A Law of Redundancy Compounds the Problem of Cancer and Precision Medicine.

Genetics and molecular biology research have progressed for over a century; however, no laws of biology resembling those of physics have been identified, despite the expectations of some physicists. It may be that it is not the properties of matter alone but evolved properties of matter in combination with atomic physics and chemistry that gave rise to the origin and complexity of life. It is proposed that any law of biology must also be a product of evolution that co-evolved with the origin and progression of life. It was suggested that molecular complexity and redundancy exponentially increase over time and have the following relationship: DNA sequence complexity (Cd) < molecular complexity (Cm) < phenotypic complexity (Cp). This study presents a law of redundancy, which together with the law of complexity, is proposed as an evolutionary law of biology. Molecular complexity and redundancy are inseparable aspects of biochemical pathways, and molecular redundancy provides the first line of defense against environmental challenges, including those of deleterious mutations. Redundancy can create problems for precision medicine because in addition to the issues arising from the involvement of multiple genes, redundancy arising from alternate pathways between genotypes and phenotypes can complicate gene detection for complex diseases and mental disorders. This study uses cancer as an example to show how cellular complexity, molecular redundancy, and hidden variation affect the ability of cancer cells to evolve and evade detection and elimination. Characterization of alternate biochemical pathways or "escape routes" can provide a step in the fight against cancer.

Decoding 'Unnecessary Complexity': A Law of Complexity and a Concept of Hidden Variation Behind "Missing Heritability" in Precision Medicine.

The high hopes for the Human Genome Project and personalized medicine were not met because the relationship between genotypes and phenotypes turned out to be more complex than expected. In a previous study we laid the foundation of a theory of complexity and showed that because of the blind nature of evolution, and molecular and historical contingency, cells have accumulated unnecessary complexity, complexity beyond what is necessary and sufficient to describe an organism. Here we provide empirical evidence and show that unnecessary complexity has become integrated into the genome in the form of redundancy and is relevant to molecular evolution of phenotypic complexity. Unnecessary complexity creates uncertainty between molecular and phenotypic complexity, such that phenotypic complexity (CP) is higher than molecular complexity (CM), which is higher than DNA complexity (CD). The qualitative inequality in complexity is based on the following hierarchy: CP > CM > CD. This law-like relationship holds true for all complex traits, including complex diseases. We present a hypothesis of two types of variation, namely open and closed (hidden) systems, show that hidden variation provides a hitherto undiscovered "third source" of phenotypic variation, beside genotype and environment, and argue that "missing heritability" for some complex diseases is likely to be a case of "diluted heritability". There is a need for radically new ways of thinking about the principles of genotype-phenotype relationship. Understanding how cells use hidden, pathway variation to respond to stress can shed light on why two individuals who share the same risk factors may not develop the same disease, or how cancer cells escape death.

Rotation of sex combs in Drosophila melanogaster requires precise and coordinated spatio-temporal dynamics from forces generated by epithelial cells.

The morphogenesis of sex combs (SCs), a male trait in many species of fruit flies, is an excellent system in which to study the cell biology, genetics and evolution of a trait. In Drosophila melanogaster, where the incipient SC rotates from horizontal to a vertical position, three signal comb properties have been documented: length, final angle and shape (linearity). During SC rotation, in which many cellular processes are occurring both spatially and temporally, it is difficult to distinguish which processes are crucial for which attributes of the comb. We have used a novel approach combining simulations and experiments to uncover the spatio-temporal dynamics underlying SC rotation. Our results indicate that 1) the final SC shape is primarily controlled by the inhomogeneity of initial cell size in cells close to the immature comb, 2) the final angle is primarily controlled by later cell expansion and 3) a temporal sequence of cell expansion mitigates the malformations generally associated with longer rotated SCs. Overall, our work has linked together the morphological diversity of SCs and the cellular dynamics behind such diversity, thus providing important insights on how evolution may affect SC development via the behaviours of surrounding epithelial cells.

Anti-breast tumor activity of Eclipta extract in-vitro and in-vivo: novel evidence of endoplasmic reticulum specific localization of Hsp60 during apoptosis.

Major challenges for current therapeutic strategies against breast cancer are associated with drug-induced toxicities. Considering the immense potential of bioactive phytochemicals to deliver non-toxic, efficient anti-cancer therapeutics, we performed bio-guided fractionation of Eclipta alba extract and discovered that particularly the chloroform fraction of Eclipta alba (CFEA) is selectively inducing cytotoxicity to breast cancer cells over non-tumorigenic breast epithelial cells. Our unbiased mechanistic hunt revealed that CFEA specifically activates the intrinsic apoptotic pathway by disrupting the mitochondrial membrane potential, upregulating Hsp60 and downregulating the expression of anti-apoptotic protein XIAP. By utilizing Hsp60 specific siRNA, we identified a novel pro-apoptotic role of Hsp60 and uncovered that following CFEA treatment, upregulated Hsp60 is localized in the endoplasmic reticulum (ER). To our knowledge, this is the first evidence of ER specific localization of Hsp60 during cancer cell apoptosis. Further, our LC-MS approach identified that luteolin is mainly attributed for its anti-cancer activities. Moreover, oral administration of CFEA not only offers potential anti-breast cancer effects in-vivo but also mitigates tumor induced hepato-renal toxicity. Together, our studies offer novel mechanistic insight into the CFEA mediated inhibition of breast cancer and may potentially open up new avenues for further translational research.

Serum microRNA profiling to distinguish papillary thyroid cancer from benign thyroid masses.

OBJECTIVES: Papillary thyroid cancer (PTC) is increasing in incidence. Fine needle aspiration is the gold standard for diagnosis, but results can be indeterminate. Identifying tissue and serum biomarkers, like microRNA, is therefore desirable. We sought to identify miRNA that is differentially expressed in the serum of patients with PTC. METHODS: Serum miRNA was quantified in 31 female thyroidectomy patients: 13 with benign disease and 18 with PTC. qPCR results were compared for significant fold-changes in 175 miRNAs, against a pooled control. RESULTS: 128 miRNA qualified for analysis. There were identifiable fold-changes in miRNA levels between benign and control, and between PTC and control. There were statistically significant fold changes in the level of four miRNAs between benign and PTC: hsa-miR-146a-5p and hsa-miR-199b-3p were down-regulated, while hsa-let7b-5p and hsa-miR-10a-5p were up-regulated. CONCLUSIONS: MicroRNA is differentially expressed in the serum of patients with PTC. Serum miRNA has the potential to aid in thyroid cancer diagnosis.

Potential pharmacological interventions against hematotoxicity: an overview.

Various treatment regimens, including chemotherapy, are known to induce heavy oxidative stress on the system, which in turn leads to adverse effects on healthy tissues. Blood being prone to oxidative stress is affected the most. At this juncture, it might not be prudent to anticipate having chemotherapeutic agents with no hematotoxicity; the best way forward is to look for potential anti-hematotoxic compounds, which could be supplemented to exposed patients, thus reducing the toxic burden on blood cells. We mined existing literature for reviewing possible interventions against hematotoxicity and figured that there is a great lacuna in this field in terms of not having such useful information at one place. This review presents the possible entities based on their antioxidant potentials, including their mechanistic pathways.

Metabolic enhancer piracetam attenuates rotenone induced oxidative stress: a study in different rat brain regions.

Piracetam is clinically being used nootropic drug but the details of its neuroprotective mechanism are not well studied. The present study was conducted to assess the effects of piracetam on rotenone induced oxidative stress by using both ex vivo and in vivo test systems. Rats were treated with piracetam (600 mg/kg b.w. oral) for seven constitutive days prior to rotenone administration (intracerebroventricular, 12 µg) in rat brain. Rotenone induced oxidative stress was assessed after 1 h and 24 h of rotenone administration. Ex vivo estimations were performed by using two experimental designs. In one experimental design the rat brain homogenate was treated with rotenone (1 mM, 2 mM and 4 mM) and rotenone+piracetam (10 mM) for 1 h. While in second experimental design the rats were pretreated with piracetam for seven consecutive days. On eighth day the rats were sacrificed, brain homogenate was prepared and treated with rotenone (1 mM, 2 mM and 4mM) for 1h. After treatment the glutathione (GSH) and malondialdehyde (MDA) levels were estimated in brain homogenate. In vivo study showed that pretreatment of piracetam offered significant protection against rotenone induced decreased GSH and increased MDA level though the protection was region specific. But the co-treatment of piracetam with rotenone did not offer significant protection against rotenone induced oxidative stress in ex vivo study. Whereas ex vivo experiments in rat brain homogenate of piracetam pretreated rats, showed the significant protection against rotenone induced oxidative stress. Findings indicated that pretreatment of piracetam significantly attenuated the rotenone induced oxidative stress though the protection was region specific. Piracetam treatment to rats led to its absorption and accumulation in different brain regions as assessed by liquid chromatography mass spectrometry/mass spectrometry. In conclusion, study indicates the piracetam is able to enhance the antioxidant capacity in brain cells in region specific manner. The study is also revealing the rationale for its clinical use in cognitive impairment and other neurological diseases.

microRNAs: role in leukemia and their computational perspective.

MicroRNAs (miRNAs) belong to the family of noncoding RNAs (ncRNAs) and had gained importance due to its role in complex biochemical pathways. Changes in the expression of protein coding genes are the major cause of leukemia. Role of miRNAs as tumor suppressors has provided a new insight in the field of leukemia research. Particularly, the miRNAs mediated gene regulation involves the modulation of multiple mRNAs and cooperative action of different miRNAs to regulate a particular gene expression. This highly complex array of regulatory pathway network indicates the great possibility in analyzing and identifying novel findings. Owing to the conventional, slow experimental identification process of miRNAs and their targets, the last decade has witnessed the development of a large amount of computational approaches to deal with the complex interrelations present within biological systems. This article describes the various roles played by miRNAs in regulating leukemia and the role of computational approaches in exploring new possibilities.

Hematological malignancies: role of miRNAs and their in silico aspects.

Hematological malignancies is a broad term that includes blood cell cancers including chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), Myelodysplastic syndrome, acute lymphocytic leukemia (ALL), multiple myelomas (MM) and lymphomas. miRNAs are ~22-nt long non-coding RNAs that play a very important role in gene regulation by binding to mRNA at their complementary sequence. These miRNAs are conceptually connected with various signal and pathway networks that make them capable of regulating various diseases including hematological malignancies. These miRNAs are not only playing regulatory roles in hematological malignancies, but are also providing new potent markers for efficient diagnosis and prognosis for hematological malignancies patients. Since the discovery of very first miRNA, the importance and role of miRNAs have been established in various fields, and there is a need to search for new potent miRNAs and their targets. A large amount of sequence data have been generated in last few years, which has further generated the need to develop efficient and reliable computational tools to analyze and extract out relevant information promptly from raw data. Here, we review various possible roles played by miRNA in hematological malignancies, principles involved in miRNA gene identification, target prediction and their preceding role in hematological malignancies research.