Wednesday, November 2, 2011

Study on “Snake oil” opens up doors for new drugs to treat heart diseases....


Most of us specially those coming from countries like China and India, where we have ago old tradition of using herbs and products from various animals to cure our ailments, may have heard of Snake oil which is a topical preparation most commonly made from the Chinese Water Snake , and other varieties of other species of snakes in other countries. Snake oil used to be known rather infamous for treatment of joint pain, and used as aphrodisiac in many ancient cultures. Medical Scientists have always seen it with skeptic eyes and it has become such a controversial research topic during 19th century, that they started using snake oil as a phrase/a derogatory term for quack medicine. The expression is also being used metaphorically to any product with questionable and/or unverifiable quality or benefit. However, after a publication recently appeared in a top notch journal Science, a collaborative effort of a reputed group of scientists from Universities of Colorado and  Alabama, USA, people have started thinking that there might be something really worth considering seriously to snake oil after all.

In their experiment, these investigators fed a group of mice (which have hearts quite similar to humans) with a chemical cocktail, which are chemically inspired by the fatty acids of Burmese pythons. After a particular time point, these mice found to have grown bigger hearts than control fed mice.

To understand the origin of the research, we must understand the physiology or functioning of the heart. When the situation demands it, the muscles of mammalian hearts grow larger and pump more vigorously. That's useful for pregnant women who need to pump for two, toddlers who need to fuel their rapid growth, or athletes who need to power their regularly exercise. But growing hearts can also be bad news if they're triggered by genetic disorders, high blood pressure or heart attacks. These situations can cause a condition called "hypertrophic cardiomyopathy", in which the heart's thickening walls force it to work harder to pump blood.

To understand how hearts get bigger, this group of scientists which include Cecilia A. Riquelme, Jason A. Magida, Brooke C. Harrison, Christopher E. Wall, Thomas G. Marr, Stephen M. Secor, and Leslie A. Leinwand who is group leader of this study, turned to an animal whose heart is known for swelling in size every time it eats – the Burmese python. As we all know Pythons can swallow extremely large prey like deer, and they remodel their organs to cope with their meals. Intestines and livers of these pythons nearly double in size and their hearts become 40% bigger in just two to three days in comparison to most mammalian hearts which become only 10–20% bigger after months of exercise.


After their swollen hearts these pythons change their heart functioning. Their bigger hearts’ vigorous pumping results into higher oxygen supply through the snake's bloodstream, leading to up its metabolism by 44 times. Its cells produce more proteins that strip electrons from food molecules and shunt them onto oxygen, producing water and liberating energy. Its blood vessels fill with 52 times the usual level of triglycerides, substances found in fats and oils. Such levels would clog mammal hearts with fat, but the pythons seem immune. These changes turn the snake into a long, supercharged energy-extracting machine.


FThese scientists discovered that there is something in the python's blood that triggers the transformation. They extracted plasma from the blood of pythons that had just been fed, and placed it on rat heart cells. They grew in size. They wondered if a protein could be responsible? Then they used either heat or digestive enzymes to destroy the proteins in the python plasma, but it still managed to engorge the rat cells. They concluded that it was not a protein as proteins would have been destroyed by heat or protein specific enzymes. Then what else it could be?

The miraculous ingredients in python blood turned out to be fats. The blood of fasted and fed pythons contained very different blends of fatty acids, and the team identified three that are particularly important – myristic acid, palmitic acid and palmitoleic acid. Well-fed pythons have lots of all three fats, balanced at a very specific ratio. When investigators mixed up this cocktail and injected it into a fasting python, the snake's heart grew as if it had just eaten a big meal.  Then they extended their study to a mouse model because they wanted to know if this phenomenon holds trues to mammalian hearts as well. Lo and behold the same fatty acid cocktail also increased the size of mouse hearts within a week. The effects were very specific – the cocktail didn't affect the size of the rodents' other muscles, but cardiac muscles. The enlarged hearts showed no signs of clumps of fat, or fibrosis – a condition that stiffens the heart and accompanies disease.

Wow……the implications are intriguing…is not it??. Might it one day be possible to give someone the heart of an athlete by administering the right combination of python-inspired fatty acids?  Dr. Leslie Leinwand herself hopes so, however, she warns  - "That is the hope, but we are not advocating that people take pills instead of exercising. We are hoping first to show that these fatty acids might be beneficial in the setting of heart disease and it is a long way off to humans from here."

On a lighter note, for the people in India, next time you see a snake charmer or a quack selling snake oil, just do not reject all his proclaims, he might well be selling something that can cure your ailing heart. And not to forget that every 4th Indian is genetically susceptible to develop cardiac problem in his/her lifetime.  




For those who want to read the technical side of the story, here is the link:


Tuesday, October 25, 2011

HPV and Oropharyngeal Cancers

Human papillomavirus (HPV) is a member of the papillomavirus family of viruses that is capable of infecting humans. HPV is the virus known for causing cervical cancer in women.  While the majority of the nearly 200 known types of HPV cause no symptoms in most people, some types can cause warts (verrucae), while others can – in a minority of cases – lead to cancers of the cervixvulvavagina, and anus in women or cancers of the anus and penis  in men. In recent years, people have started acknowledging that it can also cause cancers of the head and neck (tongue, tonsils and throat).  A recent study finds half of all American men are infected with it. The virus is responsible for 32,000 new cancer cases in the U.S. every year, and according to few other reports, a growing number of men are being diagnosed with head and neck cancers.  But emerging research suggests that HPV-related throat cancer is poised to become the leading form of head and neck cancer in the U.S. A recent study found that, at its current rate, throat cancer will surpass cervical cancer as the leading HPV-associated cancer in the next decade.



Doctors say the trend is worrisome because no screening test exists for HPV-related oral cancers, though the diagnosis is rising at a rate of 10 percent a year. HPV is so common that at least half of sexually active people contract it at some point in their lives. About 6 million people a year are newly infected with the virus each year, according to the Centers for Disease Control and Prevention. Almost all of the 12,000 cases of cervical cancer a year in the U.S. are HPV-associated.


Historically, oropharyngeal cancers have been associated with tobacco and alcohol use, but now researchers have found a link between HPV and a dramatic rise in throat cancer in patients who have neither classic risk factor.


The oropharynx is the middle part of the throat behind the mouth, and includes the base of the tongue, the side and back walls of the throat and the tonsils. Nearly 10,000 new cases of oropharyngeal cancer are diagnosed a year, according to the Centers for Disease Control and Prevention (CDC).


Between 1984 and 1989, roughly 16 percent of cancers involving the base of the tongue and the back of the throat and tonsils were HPV related. Today, the virus is detected in 70 percent of those cancers, which mostly are diagnosed in men, according to a recent study appearing in the Journal of Clinical Oncology. Researchers believe the rise in HPV-related throat cancer can be attributed to sexual transmission because at least 90 percent of HPV-positive throat cancers are the HPV16 strain, which is the same high-risk genotype most frequently observed in cervical cancer. But doctors have not determined if the virus also can be spread through casual saliva contact, such as kissing. Most people with HPV do not develop symptoms or health problems from it. In 90 percent of cases, the body's immune system clears HPV naturally within two years. When the virus persists, it can develop into cancer.


The HPV strains that can cause genital warts are not the same ones that can cause cancers. There is no way to know which people who get HPV will go on to develop cancer or other health problems.


The U.S. Food and Drug Administration has approved an HPV test that can identify 13 of the high-risk types of HPVs associated with the development of cervical cancer. There is no test to determine if a man has HPV.



Men who have had more than four oral sex partners (or intercourse with six or more partners) are at the highest risk for HPV-related oral cancers.


How do people get HPV?

HPV is passed on through genital contact, most often during vaginal and anal sex. HPV may also be passed on during oral sex and genital-to-genital contact. HPV can be passed even when the infected partner has no signs or symptoms.


Signs of HPV-related throat cancer

Persistent sore throat
Ear Pain
Painless white or red patch or a sore on the tongue
Pain or difficulty with chewing or swallowing
Swelling of the jaw
Hoarseness or other change in the voice
Pain in the ear

Source: Centers for Disease Control and Prevention, American Cancer Society

Saturday, July 23, 2011

Molecular dissection of Barrett’s esophagus

Barrett's esophagus is a disorder in which the lining of the esophagus (the tube that carries food from the throat to the stomach) is damaged by stomach acid.

When one eats, food passes from the throat to the stomach through the esophagus (also called the food pipe or swallowing tube). Once food is in the stomach, a ring of muscles keeps it from leaking backward into the esophagus. If these muscles do not close tightly, stomach acid can leak back into the esophagus. This is called reflux or gastroesophageal reflux. This reflux may cause symptoms of heartburn. It may also damage the lining of the esophagus, which is referred to as Barrett's esophagus.

Barrett's esophagus occurs more often in men than women. A person is at risk for this condition if he/she has had Gastroesophageal reflux disease (GERD) for a long time. Patients with Barrett's esophagus may develop more changes in the esophagus called dysplasia. When dysplasia is present, the risk of getting cancer of the esophagus increases; however, its underlying mechanisms have been debated. Esophageal and gastric adenocarcinoma together kill more than a million people each year in United States alone. Both cancers arise in association with chronic inflammation and are preceded by robust metaplasia with intestinal cell characteristics. Gastric intestinal metaplasia is linked to H. pylori infection, whereas Barrett’s metaplasia of the esophagus can be triggered by GERD. Although H. pylori suppression therapies have contributed to the recent decline of gastric adenocarcinoma, the incidence of esophageal adenocarcinoma, especially in the West, has increased dramatically in the past several decades. Treatments for late stages of these diseases are challenging and largely palliative, therefore considerable efforts have focused on understanding the earlier, precancerous stages of these diseases as a prerequisite to developing therapeutic approaches.    

A recent thought-provoking paper by Wang et al. (June 2011 issue of Cell) tried to elucidate the underlying mechanism of Barrett’s esophagus by focusing on two important points:  1) the function of the transcription factor p63 in epithelial tissue and, 2) the processes involved in epithelial metaplasia. p63 mainly functions in development and it is required for establishing stratified epithelia
(i.e., epithelia with more than one layer of cells) or in other words, p63 is required for the switch from the differentiation program of simple, monolayer epithelia to that of stratified, multilayerepithelia. Thus, without p63, the transition between the two tissue types fails to occur.



Metaplasia, a term originally derived from the greek (means ‘‘something formed’’), is used in medicine to refer to the conversion of one tissue, after it is formed, into another. Most frequently, metaplasia involves neighboring tissues of the same origin (e.g., epithelial or mesenchymal), suggesting that the process involves either discrete genetic/epigenetic changes or a neighboring cell population encroaching on another population’s territory. Nevertheless, the cells of origin for a metaplastic process, regardless of tissue type, remain elusive. Complicating matters are other processes that appear similar to metaplasia, such as the abnormal presence or persistence of ectopic tissues during development. Interestingly, even without metaplasia, zones of transition between simple and stratified epithelia are important sites of cancer development, raising the possibility that these sites contain reservoirs of cells with high transformation potential.

Barrett’s esophagus is an intensely studied form of epithelial metaplasia associated with a high predisposition to cancer. The condition is likely triggered by gastroesophageal reflux and chronic inflammatory conditions and is defined as the replacement of a normally stratified squamous epithelium with a simple columnar epithelium. In many cases, but not all, are normally composed of a stratified epithelium in the upper one-third and a columnar epithelium in the lower two thirds. The findings of Wang et al. are in favor of a model of cell migration, but with an interesting twist. They propose that the cells of origin of Barrett’s esophagus are a group of ‘‘primitive’’ epithelial cells, which are found in the developing esophagus and upper stomach region during embryogenesis but persist at the squamous-columnar cell junction in the adult esophagus.



Figure . p63’s Possible Involvement in Barrett’s Esophagus: )
                                                             (source: Karine Lefort and G. Paolo Dotto's  preview article in June 2011 issue of Cell
(A) The transcription factor p63 has two possible functions in epithelial cell fate commitment and tissue homeostasis: (1) p63 expression helps trigger a transition from a simple, monolayer epithelial lineage to a stratified, multilayer lineage; (2) p63 expression is required for self-renewal of cells in the basal proliferative compartment of stratified epithelia.

(B) The two current models for the underlying mechanism of Barrett’s esophagus are as follows: (1) the epithelial metaplasia results from the reprogramming of progenitor/stem cell populations from the stratified toward simple epithelial lineage; (2) cells giving rise to one compartment migrate to another
compartment.

(C) Now Wang et al. (2011) propose another possible mechanism underlying Barrett’s esophagus. ‘‘Primitive epithelial cells,’’ which originate in embryonic tissue, migrate and replace damaged squamous cells in the adult esophagus.


Wang’s model presented here models the evolution of a Barrett’s-like metaplasia in both embryonic and adult mice from precursor cells that are associated by lineage. The mechanisms by which these metaplasias arise in embryos and adults are remarkably similar and suggest a fundamentally novel evolution of precursors of certain cancers in which the earliest events depend not on genetic changes but rather on competition between cell lineages for access to basement membrane essential for proliferation. If Wang’s model turns out to be true, it would change the classic view of metaplasia, shifting the focus of attention from ‘‘after’’ to ‘‘before the fact.’’

Tuesday, May 17, 2011

The failing heart: a new therapeutic approach



Heart failure is one of major cause of death among people both in developed and developing countries. After 40 years of age, the lifetime risk of developing heart failure is 20% for both women and men. In its most common manifestation, heart failure is marked by a decrease in cardiac contractility and called systolic heart failure. To preserve cardiac output, the body increases sympathetic tone and activates neurohormonal pathways (a cascade of intracellular events occurring inside the cardiac muscle cells). These compensatory mechanisms can, however, accelerate the decline of cardiac systolic function. Patients die because of progressive weakening of the heart leading to cardiac remodelling, which further weakens it and can also cause deadly arrhythmias (irregular heartbeat or abnormal heart rhythm). Therefore a group of scientists thought that if the failing heart could be strengthened, the outcome might be more favorable. This group of researchers working at Cytokinetics, Inc., San Francisco, CA, a pharmaceutical company, recently published their exciting and very promising findings about  a small-molecule drug — omecamtiv mecarbil — that selectively enhances the activity of the motor protein myosin, the main force-generating protein of the heart.
Let us first understand the underlying mechanism of heartbeat. The sarcoplasmic reticulum (a organelle inside the striated muscle cell), major functions of which is to  release calcium ions (Ca2+) into the cytoplasm of the heart-muscle cells in a synchronized manner  as shown in following figure (Source: Bers & Harris, Nature 2011, 473; 36–39). The Ca2+ activates myofilaments — organized structures in the cytoplasm composed of interlocked (like the fingers of folded hands) filaments of either actin or myosin proteins. On activation, each myosin filament simultaneously grabs and pulls on an actin filament, in a process that uses the cellular energy molecule ATP. The coordinated contractile activity of the myofilaments develops the forceful muscle contraction that ejects blood from the heart. In heart failure, a reduced amount of Ca2+ is available for release by the sarcoplasmic reticulum, contributing to weaker myofilament activation and contraction.     
First line of drugs to teat heart failures were, inotropic drugs —that enhance contraction at a given ventricular volume — by enhancing the Ca2+ signal that activates contraction. But many of these drugs actually overload cardiac muscle cells with Ca2+, increasing both energy consumption and the risk of arrhythmias and therefore worsen a patient's prognosis. Now these drugs are not that widely used these days. Most widely used type of drugs to treat patients with chronic heart failure are β-blockers, ACE inhibitors, and ARBs, which are not inotropic drugs. These drugs block neurohumoral signalling by adrenergic and renin–angiotensin pathways. Heart failure is accompanied by a neurohumoral storm that activates these pathways by fuelling progressive remodelling and dysfunction. Thus blocking these pathways can slow the progress of heart failure. However, these drugs also increase heart rate and myocardial oxygen consumption and can produce arrhythmias and hypotension or low blood pressure, which contributes to higher mortality.




Dr. Fady Malik and co-investigators hypothesized that directly activating the contractility of the cardiac sarcomere (the smallest functional unit of cardiac muscle fiber) would improve cardiac performance while avoiding the adverse effects of indirect mechanisms. The sarcomere is made up of interdigitating thin and thick filaments. Myosin, the main component of the thick filament, uses chemical energy derived from ATP hydrolysis to produce force for contraction. Myosin motors act upon thin filaments composed of actin and the troponin-tropomyosin regulatory complex. In resting muscle, the free calcium concentration is low, and the regulatory proteins prevent myosin from interacting with actin. During each heartbeat, calcium is released transiently from the sarcoplasmic reticulum into the cytoplasm, where it binds to troponin and allows myosin to interact with actin filaments and to produce contraction. The muscle relaxes as calcium is removed from the cytoplasm.
In this report recently published in Science, (2011, 331 (6023): 1439-1443) this team established that omecamtiv mecarbil — also an inotropic drug — increases heartbeat strength by selectively enhancing the ability of the myosin molecule to generate force (see above figure). They demonstrated that omecamtiv mecarbil enhances cardiac output without changing the level of consumption of oxygen and ATP (molecular unit of cellular/chemical energy) by the heart. As the heart weakens, it receives less nutritive, oxygen-rich blood (that is, the heart pumps blood through its own coronary arteries), which further limits cardiac contraction. By augmenting force while avoiding extra energetic costs, omecamtiv mecarbil increases the apparent efficiency of cardiac contraction and preserves the energy supply–demand balance.

Though tested in a dog model of heart failure, omecamtiv mecarbil holds lot of promises as a selective activator of cardiac myosin, and a rare example of a drug whose action depends on activation rather than inhibition of an enzyme, an approach that may have broader application for therapeutic intervention. Further studies in patients with heart failure will eventually define the clinical benefit and risk profile of cardiac myosin activation in a condition that is still marked by substantial rates of mortality and morbidity. Also this drug gives a new direction of research in which more drugs need to be developed to activate cardiac myosin as a new therapeutic approach to treat heart failure conditions.

For details, please read the article:
http://www.sciencemag.org/content/331/6023/1439.full

Wednesday, May 11, 2011

Economics of drug development

A friend of mine recently quipped that pharmaceutical companies make lot of profit and also they put high price tag on their products than the real cost on the name of research and development. Obviously, this gentleman was completely oblivious of the procedure of drug development. Though, I do not want to go into the details of the politics and economics of drug development, however, I thought it was good idea to let people know the basics of drug development.
 
The discovery and development of new drugs is a very lengthy and costly process. Candidates for a new drug to treat a disease might theoretically include from 5,000 to 10,000 chemical compounds. On average, about 250 of these will show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these will qualify for tests on humans. A study conducted by the Tufts Center for the Study of Drug Development covering the 1980s and 1990s found that only 21.5 percent of drugs that start phase I trials are eventually approved for marketing.


In the research-based drug industry, research and development (R&D) decisions have very long-term ramifications, and the impact of market or public policy changes may not be fully realized for many years. Recently it has been estimated that the cost of bringing a new drug to market ranges up to 1.3 billion US dollars. Thomas Lönngren, former chief of European Medicines Agency (EMA) for almost 10 years, recently complained that of the estimated US$85 billion spent globally each year on drug research and development (R&D), around $60 billion was wasted while very few new drugs (some of them are still in question for their efficacy and toxicity) were produced. In the area of Cancer Research itself, currently, almost 900 novel cancer agents are undergoing investigation in more than 6,000 clinical trials. Owing to this large number of investigational agents, a critical lack of financial and patient resources significantly reduces the chances for adequate development of many of these agents. As a result, clinical drug developers require continual innovation in their approaches to best determine which drugs to develop further, in which patient population to test the novel agents, and how to maximize resources.


            Undoubtedly, drug discovery is a big challenge, as for every new drug that is approved on average $1 billion is spent on research, at least 10 years of development are required, and nine of every ten drugs fail. With the blockbuster pipeline drying up, increasing drug development costs, and higher regulatory standards for drug approval, innovation has become even more difficult. Also, the cost of a new drug has direct bearing on the organizational structure of innovation in pharmaceuticals. With the same context, it is important to note that higher real costs in research and development of drugs have been cited as one of the main reasons underlying the recent trend toward especially in last 3 years, more mergers of big pharmaceutical companies. According to Boston Consulting Group, which published their study in 2001, average 880 Million US dollars spent to develop one single drug, have following components of costs estimates:

Component                 Pre-approval Cost (in US $ Million)
Biology                                     370 (42%) –
Chemistry                                 160 (18%) –
Preclinical safety                        90 (10%) –

Overall preclinical                    620 (70%)
Clinical                                    260 (30%)                             
Total                                       880 (100%)


 
             We have reaped extraordinary benefits from the pharmacological revolution of the twentieth century. Diseases such as such as polio, diphtheria, and whooping cough have almost been eliminated in developed countries by extensive use of vaccines. Many fatal communicable diseases can be readily cured with antibiotics. Complex surgical procedures such as heart surgeries, organ transplants are now safely and effectively undertaken using modern anaesthetics. And drugs have improved the quality of life for many people with chronic diseases such hepatitis B, and C, vascular diseases, and diabetes, to an extent that would have been unthinkable in the first half of 20th century. Nevertheless, there remains massive unmet medical need in both developed and developing countries. For example, there is a growing requirement for effective vaccines against HIV/AIDs, malaria and tuberculosis. We have little to offer those with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease or Huntington’s disease. Current treatments for many psychiatric disorders leave much to be desired. And the outlook for patients with the most common advanced malignancies, such as lung, breast, prostate and colorectal cancers, is still poor.

             However, it must be acknowledged that most of the drug related R&D related research has been sponsored primarily by pharmaceutical industry in North America and Europe. Also, government agencies such as NIH and few others in Europe have been contributing significantly financially   towards new drug developments. However, it is a reality that people from developing countries are equally being benefitted by all the developments in biomedical sciences without investing their share of cost. It must be noted that the increasing cost of drug development is likely to promote the situation whereby companies invest only in the development of those new drugs that are expected to yield peak annual sales greater than US $500 million. It is also worth noting that completely novel drug development — that is, against unproven disease targets— poses a greater risk of failure than developing drugs against proven targets, which means the diseases whose mechanisms have been largely deciphered versus those which are still being explored. This provides additional incentive for companies to focus on improving on approaches that have been clinically and financially successful, and a disincentive to develop products for unmet medical needs. In summary, the fact that the discovery and development of a new drug now costs in excess of US $800 million, and is rising at an annual rate of 7.4% above general price inflation, raises concerns. If the pharmaceutical industry’s R&D efforts become concentrated solely on high-selling products, the outlook in many areas of pharmacotherapy — in particular those in which the risk of failure is high — is bleak. Not only will less common conditions be ignored, but many of the potential benefits of knowledge about advances in genomics will not be realized.

           With the advancement in genomics and proteomics, the future of pharmacotherapy in the twenty-first century should be bright. Our capabilities to meet unmet clinical need should be great. We are, though, in danger of jeopardizing this potential if we do not make every attempt to reduce the cost of drug development. It will not be easy; nor will it be uncontroversial. There will be political, social and legal challenges to be addressed. But if we do not work towards this goal, we will fail future patients, their families and society as a whole. And this will and should not be expected alone from pharmaceuticals. Governments in countries whose economy is booming such as China and India must ensure sufficient funding for research into new medicines, especially for curiosity-driven science. Basic research might not have an immediate effect on medical treatments, and because of the short-term nature of research based on academic review cycles and shareholder dividends it is always difficult to get adequate funding. However, history shows us that in many instances it is such “untargeted” research that has led to major scientific advances. Also, now this is high time when developing nations must realize their responsibility and share the costs of drug development by investing into biomedical research initiatives and forcing their local pharmaceutical companies into start new research and development efforts rather than let them flourish as only money making companies that make only generics.

Thursday, April 14, 2011

Chloroquine and Cancer Treatment !

Strange as it may sound, but it is true. Yes, this is what a group of researchers from Harvard Medical School recently reported in a reputed journal.  I believe most of us especially those living in India and Africa, are well aware of Chloroquine, which is known as one of the most widely and successfully used first generation anti-malarial drug.  It is very famous (for its effectiveness) rather infamous (for its characteristic bitter taste), I still remember during my childhood back in India, elders used to threaten kids that if they won’t sleep in bed equipped with mosquito nets, they would have to eat chloroquine, and all kids out of fear for chloroquine rather malaria itself, would immediately agree to go to bed under the net (which they otherwise did not like normally). Anyways, in last few decades because of emerging chloroquine-resistant malaria parasites, chloroquine was almost forgotten and researchers started to look for other more effective and less toxic drugs to treat and prevent malaria. It is only last couple of years that chloroquine got sudden attention especially among biologists when cancer biologists noticed its role as an inhibitor of autophagy.


Autophagy (from Greek auto-oneself, phagy-to eat) is a process of self-cannibalization which is dependent on the presence of autophagosomes, autolysosomes, as well as an intact nucleus in the cell. Autophagy was first described in the 1960s but many questions about the actual processes and mechanisms involved still remain to be elucidated. Cells capture their own cytoplasm and organelles and consume them in lysosomes. The resulting breakdown products are inputs to cellular metabolism, through which they are used to generate energy and to build new proteins and membranes. Autophagy preserves the health of cells and tissues by replacing outdated and damaged cellular components with fresh ones. In starvation, it provides an internal source of nutrients for energy generation and, thus, survival. A powerful promoter of metabolic homeostasis at both the cellular and whole-animal level, autophagy prevents degenerative diseases. It does have a downside, however--cancer cells exploit it to survive in nutrient-poor tumors. However, the role of autophagy in cancer is complex and may differ depending on tumor type or context.

 
Pancreatic cancer is highly lethal disease. It is estimated that in 2010 more than 43,000 individuals in the United States have been diagnosed with this condition, and 36,800 have died from the disease. Most of these tumors tend to be therapeutically resistant against cytotoxic chemotherapies, targeted agents, and radiotherapy. Most common form of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which contains activating KRAS mutations in the great majority of cases, making this an ideal target for therapeutic intervention. Unfortunately, effective KRAS inhibitors have yet to be developed. The inhibition of pathways downstream from KRAS is a potentially viable approach to circumventing the difficulties in KRAS inhibition. However, KRAS has a multitude of effectors, many of which are poorly characterized, making it a significant challenge to completely shut off the KRAS pathway.

In their study Dr. Alec Kimmelman, MD, PhD, a radiation oncologist at Harvard Medical School, and his group demonstrated that pancreatic tumor derived cell lines and tumors isolated from patients with pancreatic cancers had activated autophagy. Cleaved form of LC3, a protein which associates with autophagosome membranes, widely used as a marker protein for autophagy in the field, was found to be over-expressed in these cells lines and primary tumors. Realizing that profuse activation of autophagy may contribute to pancreatic tumor growth, researchers designed an experiment in which they planned to treat the pancreatic cancer cell lines with Chloroquine, already known as inhibitor of autophagy. As a control, chloroquine was also used to treat normal cell lines with low expression of autophagy. Lo and behold, these researchers found that cell lines derived from pancreatic cancers which had higher level of autophagy were highly sensitive to autophagy inhibition by Chloroquine but this drug had minimal effects on those non cancerous cell lines which had lower levels of autophagy. In many other supporting experiments, researchers confirmed that in keeping with their elevated basal autophagy, pancreatic cancer derived cell lines exhibited a marked sensitivity to chloroquine.

However, apart from having a translational implication, this study must be taken as an indicator of levels of complexities of ongoing cellular processes inside a growing tumor. It is important to re-emphasize that autophagy may act to promote tumorigenesis in other types of cancer, but it may not be as prevalent or as pronounced as in pancreatic cancer, in which the overwhelming majority of tumors are dependent on this process. This study also warrants for further work to be performed to determine the specific roles of autophagy in other tumor types as it should not be forgotten that the positive role for autophagy in the maintenance of advanced pancreatic cancers stands in contrast to a number of other malignancies, in which genetic evidence from human specimens and mouse models shows that inactivation of autophagy can promote tumorigenesis.

The most important aspect of this study is that chloroquine and its derivatives which effectively inhibit autophagy, and in this study, inhibit pancreatic tumor growth—have been safely used in patients for many years as anti-malarial therapies. Given all these factors, we all should hope to see clinical trials to begin soon in pancreatic cancers using these drugs targeting autophagy.

Thursday, April 7, 2011

Superbug in New Delhi

Antibiotic resistance is a type of drug resistance where microorganisms especially bacteria are able to survive exposure to an antibiotic. The primary cause of antibiotic resistance is genetic mutation in bacteria. The prevalence of antibiotic resistant bacteria is a result of unsupervised use of antibiotics or use of too many antibiotics by careless physicians without much rationale in order to treat the infection quickly. The greater the duration of exposure the greater the risk of the development of resistance irrespective of the severity of the need for antibiotics.  The production of β-lactamases in Gram-negative bacteria, is a serious bacterial resistance problem worldwide. If a bacterium carries one or several resistance genes, it is called, informally, a superbug or super bacterium. Antibiotic resistance poses a significant health problem, as in some cases, people infected with resistant bacteria can not be treated effectively by wide variety of antibiotics which could ultimately lead to fatalities.

Until late 90s, antibiotic resistance was not very fashionable beyond clinicians and researchers with first-hand knowledge of the topic. However, now that it is the focus of WHO's World Health Day on April 7, resistance has joined the front rank of global health concerns. What has brought antibiotic resistance into the limelight, and can this new-found status be harnessed to “safeguard these medicines for future generations”, to use the words of the World Health Day website? Recent studies have identified extended-spectrum β-lactamases in high proportions in enterobacteria from India; faced with this problem, the use of reserved antibiotics such as carbapenems has become necessary.

Last year, there was a study published in Lancet which reported the presence of superbug (antibiotic resistance bacteria) in the British patients that had been treated in India. It is important to note that India is fast becoming a hub for medical tourism given its cheaper and good quality health services especially for those who can not afford to have treatment in western health system due to financial constraints. However, government of India and several health experts in India rejected that study based on some technical flaws in the study and also because they thought this study could be biased and politically motivated to discourage rapidly growing health industry in India. Now this another study again by a British group, forces us to take this problem more seriously rather than rejecting as this time they reported the presence of NDM-1 β-lactamase-producing bacteria in environmental samples in New Delhi has important implications for people living in the city who are reliant on public water and sanitation facilities. Researchers collected samples by swabbing seepage water such as water pools in streets  and public tap water from sites within a 12 km radius of central New Delhi, with each site photographed and documented and then analyzing them for the presence of the NDM-1 gene, blaNDM-1, by molecular detection methods.

Though only small percentage of these samples were tested positive for superbug, implications of these results for people living in the Delhi city who are reliant on public water and sanitation facilities are far more serious. International surveillance of resistance, incorporating environmental sampling as well as examination of clinical isolates, needs to be established as a priority. Of course as true with many scientific studies, this study is also not flawless; as microbiologists can certainly comment on the technical issues, but no one would disagree that now health regulatory boards and health policy makers in the countries where they have no or less regulation on the use of antibiotics, should wake up and implement the necessary measures. It is a common practice in India (except few big metropolitan cities) that people go to a pharmacy and ask for an antibiotic of their choice to treat their common health problem, some of these short term health conditions  may not even need antibiotics as there is no bacterial infection yet such as seasonal cold/fever or viral gastroenteritis. This practice should immediately be stopped irrespective of results and intention of recent  Lancet study.  

Friday, April 1, 2011

Asbestos and Risk of Cancer

Asbestos (from Greek σβεστος or asbestinon, meaning "unquenchable" or "inextinguishable") is a set of six naturally occurring silicate minerals exploited commercially for their desirable physical properties. They all have in common their asbestiform habit, long, thin fibrous crystals. The inhalation of asbestos fibers can cause serious illnesses, including malignant lung cancer, mesothelioma (a type of cancer strongly associated with exposure to amphibole asbestos), and asbestosis (a type of pneumoconiosis). Long exposure to high concentrations of asbestos fibers is more likely to cause health problems, as asbestos exists in the ambient air at low levels, which itself does not cause health problems. The European Union has banned all use of asbestos and extraction, manufacture and processing of asbestos products.


 
Asbestos became increasingly popular among manufacturers and builders in the late 19th century because of its sound absorption, average tensile strength, and its resistance to heat, electrical and chemical damage. When asbestos is used for its resistance to fire or heat, the fibers are often mixed with cement or woven into fabric or mats. Asbestos was used in some products for its heat resistance, and in the past was used on electric oven and hotplate wiring for its electrical insulation at elevated temperature, and in buildings for its flame-retardant and insulating properties, tensile strength, flexibility, and resistance to chemicals.
Worldwide, at least 90 000 people die every year from illnesses resulting from occupational exposure to asbestos. However, this number only takes into account workers and ex-workers who have been identified with asbestos-related lung cancer, mesothelioma, and asbestosis. But asbestos has also been linked to laryngeal and ovarian cancer. Factor in asbestos-related illness among individuals whose work history has not been recorded, the family members of those who work with asbestos, and people living near asbestos factories and mines, and the death toll is much higher.


The lengthy latency period of asbestos-related malignant diseases—in some cases more than 40 years—means that even in countries that no longer use the material, the disease burden continues to rise. The UK, for example, banned all forms of asbestos in 1999 but at least 3500 people die from asbestos-related illnesses every year, and this figure is expected to increase to about 5000 in the coming years.
All of which has prompted more than 40 countries—including all member states of the European Union—to ban chrysotile. The World Bank has determined not to use it in any new development projects; and WHO has noted that “the most efficient way to eliminate asbestos-related disease is to stop using all types of asbestos”.



Nevertheless, about 125 million people across the globe are exposed to Asbestos in their working environment. Worldwide production remains at roughly the same level as in 1960: nearly 2·2 million metric tonnes per year. Vast development projects in Asia are largely responsible for maintaining the market. In particular, India’s asbestos industry is burgeoning. Only in first decade of 21st century, the demand of asbestos in India has doubled from roughly 125 000 metric tonnes to about 300 000. Nearly all of India’s asbestos is mixed with cement to form roofing sheets. The health consequences especially rise in lung diseases in India are already well known, but for various political reasons, the cause behind this meteoric rise in lung diseases has never been attributed to the extensive use of asbestos or at least there has been no campaigns by government agencies to make people aware about the consequences of using this disastrous material. Though mesothelioma has never been documented as a major cancer in India, however we can not ignore the fact that current health system which is primarily under control of government of India, does not have sufficient resources to record death and diseases and most of the deaths due to any disease especially in rural areas go unnoticed and without proper diagnoses due to poor infrastructure in medical health.  Besides, there is nihilistic attitude prevailing among people as well health care providers towards cancer in India as it primarily victimizes older people.  Therefore I believe that there is a need for a real assessment of asbestos related diseases especially mesothelioma in order to achieve real statistics.



Also, it is important to notice that out of India’s 300 or so medical schools, few have a training program in occupational health. Out of several thousands of physicians in India, only few of them have had training in occupational health. Consequently, asbestosis is frequently misdiagnosed as tuberculosis or bronchitis. The latest cancer registry data have no information on mesothelioma. The health and safety legislation does not cover 93% of workers in the unorganized sector where asbestos exposures are extremely high. Workers remain uninformed and untrained in dealing with asbestos exposure. Enforcement agencies are not fully conscious of the risks of asbestos exposure. Industrial hygiene assessment is seldom carried out and pathologists do not receive training in identifying mesothelioma histopathologically. The lack of political will and powerful influence of the asbestos industry are pushing India toward a disaster of unimaginable proportion. Rapidly industrializing India is described by the International Monetary Fund as a young, disciplined, and vibrant economy with an average GDP of 8.6% for last 4 years. But now it is time to introspect and question: are Indians going to pay a heavy price in the terms of health for this rapidly growing economy???



Thursday, March 24, 2011

40 Years of the War on Cancer

War on Cancer is still ongoing, however, we have seen some progress which is significant, at least for those who have benefited from all these developments. A nice article (published in Science magazine) summarizes important feats that cancer researchers achieved in the last 40 years:

 (Courtesy: Science  25 March 2011: Vol. 331 no. 6024 pp. 1540-1544 )

Timeline

1971

Figure
PHOTO: LINDA BARTLETT/NCI
President Richard Nixon signs the National Cancer Act promoting the National Cancer Institute.

1973

NCI launches Surveillance Epidemiology and End Results program to collect U.S. cancer data.

1978

Figure
PHOTO: BILL BRANSON/NCI
Clinical testing begins of interferon-α, the first biological cancer therapy. FDA approves tamoxifen to prevent breast cancer recurrence.

1979

Researchers discover p53, the mutated gene most often seen in tumors.

1980

Figure
PHOTO: NCI
Robert Gallo and others isolate human T-cell lymphotropic virus-1, a cause of cancer.

1981

First cancer-prevention vaccine introduced— against human hepatitis B virus.

1983

Researchers create severe combined immunodeficient mice, a model for cancer research.

1985

Figure
PHOTO: NCI
Randomized trial shows that lumpectomy plus radiation are as effective as mastectomy for breast cancer.

1986

Biostatistician John Bailar writes in The New England Journal of Medicine, “We are losing the war against cancer.”

1989

Figure
PHOTO: PAUL SAKUMA/AP
Nobel Prize for discovering the first proto-oncogene (Src) awarded to Harold Varmus and Michael Bishop.

1991

National Breast Cancer Coalition launched, in the AIDS activist style.

1992

Figure
PHOTO: GEORGE MCGREGOR/NCI
FDA approves synthetic yew bark derivative, Taxol (paclitaxel), for breast cancer.

1993

Figure
PHOTO: SCIENCE
Congress orders study of environmental causes of breast cancer on Long Island; the 10-year study will yield no significant findings. Science names p53 “Molecule of the Year.”

1994

BRCA1 gene, identified as a risk for breast and ovarian cancer, is cloned; BRCA2 cloned the next year.

1996

American Cancer Society and others report the “first sustained decline” in overall U.S. cancer deaths, a drop of 2.6% from 1991 to 1995.

1998

FDA approves Herceptin (trastuzumab), a monoclonal antibody, for metastatic breast tumors that overproduce HER2.

1998

Figure
PHOTO: NCI
Nobelist James Watson tells The New York Times that blocking the growth of tumor blood vessels (antiangiogenesis) can “cure cancer in 2 years.”

2001

FDA approves Gleevec (imatinib), a targeted drug, for chronic myelogenous leukemia; Time calls it a “magic bullet.”

2003

Figure
PHOTO: GLOGAU PHOTOGRAPHY/NCI
NCI Director Andrew von Eschenbach vows to “eliminate suffering and death from cancer by 2015.”

2004

FDA approves Avastin, an antiangiogenesis drug, for colon cancer, with chemotherapy. Childhood cancer landmark: nearly 80% of those treated for acute lymphoblastic leukemia are free of cancer “events” for 5 years or more.

2005

Figure
CREDIT: NCI
NIH launches The Cancer Genome Atlas to catalog genomic changes in tumors.

2006

FDA approves Gardasil vaccine to prevent HPV infection, which can lead to cervical cancer.

2007–2008

Breast cancer incidence declines, attributed to better screening and reduced use of hormone replacement therapy.

2009

James Watson writes that it's time to turn from cancer genetics to “understanding the chemical reactions within cancer cells,” or cell metabolism.

2010

Figure
PHOTO: JUPITER IMAGES/THINKSTOCK
National Lung Cancer Screening Trial finds that helical CT screening can reduce cancer deaths among smokers. FDA approves Provenge, an immune treatment for metastatic prostate cancer. It extends life about 4 months and costs $93,000.

2011

PLX4032, a targeted cancer drug, extends life in patients with advanced melanoma.

Wednesday, March 23, 2011

Translational medicine: a hope for patients with Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (also known as Islet cell carcinoma) or PNETs are a type of neuroendocrine tumor found in the pancreas. Only 5 percent of pancreatic tumors arise in the islet cells. The vast majority of tumors found in the pancreas are adenocarcinoma, which is more commonly referred to as pancreatic cancer.  PNETs are very uncommon though, but are very difficult to diagnose and treat. These cancers, which originate from the hormone-producing pancreatic islet cells, stand in stark contrast to another type of pancreatic cancer, pancreatic ductal adenocarcinoma, which is much more prevalent and deadly: a larger proportion of patients with PNET undergo surgical excision, and the clinical course of the disease is highly variable. Nonetheless, patients with advanced PNET who are not candidates for surgery have a terminal illness, and their tumors are difficult to manage. So for only few chemotherapeutic agents are  available to treat PNET but they have only modest activity in these patients.

Two recent translational studies published back to back in 10 Feb issue of NEJM show a ray of hope for the patients with these tumors. One study conducted by Dr. Eric Raymond concluded that Continuous daily administration of sunitinib (a multi-tyrosine kinase inhibitor) at a dose of 37.5 mg improved progression- free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors.


While other study by Yao and colleagues  demonstrated that Everolimus which acts as an oral inhibitor of mammalian target of rapamycin (mTOR),, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. Although it must be taken with pinch of salt as Yao and colleagues note that, whereas everolimus delays time to progression of the disease (progression-free survival), it seemingly does not increase overall survival rates. This trial is still ongoing, however, so the lack of effect on overall survival is not yet conclusive.



These clinical trails, however, have their own limitations and moderate success rate, can be considered as landmarks for treating PNET. The approach that led to this — a long and well designed preclinical studies to elucidate the pathways underlying the disease and mechanism of tumor progression in a representative mouse model and human clinical trials — could also be used to test the efficacy of other anticancer drugs and may well replicate this success story. This strategy from going to preclinical studies to clinical trials is certainly going to prove as model study for other similar investigations in future in which preclinical trials in genetically engineered mouse models, and in other representative animal models, could guide the development of more effective therapies for human cancers, revealing efficacy, beneficial drug combinations and mechanisms of therapeutic resistance.