial iron. The mechanisms that produce the anemia include impaired production of erythropoietin (EPO), blunted marrow erythroid response to EPO, iron-restricted erythropoiesis, and a diminished pool of EPO-responsive cells.
Among the conditions associated with ACD are viral, bacterial, parasitic and fungal infections, hematological and solid tumor malignancies, autoimmune conditions like rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, vasculitis, polymyalgia, systemic sclerosis, polymyositis, sarcoidosis and inflammatory bowel disease, and some cardiac diseases such as chronic heart failure.
John 6:27: The son of man brings eternal life.
Do not look for food that spoils, but for the food that endures to eternal life, which the Son of Man will give you. On him God the Father has placed his seal of approval.
At Jacob's well Jesus had offered water as a metaphor for eternal life; now he offers bread. He is using what is around him - Jacob's well and the young man's barley loaves - as illustrations. Preachers would do well to illustrate their sermons with what is contemporary and immediate in order to get their message across. But here as with the water listeners can get hold of the wrong end of the stick.
We learn later that the whole 'bread of life' discourse took place in the synagogues at Capernaum, so perhaps it began here at v 27.
Jesus does not call himself the Messiah of the Christ in order not to get caught up in the movement to force him to become king, but the term 'son of man' becomes increasingly loaded in the text.
At Jacob's well Jesus had offered water as a metaphor for eternal life; now he offers bread. He is using what is around him - Jacob's well and the young man's barley loaves - as illustrations. Preachers would do well to illustrate their sermons with what is contemporary and immediate in order to get their message across. But here as with the water listeners can get hold of the wrong end of the stick.
We learn later that the whole 'bread of life' discourse took place in the synagogues at Capernaum, so perhaps it began here at v 27.
Jesus does not call himself the Messiah of the Christ in order not to get caught up in the movement to force him to become king, but the term 'son of man' becomes increasingly loaded in the text.
Saturday, August 06, 2011
Letters to Juliet and My Cousin Rachel
We have watched a couple of OK films this week. Letters to Juliet is set in Verona where Romeo and Juliet is set by Shakespeare. The story is that the wall where the statue of Juliet is situated gets plastered by letters from girls who have been hurt in their relationships. A coterie of "Agony Aunts" answers their letters. An Ameican girl on holiday finds a letter that is 50 years old and seeks to trace the younf English girl who had decided to return home rather than met her Italian lover. That girl is now the 65 year old Vanessa Redgrave who comes with her grandson to seek her old beau. After a long hunt they eventually find Franco Nero (remember them together in Camelot?). Altogether a nice film with predictable plot twists and a gentle theme. No sex, violence or bad language.
The other was an old monochrome Daphne Du Maurier movie, My Cousin Rachel starring Olivier De Havilland and Richard Burton. I hadn't seen it previously but it was a timely reminder of what a great actor Richard Burton was, and how handsome a guy before the loose living got to him.
The other was an old monochrome Daphne Du Maurier movie, My Cousin Rachel starring Olivier De Havilland and Richard Burton. I hadn't seen it previously but it was a timely reminder of what a great actor Richard Burton was, and how handsome a guy before the loose living got to him.
Hepatocyte growth factor is essential to keep CLL cells alive
It is well known that CLL cells survive better in the body than outside it. This is thought to be caused by cell contact with stromal cells of some sort, but the exact mechanism is unclear. Now an interesting paper from Italy sheds some light on it. (incidentally I have identified Italy where they have spent a lot of public money on CLL research as a place where good papers seem to be coming from, but perhaps signor Berlesconi has been a bit rash?)
They have used various types of tissues to stabilize CLL cells in cell culture. Human bone marrow stromal cells, fibroblasts, trabecular bone derived cells and an osteoblast like cell line enhanced the survival of leukemic cells but endothelial cells and chondrocytes did not. Gene expression profile analysis identified two soluble factors, hepatocyte growth factor and CXCL12, that were produced only by the mesenchymal lineages that sustain CLL cells. Indeed CLL cells express a functional receptor gor hepatocyte growth factor (c-MET). They demonstrated that hepatocyte growth factor enhanced the viability of CLL cells through STAT3 phosphorylation which can be blocked by a c-MET TKI. The use of si-RNA knockdown of Hepatocyte growth factor in mesenchymal cells confirmed the interaction.
Whether this might of might not be a safe target for therapy is an open question. What would it do to the liver? And would CXCL12 also have to be targeted.
They have used various types of tissues to stabilize CLL cells in cell culture. Human bone marrow stromal cells, fibroblasts, trabecular bone derived cells and an osteoblast like cell line enhanced the survival of leukemic cells but endothelial cells and chondrocytes did not. Gene expression profile analysis identified two soluble factors, hepatocyte growth factor and CXCL12, that were produced only by the mesenchymal lineages that sustain CLL cells. Indeed CLL cells express a functional receptor gor hepatocyte growth factor (c-MET). They demonstrated that hepatocyte growth factor enhanced the viability of CLL cells through STAT3 phosphorylation which can be blocked by a c-MET TKI. The use of si-RNA knockdown of Hepatocyte growth factor in mesenchymal cells confirmed the interaction.
Whether this might of might not be a safe target for therapy is an open question. What would it do to the liver? And would CXCL12 also have to be targeted.
When to use FLUCAM
A small study from Sienna from Professor Forconi (who it is rumored may be relocating to Southampton) on FLUCAM in TP53 dysfunctional CLL patients is published in last month's BJHaem
Only 27 patients were treated. the CLL1 group stood out as responding better than the CLL2 and CLL3 group. CLL1 patients were older and all were treated first line. The re were 6/7 CRs, 1/7 PRs 5/7 MRD neg and only one with hematological toxicity. CLL2 patients had relapsed/ refractory TP53- CLL. The CR rate was 1/5 with 4/5 SD or PD, 3/5 hematological toxicity and 3/5 CMV reactivation. CLL3 patients were historical patients having received other treatments as first line but FLUCAM as second line. They were not relapsed/refractory patients but the CR rate was 1/15, MRD- was 1/15, PR 3/15, SD and PD was 11/15. At 100 weeks the TFI for CLL2 and CLL3 was <10% but for CLL1 it was >70%.
The conclusion from this small study seems to be that FLUCAM looks like a good first line option for TP53 dysfunctional CLL, but not as second or subsequent line treatment.
Only 27 patients were treated. the CLL1 group stood out as responding better than the CLL2 and CLL3 group. CLL1 patients were older and all were treated first line. The re were 6/7 CRs, 1/7 PRs 5/7 MRD neg and only one with hematological toxicity. CLL2 patients had relapsed/ refractory TP53- CLL. The CR rate was 1/5 with 4/5 SD or PD, 3/5 hematological toxicity and 3/5 CMV reactivation. CLL3 patients were historical patients having received other treatments as first line but FLUCAM as second line. They were not relapsed/refractory patients but the CR rate was 1/15, MRD- was 1/15, PR 3/15, SD and PD was 11/15. At 100 weeks the TFI for CLL2 and CLL3 was <10% but for CLL1 it was >70%.
The conclusion from this small study seems to be that FLUCAM looks like a good first line option for TP53 dysfunctional CLL, but not as second or subsequent line treatment.
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