Enhancer hijacking: Innovative ways of carcinogenesis

Enhancer elements are specific DNA sequences that play a crucial role in regulating gene expression. Located upstream or downstream in the genomic context, enhancers enhance the transcription of linked genes. This is achieved by providing binding sites for transcription factors and other proteins, acting as a nucleation point that promotes the assembly of the transcriptional machinery. What makes enhancers unique is that located even thousands of base pairs away, they can exert their function. They can act over long distances, looping to interact with the promoter region of their target genes. Enhancers are often involved in cell type-specific gene expression as different cells express different sets of genes by activating and repressing cell type-specific enhancers. Cancer cells seem to co-opt this mechanism and hijack it for their own survival. In this process, an aberrant enhancer element activates the transcription of oncogenes (genes that have the potential to cause cancer) due to some alterations in genomic structure or regulatory elements that happen in cancer, contributing to tumorigenesis and cancer progression. Enhancer hijacking often occurs through complex genomic rearrangements such as chromosomal translocations and other structural rearrangements such as deletions or amplifications.8 These alterations can bring a usually distant, far-located enhancer into proximity with an oncogene, leading to its inappropriate activation. This is often seen in various cancers, including leukemias and solid tumors. Enhancer hijacking and its effects on gene regulation in cancer are frequently studied using methods such as RNA sequencing, chromatin conformation capture, and CRISPR-Cas9. Finding an enhancer hijacking event may be used to inform treatment choices, especially in precision medicine settings, and may also function as a biomarker for particular cancer types

Maternal dietary habit influences fetal life

Diet and nutrition have a tremendous influence on health and disease. Dietary constituents can affect health and have been known to supplement with essential nutrients, minerals, and calories for physiological homeostasis. However, diet can also affect gene expression through epigenetic reprogramming or by altering the level of micronutrients. While a nutrigenomics study has delineated this causal link, a recent study published in EMBO Molecular Medicine by Grant et al. went a step further to establish that maternal intake of dietary fibers can alter the fetal gut microbiome, influencing the diversity of the intestinal bacterial flora, thereby affecting the gut-brain axis. Although the relationship between diet and fertility in males and females has been reported, the effect on postnatal life is not well documented. In this study by Grant et al. at the (Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg), the authors reported that selected feeding of fiber-free diets to pregnant mice alters the gut microbiome composition of their neonate pups depriving them of protective and beneficial commensal, Akkermansia muciniphila, a mucin-foraging bacterium. Further, these animals exhibited heightened immune activity by enriching defense response pathways and IL-22 expression. Therefore, the protective role of A. muciniphila is associated with its protection against chronic inflammation through TLR4 signaling. The author’s study has far-reaching conclusions on improving human health outcomes by the rational choice of food, drugs, and lifestyle to prevent gut dysbiosis and colonization of the right microbiome

The obesity-cancer nexus: A growing global health crisis demanding urgent action

The intersection of obesity and cancer represents a critical global health crisis requiring urgent attention and coordinated intervention strategies. With over 650 million adults worldwide classified as obese, epidemiological evidence demonstrates that excess adiposity significantly increases risk for at least 13 cancer types, accounting for approximately 3.9% of global cancer cases and potentially contributing to over 500,000 additional annual cases by 2030. The pathophysiological mechanisms underlying this relationship are complex and multifactorial, involving chronic inflammatory processes characterized by elevated pro-inflammatory cytokines, hormonal dysregulation including increased estrogen production through enhanced aromatase activity, insulin resistance leading to hyperinsulinemia and elevated insulin-like growth factor-1 levels, and adipokine imbalances that create pro-carcinogenic cellular environments. These biological perturbations facilitate malignant transformation through DNA damage, enhanced angiogenesis, immune surveillance suppression, and promotion of cellular proliferation while inhibiting apoptotic mechanisms. Beyond cancer incidence, obesity adversely affects treatment outcomes, increasing chemotherapy toxicity, surgical complications, and reducing overall survival rates across multiple cancer types. Despite robust scientific evidence establishing these connections, current healthcare approaches inadequately integrate obesity management into cancer prevention strategies, treating these conditions as separate entities rather than interconnected health challenges. This fragmentation undermines prevention efforts and limits intervention effectiveness, contributing to substantial economic burdens estimated in billions of dollars annually. Addressing this dual epidemic requires comprehensive, multisectoral approaches including integration of weight management into routine cancer screening protocols, development of precision prevention strategies through risk profiling, implementation of population-level policy interventions targeting obesogenic environments, and enhanced medical education emphasizing the obesity-cancer nexus. The modifiable nature of body weight through lifestyle interventions and policy changes presents unprecedented opportunities for preventable cancer reduction, making coordinated action imperative for reducing the global burden of both obesity and cancer

Tree elements: Branching hopes after tissue injury in regenerative medicine

Humans are poor model systems for studying tissue regeneration. Unlike their amphibians or rodent counterparts, humans are deficient in this quality, making the repair process following a tissue injury infrequent and limited. Most human tissues or organs, except the liver, lack in their regenerative potential. This tends to be a serious problem in organ damage until recently with the identification of enhancer regulatory elements that engage in regenerating tissue. Tissue regeneration enhancer elements (TREEs) trigger gene expression in injury sites and can be engineered to modulate the regenerative potential of vertebrate organs. TREE orchestrates selective gene expression at the injury sites, thereby modulating the regenerative activities and potential of vertebrate organs. Using a genetic screen of a zebrafish-based tissue injury model, Kang et al., identified the gene expression signature associated with regeneration. This concept is being tried and tested to see its possibility in regenerating injured myocardium following myocardium infraction leading to ischemia and tissue damage. TREEs displayed specificity and efficacy in a systemically delivered recombinant AAV vector system in mice and can be used as a gene-therapy module to repair damaged tissue. A team of researchers at the Duke School of Medicine, USA, headed by Ken Poss, reported their findings in cell stem cell, 2022. These researchers further took a step ahead to actually orchestrate a damaged myocardium repair and the growth of new muscles to restore normal cardiac function. Even more spectacular is that tissue growth is selective only at injury sites and becomes quiescent once the damage is repaired. HOW THIS MAY IMPACT REGENERATIVE MEDICINE Using a TREE-based system, one can attempt to use gene therapy with viral vectors to enhance heart tissue cell proliferation and growth, thus improving cardiac regeneration. This system will further strengthen by incorporating better gene payloads, thereby opening new possibilities to rescue scar tissue and restore function. According to the World Health Organization, MI-related death in India accounts for one-fifth of deaths worldwide, which is alarmingly higher in the younger population. The age-standardized cardiovascular disease (CVD) death rate of 272/100,000 in India is much higher than the global average of 235. Under these circumstances, these findings seem extremely relevant. Although we may not fix a broken heart, engineered TREE elements might at least fix a damaged myocardium branching hopes for numerous suffering from CVD

Extrachromosomal DNA : New Players in Oncology

DNA that is found outside the main chromosomes in a cell's nucleus is known as extrachromosomal DNA. This type of DNA is not part of the standard 23 pairs of chromosomes in humans and instead exists as standalone circular or linear DNA structures. Unlike bacterial plasmids, extrachromosomal DNA in human cells contains important genetic material and holds particular significance in cancer cells. Critical characteristics of ecDNA in Cancer is that they frequently harbour amplified versions of oncogenes such as MYC, EGFR, and CCND1. These oncogenes propel the growth and survival of tumors. Cancer cells utilize ecDNA to generate multiple copies of these oncogenes, amplifying their expression without requiring alterations to the chromosomal structure. This amplification grants the cancer cells a competitive edge in growth. ecDNA plays a crucial role in the advancement and growth of cancer, as it amplifies oncogenes, genetic diversity, and resistance to treatments. Its adaptable and ever-changing characteristics empower cancer cells to adjust to external influences such as medication. Gaining insights into ecDNA's operations and impacts could lead to new possibilities for diagnosing and treating cancer, as well as developing therapies aimed at this distinct DNA structure

Checkmate with checkpoint inhibitors: New paradigm in immunotherapy

Cancer immunotherapy is a form of biotherapy (also called biological response modifier therapy) that refers to a broad array of anti-cancer therapies targeted to activate and trigger the body’s immune system against cancer. This includes targeted antibodies to specific cell surface entities on cancer cells, anti-cancer vaccines like vaccines against HPV in cervical cancer, cytolytic virus, adoptive cell transfer, biologicals like cytokines and other small molecular agents, and the most explored immune checkpoint inhibitors. Immunotherapies use immune modulatory materials from the same organism to fight disease, while some immunotherapy treatments use genetic engineering-based gene editing approaches to enhance the host immune system in an effort to eradicate the cancer cells and boost its cancer-fighting capabilities. Used in combination with surgery, chemotherapy, and radiotherapy, cancer immunotherapy improves their overall effectiveness. WHAT IS AN IMMUNE CHECKPOINT T cell activation involves the engagement of a number of signaling cascades, originating from the interaction between T cell receptors (TCR) with antigen-presenting cells (APC) that ultimately determine cell fate through regulating cytokine production, cell survival, proliferation, and differentiation. TCR alone is not sufficient to generate an adequate response. It needs the participation of coreceptors. Primary T cell activation involves the integration of three distinct signals (1) antigen recognition in the presence of APC, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. To make sure that these activated T cells do not cross-react with self-antigens, these are rendered inactive by immune checkpoints. PDL on T cells and PDL1 on host cells engage in bringing about this. Programmed Cell Death Protein 1 (PD-1) inhibits immune responses by fostering a state of self-tolerance. This is achieved by activating apoptosis, anergy, and avoidance of antigen-specific T cells. The functional counterpart of PD-1, the Programmed Cell Death Ligand 1 (PD-L1), is a trans-membrane protein that acts as a coinhibitory immune response factor. This is what the cancer cells hijack for their survival. PD-L1 expressed on cancer cells attenuates the host T cell response transmitting negative signals. Therefore, the PD-1/PD-L1 axis is the main driver of cancer immune evasion, which needs serious attention. WHAT IS IMMUNE CHECKPOINT INHIBITORS These classes of molecules are designed to block the cross-talks between cancer cells expressing PD-L1 with T cells expressing PD-1 receptors. When the interaction is blocked, inhibitory influence on T-cells is circumvented, and an attack may be launched. Checkpoint inhibitors are used in cancer immunotherapy, including a wide range of cancers, such as melanoma, skin cancer, and lung cancer. Different drug classes block checkpoint proteins like CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors. Commercially checkpoint inhibitors include pembrolizumab (Keytruda), ipilimumab (Yervoy), nivolumab (Opdivo), and atezolizumab (Tecentriq). RAYS OF HOPE AND CAUTION Because checkpoint inhibitors stimulate the immune system and are immunomodulatory, their usage has significantly improved cancer treatment and management, extending the life span for numerous patients. However, we need to be cautious as they may cause immune cells to attack healthy cells, causing side effects such as fatigue, nausea, high fever, flu-like symptoms, and inflammation

Therapeutic siRNAs: small molecules with bigger function

In the realm of molecular medicine, therapeutic small-interfering RNA (siRNA) is a promising class of molecules with exciting new opportunities in healthcare. An essential component of RNA interference (RNAi) is siRNA. In clinical setup, siRNA may be engineered to specifically target genes linked to certain diseases, providing a focused and accurate method of modulating gene expression. Many important factors characterize the use of therapeutic siRNA. Target gene expression is selectively silenced by therapeutic siRNA through the use of the RNAi pathway. Guided by corresponding messenger RNA (mRNA) sequences, the double-stranded siRNA molecule is integrated into the RNA-induced silencing complex (RISC). This mechanism causes translational repression or mRNA cleavage, which in turn causes the relevant protein to be downregulated. Therapeutic siRNA is a promising avenue in several areas. siRNA can be used in oncology to target oncogenes or other important regulators, inhibiting cancer cell proliferation. Furthermore, by modifying the expression of genes linked to disease, siRNA may be used to treat viral infections, neurological conditions, and other rare and hereditary diseases. The selectivity of therapeutic siRNA is one of its main advantages. siRNA sequences can be engineered and customized to target specific genes linked to different diseases like cancer or genetic disorders. This focused strategy improves the accuracy of the therapeutic intervention and reduces off-target effects. In a recent article by Nissen et al., siRNA targeting LP(a) in a trial with 48 participants without cardiovascular disease and with lipoprotein(a) concentrations of 75 nmol/L or greater (or ≥30 mg/dL), was used to evaluate its tolerability and efficacy to reduce LP(a). Results showed that Lepodisiran was found to be well tolerated and resulted in dose-dependent, long-lasting reduction in serum lipoprotein(a) concentrations in phase 1 trial with elevated lipoprotein(a) levels. Therapeutic siRNA-based diagnosis is rapidly advancing, and several siRNA-based medications are now entering clinical trials. These trials aim to assess the pharmacokinetics, safety, and effectiveness of siRNA therapeutics in human subjects, offering crucial new information about their potential as a treatment option. Despite the therapeutic potential of siRNA, clinical translation of siRNA faces a challenge in its effective delivery. Naked siRNA molecules are more likely to degrade with a poor half-life and poor cellular uptake. Therefore, to increase the stability and delivery of therapeutic siRNA to target cells, a variety of delivery systems, such as lipid nanoparticles, viral vectors, and polymer-based carriers, are being investigated

Depression and anemia: Missing link

Anemia has been a significant public health concern in India, especially among women and children. The National Family Health Survey (NFHS) is one of the primary sources of health-related data in India. The NFHS-4, conducted in 2015–2016, reported that around 53% of women aged 15–49 in India were anemic. The symptoms of depression, a serious psychiatric condition, include low mood, energy loss, low self-esteem, and both physical and psychological sluggishness. According to the 2019 Global Burden of Disease Study, depression is one of the most incapacitating mental diseases. Depression and related psychological illnesses and physical discomfort have an impact on the health and quality of life. Although seems disconnected, there are some potential molecular links between depression and anemia. Both depression and anemia are associated with inflammation. Chronic inflammation has the potential to impact the generation and operation of red blood cells in anemia, as well as play a role in neuroinflammation that affects neurotransmitter systems linked to depression, such as serotonin and dopamine pathways. Depression is often associated with irregularities in neurotransmitters such as serotonin, dopamine, and norepinephrine, which not only influence mood but also have implications for erythropoiesis and iron metabolism. The dysregulation of the HPA axis in depression can result in heightened cortisol levels and changes in stress response, affecting erythropoiesis and iron metabolism, thus contributing to anemia. Nutritional deficiencies, particularly in Vitamins B12 and folate, can also lead to both anemia and mood disturbances, including symptoms of depression, as these nutrients are crucial for proper erythropoiesis and neurotransmitter synthesis. We, however, need to note that not all cases of depression or anemia are directly linked in every individual. The relationship between these conditions can be complex and multifactorial, influenced by various genetic, environmental, and physiological factors. What is more important is that there are real possibilities of a potential cross-talk between the two. Managing anemia in women is therefore of prime importance both for health issues as well as for mood and psychological well-being

How maternal caring affects longevity

When it comes to longevity, everyone wants to live for eternity. Longevity research has often led scientists to dark alleys with several candidate molecules responsible for aging. Pioneering genetic studies on model organisms like Caenorhabditis elegans and Drosophila melanogaster discovered the most well-conserved longevity pathways, mainly caloric restriction and the insulin/insulin-like growth factor 1signaling pathways. Apart from these complex molecular circuitries that drive longevity, a recent study published by Zipple et al. (Proceedings of the National Academy of Sciences, 2024) showed that the relationship between mother and grandmother with the child may determine why some animals and humans live longer than expected for their size. Animals that spend more time with their mothers during early life end up living longer but with reduced capacity to produce offspring. This exciting piece of research has far more consequences than just these findings. It implies the importance of the mother in one’s life and the role of parental care in providing longevity and reproductive success

Monobodies and nanobodies: The era of diagnostic miniature antibodies

Monobodies, as the name suggests, are the simplest synthetic version of antibodies engineered to mimic antibodies (antibody mimetics) without their complexity. These are constructed using a fibronectin type III domain (FN3) as a molecular scaffold. With a molecular mass of not more than 20 kDA at max, monobodies are excellent tools for in-vivo diagnosis. Unlike the conventional Ab that needs particular treatment protocols to enable them to enter into cells, mono, and nano bodies can be expressed inside the cells with expression cassettes. With high affinity and selectivity, mono and nanobodies can be developed in the shortest possible time with ease that otherwise can't be done by conventional antibodies. Produced from combinatorial libraries and diversified using phage display techniques, monobodies can be generated that are highly specific for their intracellular targets, like monobodies to detect COVID antigens. Similarly, monobodies against KRAS mutants using protein engineering technologies can be sued to detect mutant KRAS in solid tumors. They have a strong tendency to bind to functional sites of specific intracellular target proteins and thus exhibits drug-like properties as well as specific `inhibitors. Monobodies are evolving with additional diverse functions and may soon be used as am indispensable tool in biology and medicine