Sunday, December 31, 2017

To my readers -

Wish you and your family a very Happy and Prosperous New Year!

Selenium as an antioxidant and protector of brain

Selenium (Se) is a trace element, a powerful antioxidant and an important micronutrient that’s absolutely essential for human health. Selenium plays an important role in human cell function - it strengthens and protects cell structure and supports cellular metabolism. As an antioxidant, selenium helps fight free radical damage and moderates reactive oxygen species (ROS), which cause cellular oxidative stress. In addition to acting as an essential nutrient for the immune system and overall body function, selenium also plays a critical role in the operation of the nervous system and in human brain function.The functions of selenium are carried out by selenoproteins, in which selenium is specifically incorporated as the amino acid, selenocysteine (21st amino acid).

Human beings have 25 selenoproteins in their genome and majority of these are relative to the antioxidant defence of the body. The three well-studied subfamilies of selenoproteins include thioredoxin reductase (TrxR), glutathione peroxidase (GPx), and iodothyronine deiodinases (DIO). Three of these TrxR selenoproteins have been identified in mammals that includes TrxR1, which functions in the cytosol and nucleus, TrxR2, which functions in the mitochondria, and TrxR3, which functions in testis. The TrxRs are also important components of the mechanism to reduce peroxide. This group of selenoproteins is required for reduction of thioredoxin (Trx), which uses a cysteine thiol-disulfide exchange for reduction of thiol groups in protein residues. Trx can inhibit apoptosis signaling regulating kinase1 (ASK1) and prevent apoptosis to control cell division, longevity, and cell death. The Trx–TrxR systems are also important for reducing proteins that have cysteine in DNA-binding domains, which include NF-kB, AP-1, p53, and glucocorticoid receptors [1]. Also Selenoprotein P has been reported to possess antioxidant activities and the ability to promote neuronal cell survival according to recent research. Selenium and selenoproteins are also involved in brain metabolism and brain signalling pathways. Selenoproteins have special importance to the neuronal cells, which utilise γ-aminobutyric acid (GABA) as their signalling molecule (GABAergic neurons). In both selenium deficient organisms and organism with genetic impairment of selenoprotein biosynthesis this kind of neurons are affected most heavily [2]. Severe selenium deficiency or malfunction of selenium transporting protein, selenoprotein P, causes degeneration of special group of GABAergic neurons leading to impaired neuronal function that results in motor function disorders, including seizures, and cognitive impairments like affected learning. This is because of the abundance of the GABA-utilising neurons in the corresponding brain regions – hippocampus, cerebral cortex and cerebellum.

Through selenoproteins selenium is involved in the diverse functions of the brain including motor performance, coordination, memory and cognition. Selenoproteins are important for normal brain function, and decreased function of selenoproteins can lead to impaired cognitive function and neurological disorders such as Alzheimer's disease, Parkinson's disease (impaired function of glutathione peroxidase selenoenzymes), Huntington's disease (here selenium deters lipid peroxidation by increasing specific glutathione peroxidases/GPX), amyotrophic lateral sclerosis and epilepsy [3]. Since the human body cannot produce selenium, it must be consumed from an external source and generally an adult human requires a minimum of 55 micrograms per day. Women who are pregnant or breastfeeding require slightly more.

References:

Pillai, R., Uyehara-Lock, J. H. and Bellinger, F. P. (2014), Selenium and selenoprotein function in brain disorders. IUBMB Life, 66: 229–239. doi:10.1002/iub.1262
https://atlasofscience.org/importance-of-selenium-for-brain-function/
https://www.ncbi.nlm.nih.gov/pubmed/12807419

Sunday, December 17, 2017

Dengue virus pathogenesis

Dengue virus (DENV) is a mosquito-transmitted (primarily from the female mosquitoes of genus Aedes) RNA virus that infects an estimated 390 million humans each year. DENV is a member of the Flavivirus genus of single-stranded positive-sense RNA viruses that cause visceral and central nervous system disease in humans. Dengue is currently the most prevalent arthropod-borne viral disease of humans that is caused by four antigenically distinct serotypes of dengue virus (DENV 1–4) that are genetically similar and share approximately 65% of their genomes. Infection with any of the DENV serotypes may result in a wide spectrum of clinical symptoms, ranging from a mild flu-like syndrome (known as dengue fever [DF]) to the most severe forms of the disease, which are characterized by coagulopathy, increased vascular permeability (increased hemoconcentration or fluid effusion in chest or abdominal cavities), fragility (dengue hemorrhagic fever [DHF]) and dengue shock syndrome [DSS]. Severe dengue is a potentially deadly complication due to plasma leaking, fluid accumulation, respiratory distress, severe bleeding and organ impairment [1]. The World Health Organization (WHO) classifies DHF in four grades (I to IV). DHF grades I and II represent relatively mild cases without shock, whereas grade III and IV cases are more severe and accompanied by shock. Recovery from infection by one serotype provides lifelong immunity against that particular serotype, and does not provide cross-immunity against other serotypes.

The primary vector of dengue is Aedes aegypti mosquito that lives in urban habitats and breeds mostly in man-made containers. Ae. aegypti is a day-time feeder and its peak biting periods are early in the morning and in the evening before dusk. Aedes albopictus is the secondary dengue vector in Asia, has spread to North America and more than 25 countries in the European Region. During the feeding of mosquitoes on humans, DENV is presumably injected into the bloodstream, with spillover in the epidermis and dermis, resulting in infection of immature Langerhans cells (epidermal dendritic cells [DC]) and keratinocytes. Infected cells then migrate from site of infection to lymph nodes, where monocytes and macrophages are recruited, which become targets of infection. Consequently the infection is amplified and virus is disseminated through the lymphatic system. As a result of this primary viremia, several cells of the mononuclear lineage, including blood-derived monocytes, myeloid DC, and splenic and liver macrophages are infected [2]. There are several immune cells associated with the pathogenesis of DENV infection and systemic spread, including dendritic cells, macrophages, and mast cells (MCs). MCs are widely recognized for their immune functions and as cellular regulators of vascular integrity in human skin [3].

Several genetic factors have been shown to be associated with the development of DHF/DSS and some have been shown to be protective. Certain HLA- class I and class II allele polymorphisms in the tumor necrosis factor alpha (TNF-α), Vitamin D receptor, CTLA-4 and transforming growth factor ß (TGF-β) have been shown to be associated with development of DHF/DSS. Several studies have shown that concentrations of multiple cytokines and other mediators, as well as soluble receptors, are significantly increased during severe dengue infections. Higher plasma levels of IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-13, IL-18, TGF-1β, TNF-α, and IFN-γ have been found in patients with severe DENV infections, in particular in patients with DSS [4].

There is no specific treatment for dengue fever. Maintenance of the patient's body fluid volume is critical to severe dengue care. In late 2015 and early 2016, the first dengue vaccine, Dengvaxia (CYD-TDV) by Sanofi Pasteur, was registered in several countries for use in individuals 9-45 years of age living in endemic areas. WHO recommends that countries should consider introduction of the dengue vaccine CYD-TDV only in geographic settings (national or subnational) where epidemiological data indicate a high burden of disease.

References:

Tuesday, October 31, 2017

Herbal supplements and cancer

Herbal supplements as well as dietary supplements could cause cancer. According to recent research one in five cases of chemical-induced liver damage come from herbal and dietary supplements. Herbal remedies containing aristolochic acids (AA), a compound found in leafy, flowery vines called Aristolochia (or birthwort) and Asarum is the most potent carcinogen that have been linked to several types of cancer. Aristolochic Acid is a natural product of plants used in some weight loss supplements too. A study, published in Science Translational Medicine found that in 78 percent of liver cancer samples collected in Taiwan showed a distinctive mutation consistent with AA exposure. The research team looked at 98 samples of hepatocellular carcinoma, the most common type of liver cancer, and the most common cause of death in people with cirrhosis [1]. Also cancers of the upper urinary tract (renal pelvis and ureter) and bladder have been reported among individuals who had kidney damage caused by the consumption of herbal products containing AA.

Aristolochic acid is absorbed from the gastrointestinal tract and distributed unchanged and/or in metabolized form throughout the body. The major activation pathway of AA involves reduction of the nitrogroup, and is catalysed by several human cytosolic and microsomal enzymes such as hepatic and renal cytosolic NAD(P)H:quinone oxidoreductase (NQO1), hepatic microsomal cytochrome P450 (CYP)1A2 and renal microsomal NADPH:CYP reductase – NQO1 being the most important [2]. During reductive activation, aristolochic acids form an electrophilic cyclic N-acylnitrenium ion that reacts with purine bases to form DNA adducts. These DNA adducts found in patients with liver, bladder and renal cancer, act as biomarker for exposure to AA.

AA has been officially banned in Europe since 2001 and in Singapore since 2004. Some herbs that contain AA have been banned in Taiwan since 2003, and in China, the use of some, but not all, AA-containing herbs in traditional medicine is restricted. But the United States Food and Drug Administration has issued strong warnings about herbs containing AA. Food and Drug Administration (FDA) is advising consumers to immediately discontinue use of any botanical products containing aristolochic acid. These products may have been sold as "traditional medicines" or as ingredients in dietary supplements [3].

References:

Wednesday, October 11, 2017

Neuroligin-3 and brain cancer

NLGN3 (neuroligin 3) is a mitogen/synaptic protein that promotes glioma proliferation through the PI3K–mTOR pathway. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K–mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. The tumors, called high-grade gliomas (HGG), are a group of deadly brain cancers that include adult glioblastoma, anaplastic oligodendroglioma, pediatric glioblastoma (GBM) and pediatric diffuse intrinsic pontine glioma (DIPG) [1]. Recent research in Stanford University found that interrupting the neuroligin-3 signal could be a helpful strategy for controlling high-grade gliomas in human patients. Neuroligin-3 activates multiple cancer promoting signaling pathways and increases the expression of genes involved in cell proliferation, promotion of malignancy, function of potassium channels and synapse function [2]. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors block the release of NLGN3 into the tumor microenvironment and robustly pause HGG xenograft growth [3]. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth [4]. Recent research suggests that interrupting the neuroligin-3 signal could be a helpful strategy for controlling high-grade gliomas in human patients. Using mice with normal neuroligin-3 brain signaling and human high-grade gliomas, the researchers tested whether two inhibitors of neuroligin-3 secretion could stop the cancers’ growth. One of the inhibitors has never been tested in humans, but the other has already reached phase-2 clinical trials as a potential chemotherapy for other forms of cancer outside the brain.

References:

Wednesday, August 30, 2017

Role of cardiotrophin-1 in cardiovascular regulation

Cardiotrophin-1 (CT-1) is a transmembrane signaling glycoprotein (gp)130 ligand, a leukemia inhibitory factor (LIF) receptor and a heart-targeting cytokine. CT-1 is a new member of the interleukin IL-6 type cytokine family and has potent hypertrophic and survival effects on cardiac myocytes [1]. Several factors could stimulate cardiac CT-1 expression such as hypoxia, reactive oxygen species, angiotensin II, aldosterone, urocortin, glucose and insulin, and fibroblast growth factor-2. CT-1 mediates its hypertrophic and cytoprotective properties through the Janus kinase/signal transducers and activators of transcription (JAK/STAT), mitogen-activated protein (MAP) kinase, phosphatidylinositol (PI-3) kinase, and nuclear factor kappa B (NFκB) pathways [2]. CT-1 was originally identified in cardiomyocytes (heart) but CT-1 gene (located on chromosome 16p11.1–16p11.2) and protein (that encodes 201 amino acids) expression also occurs in the liver, lung, kidney, skeletal muscle and adipose tissues (adipocytes is an important cellular source of CT-1).

Plasma cardiotrophin-1 (CT-1) levels are elevated in cardiovascular diseases (CVDs) such as hypertension, valve diseases, congestive heart failure, coronary artery diseases, metabolic syndrome, and chronic kidney diseases. Circulating levels of CT-1 increase with the severity of the CVDs [3]. CT-1 exerts a protective function in the adult heart by inducing cell hypertrophy (enlargement). Recent research says that CT-1 specifically protects the cardiac myocytes from ischaemic damage when given prior to the ischaemia and at the time of reoxygenation. CT-1 induces the pathological hypertrophic response and could be therapeutically used in the treatment of ischaemic damage in the heart [4].

Recent evidence suggests that CT-1 acts as a biomarker for LVH (left ventricular hypertrophy) and impaired cardiac function in patients with hypertension. Recent study, by a team of researchers from The Ottawa Hospital, the University of Ottawa, the University of Ottawa Heart Institute and Carleton University discovered that CT-1 protein could be used as an “exercise pill” that can trick the heart into repairing damage and improving blood flow. This “pill” i.e. CT-1 protein could help improve the function of a failing heart and boost blood flow by mimicking the effects of a visit to the gym that could revolutionize the lives of hundreds of thousands of heart disease sufferers [5].

Also local and systemic concentrations of CT-1 plays a critical role in obesity. A recent study showed that acute and chronic treatments with recombinant CT-1 were able to correct insulin resistance in animal models of genetic and acquired obesity. A recent study also found that cardiotrophin-1 induces Matrix Metalloproteinase-1 (MMP) in human aortic endothelial cells (HAECs) [6]. Recent research suggests that CT-1 induces the proteolytic potential in HAECs by upregulating MMP-1 expression through ERK1/2, p38 MAP kinase, JNK and JAK/STAT pathways, and also suggests that CT-1 may play an important role in the pathophysiology of atherosclerosis and plaque instability. All data shows that CT-1 has a huge impact on cardiovascular regulation and heart disease protection.

References:

Sunday, July 30, 2017

Genes lead to mind reading capabilities

DNA influences the ability to read a person's thoughts and emotions from looking at their eyes, according to a new study. The ‘cognitive empathy'/'Reading the Mind in the Eyes' Test by the scientists of University of Cambridge revealed that people can rapidly interpret what another person is thinking or feeling from looking at their eyes alone and women on average score better on this test than men. The team found that genes influence the performance on the Eyes Test, and identified genetic variants on chromosome 3 in women that are associated with their ability to "read the mind in the eyes." Interestingly, performance on the Eyes Test in males was not associated with genes in this particular region of chromosome 3. The closest genes in this tiny stretch of chromosome 3 include LRRN1 (Leucine Rich Neuronal 1) which is highly active in a part of the human brain called the striatum, and which has been shown using brain scanning to play a role in cognitive empathy. Also the genetic variants that contribute to higher scores on the Eyes Test also increase the volume of the striatum in humans [1].

Studies also found that people with autism and anorexia tend to score lower on the Eyes Test and genetic variants that contribute to higher scores on the Eyes Test also increase the risk for anorexia, but not autism. The scientists speculate that this may be because autism involves both social and non-social traits, and this Eyes Test only measures a social trait [2].

References:

1.http://www.cam.ac.uk/research/news/genes-influence-ability-to-read-a-persons-mind-from-their-eyes

2.https://www.sciencedaily.com/releases/2017/06/170607123843.htm

Friday, June 30, 2017

Broccoli : A weapon against diabetes and cancer

Type 2 diabetes affects around 300 million people globally, and as many as 15% of those patients cannot take the first-line therapy metformin because of kidney damage risks. Type 2 diabetes occurs when the body is not able to make enough insulin or to use the hormone to regulate blood glucose levels. This causes a build-up of sugar in the blood and for obese patients, their excess body fat makes it harder for the liver and muscle tissue to absorb this excess blood glucose. Researchers have identified an antioxidant sulforaphane (which is present in high amounts in broccoli) as a new anti-diabetic substance. This antioxidant also has huge impacts for the treatment of cancer and inflammatory diseases so it is identified as a secret weapon against diabetes and cancer. Sulforaphane stops the liver enzymes from over-producing glucose and thus offers a viable alternative for those who can't take metformin and as a naturally occurring compound, it could also have other benefits. When tested on rodents with dietary-induced diabetes, the researchers found that their blood sugar dropped by 23 percent in four weeks when they were given sulforaphane, which was comparable to the 24 percent drop in those that were given metformin [1].

Also research found that during food preparation the glucosinolates in broccoli and other cruciferous vegetables are broken down into biologically active compounds such as indoles, nitriles, thiocyanates, and isothiocyanates and among them indole-3-carbinol (an indole) and sulforaphane (an isothiocyanate) have been most frequently examined for their anticancer effects. Indoles and isothiocyanates have been found to inhibit the development of cancer by protecting cells from DNA damage and blocks DNA methylation, helping inactivate carcinogens, induce cell death (apoptosis) and inhibit tumor blood vessel formation (angiogenesis) and tumor cell migration [2]. A number of studies showed that sulforaphane may target CSC (cancer stem cells) in different types of cancer through modulation of NF-κB, SHH, epithelial-mesenchymal transition and Wnt/β-catenin pathways [3]. Also sulforaphane works variably to help the body avoid genetic failures, and thus operates as a cancer antagonist and it is also a potent compound that boosts the body's protective enzymes and flushes out cancer-causing chemicals.

References:

Saturday, May 27, 2017

Exercise can make you young biologically

Regular exercise and physical activity could make you 9 to10 years young biologically. A new research from Brigham Young University reveals that exercise could slow down cellular aging. The study, published in the medical journal Preventive Medicine, finds that people who have consistently high levels of physical activity have significantly longer telomeres than those who have sedentary lifestyles. Telomeres are tiny protein end caps found on the end of DNA strands (chromosomes) and they protect the DNA from damage during cell division and replication. Telomeres are correlated with age, each time a cell replicates / ages, its telomeres naturally shorten and fray and exercise may slow the fraying of telomeres. A study found that shortest telomeres came from sedentary people and had 140 base pairs of DNA less at the end of their telomeres than highly active people [1].

Recent research found that adults with high physical activity levels have telomeres with a biological aging advantage of 9 to 10 years over those who are non active, and a 7 year advantage compared to those who are moderately active. Highly active means women had to engage in 30 minutes of jogging/brisk walk per day (40 minutes for men), five days a week.

Also physical activity can slow brain aging by as much as 10 years, according to a new study. Studies found that people who used to do more physical activity showed higher scores on cognitive tests and better brain health. Several factors such as high blood pressure, diabetes, smoking & alcohol consumption and heart disease could impair blood flow to the brain and therefore compromise cognitive/brain functions [2].

But over exercise may result in free radical-mediated oxidative damage / overproduction of reactive oxygen (ROS) and nitrogen species. Muscle fibers/myocytes contain both enzymatic and nonenzymatic (e.g., GSH/Glutathione, uric acid, bilirubin, etc) antioxidants defense networks that exist in both the extracellular and vascular space and work as a complex unit to regulate ROS. These antioxidants protect muscle fibers from oxidative injury during increased oxidant production (e.g., intense or prolonged exercise) [3]. Antioxidant enzymes (by which free radicals are neutralized) includes superoxide dismutase, glutathione peroxidase, and catalase, peroxiredoxin, glutaredoxin, and thioredoxin reductase that contribute to cellular protection against oxidation. Various dietary antioxidants may contribute to cellular protection against free radicals and other ROS including vitamin E, vitamin C, and carotenoids.

References:

Saturday, April 29, 2017

Role of Berries in cancer prevention

Berries are loaded with antioxidants that can prevent cancer by mopping up the free radicals i.e. the oxygen molecules. Also all types of berries particularly strawberries and raspberries have high content of ellagic acid that can fight various types of cancers (skin, bladder, lung, esophagus and breast). Ellagic acid acts as an antioxidant, helps to deactivate specific carcinogens, slowing down the reproduction of cancer cells and it is also a potent anti-angiogenetic factor, which can slow the growth of blood vessels that feed new tumor cells. Another phytonutrient Quercetin that is found in abundance in strawberries, can induce apoptosis (programmed death of cancer cells). According to a recent study published in the Journal of Agriculture and Food Chemistry, Quercetin and whole strawberry extract inhibited the proliferation of human liver cancer cells, produced a dramatic increase in cell death (up to 80 percent) after 18 hours of treatment and retarded the proliferation of these cells prior to their death [1].

Blueberries contain a family of phenolic compounds called anthocyanosides (because of which these berries are blue), which are among the most potent antioxidants yet discovered [2]. Recent research found that black raspberry and strawberry extracts have the most effective apoptosis inducing effects. Recent studies from the College of Public Health at Ohio State University, Comprehensive Cancer Center in Columbus, Ohio, discovered that black raspberries prevent cervical cancer cell growth and tumor formation and also they inhibit inflammation and induce apoptosis in esophageal and colorectal cancer tissues [3]. The ellagic acid in strawberries can deactivate specific carcinogens and decrease the replication of cancer cells. Also The College of Pharmacy at the University of Rhode Island analyzed the Jamun berries (Indian blackberry) extract and found that it exhibited pro-apoptotic effects against breast cancer cells.

But it is very important to consume only organic berries because recent report from the U.S. Department of Agriculture found that a single sample of berries contained 13 different pesticides. Also a Pesticide Action Network analysis found 54 different pesticides among strawberry samples, including nine probable carcinogens, 24 suspected hormone disruptors, 11 neurotoxins and 12 reproductive toxins. Also the phytonutrient content of organic strawberries is higher than in conventionally grown strawberries, especially vitamin C. Compost as a soil supplement increases the level of antioxidant compounds in strawberries. A Swedish research found the most effective extracts at inhibiting cell proliferation contained 48 percent more ascorbate and five times more dehydroascorbate (Vitamin C is ascorbate plus dehydroascorbate.) The organic strawberries had more antioxidants and a higher ratio of ascorbate to dehydroascorbate. So adding a cup of cancer-fighting berries a day to diet may reduce many risk factors, and help battle certain types of cancers.

References:

https://www.wsj.com/articles/SB10001424052748703280904576246854013624530

Friday, March 31, 2017

Electronic nose

The electronic nose or nano nose is an artificial olfactory device that has a small array of flexible gold nanoparticle sensors that can accurately detect compounds in a breathing sample. Currently researchers tried to use this nano nose to detect various types of cancer such as ovarian, lung and brain cancer and got 82% accuracy. Disease detection by electronic nose is safer, simpler, more portable, inexpensive and less invasive diagnostic method than traditional methods such as imaging technique, biopsies etc. The nano nose comprises of a large number of flexible sensors that are based on molecularly modified gold nanoparticles (GNPs) [1]. These sensors are integrated into a dynamic cross-reactive diagnostic sensing array. Gold nanoparticles are highly sensitive in the detection of biomarkers at lower concentration levels and they are biocompatible. Each bending state of the flexible sensor gives unique nanoparticle spatial organization, altering the interaction between GNP ligands and volatile organic compounds (VOCs) that increases the amount of data obtainable from each sensor.

The individual dynamic flexible sensor of the nano nose could selectively detect ppb (parts per billion) level VOCs that are linked with cancers in exhaled breath. VOCs can be produced endogenously or exogenously and are used as biomarkers to detect diseases such as cancer in early stages fast and accurately. For example, lung cancer tissue emits some specific VOC biomarkers such as acetaldehyde, formaldehyde, undecane, isopropene, methanol, ethylbenzene and acetone that can be detected by sensors/chemiresistors coated with gold nanoparticles of a nano nose [2]. Breast cancer patients emit VOC biomarkers that includes derivatives of alkanes such as tridecane, hexanol, formaldehyde etc and bladder, and prostate cancer patients exhaled toluene, p-xylene, acetic acid etc. This electronic nose has a huge potential to detect and diagnose various types of diseases including cancer that can enhance the opportunities to save lives.

References:

1. https://phys.org/news/2015-09-sniffing-cancer-electronic-nose-sensors.html

2.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4645969/

Monday, February 20, 2017

KRAS - the protooncogene

KRAS gene is Kirsten ras oncogene homolog of mammalian ras gene family and encodes K-Ras protein which regulates cell division and proliferation. Cytogenetically this gene is located in the short arm of chromosome 12 (12p12.1), encoded by 189 amino acids [1]. KRAS protein (also called p21) is a member of RAS/MAPK signalling pathway (for cellular signal transduction) and acts as molecular switch which is turned on by GTP (for cell growth and differentiation) and turned off by GDP molecules. KRAS gene is activated by guanine nucleotide exchange factor (GEF) and inactivated by GTPase activating proteins (GAP) [2]. KRAS is the most frequently mutated oncogene and somatic mutation in this gene results in various types of cancer such as lung, colon and pancreatic.

Around 15 - 25% lung adenocarcinoma/non small cell lung cancer (NSCLC) is related with KRAS mutation (missense mutation that introduces an amino acid substitution most frequently at codons 12, 13 and less frequently codon 61) which affects the KRAS signalling pathways (MAP kinase pathway, AKT/MTOR pathway etc.). The unregulated signalling of RAS through these pathways results in increased cell proliferation, decreased apoptosis, disrupted cellular metabolism and increased angiogenesis that leads to tumor cell proliferation [3]. Currently there is no targeted therapy for the NSCLC patients with KRAS mutation except some promising drug agents such as mitogen activated enzyme kinase inhibitors/MEKi (Trametinib and Selumetinib in combination with chemotherapy), CDK/Cyclin dependent kinase inhibitors (Palbociclib, Abemaciclib) in clinical trial.

Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer which develops via acinar-ductal metaplasia and pancreatic intraepithelial neoplasia (PIN/PanIN), IPMN (intraductal papillary mucinous neoplasia) and AFLs (atypical flat lesions). 90% of PDAC is driven by mutationally (point mutation at codon G12) active KRAS oncogene/oncogenic KRAS signalling which results in intrinsic GTPase activity that block the KRAS and GAP interaction. Oncogenic KRAS signalling involves Raf/Mek/Erk pathway and P13K/Pdk1/Akt pathway and signalling in pancreas generates a fibro-inflammatory microenvironment which promotes neoplastic progression by paracrine stimulation. Also oncogenic KRAS drives metabolic reprogramming in tumor cells by aerobic glycolysis (by increasing glycolytic enzyme expression). Until now there is no cure for PDAC and average life expectancy is less than 5 years.

Around 30% to 50% colorectal cancer (CRC) is associated with KRAS mutation/point substitution (the most frequent is glycine for aspartate) mutation in codon 12, 13, 61, 146 and 154. KRAS gene is an important member of EGFR signalling cascade and involved in intracellular signal transduction [4]. EGFR is a transmembrane receptor tyrosine kinase that is overexpressed in 25% to 75% colorectal tumor/cancer. CRC carcinogenesis involves 3 pathways including chromosomal instability pathway/CIN (defects in chromosomal segregation and telomere stability), microsatellite (short tandem repeats/STRs) instability pathway/MSI (loss of DNA mismatch repair which is most common in CRC) and serrated pathway (progression of serrated polyps)/CpG island methylator phenotype pathway [5]. CIN pathway (also known as adenoma-carcinoma sequence) is the most common one (70%) which involves activation of KRAS proto-oncogene and inactivation of tumor suppressor genes such as APC (that normally blocks transition from G1 to S phase in cell cycle), p53 (that is involved in cell cycle control). CIN also results in aneuploid karyotype, loss of heterozygosity at tumor suppressor gene loci and chromosomal rearrangements [6]. Cetuximab and panitumumab are anti EGFR monoclonal antibodies which are engineered to block the EGFR signalling pathway at the extracellular domain of EGFR receptor. These are currently FDA approved CRC drugs but KRAS mutated patients showed no response to these drugs.