Amplification editing enables efficient and precise duplication of DNA from short sequence to megabase and chromosomal scale.

Duplication is a foundation of molecular evolution and a driver of genomic and complex diseases. Here, we develop a genome editing tool named Amplification Editing (AE) that enables programmable DNA duplication with precision at chromosomal scale. AE can duplicate human genomes ranging from 20 bp to 100 Mb, a size comparable to human chromosomes. AE exhibits activity across various cell types, encompassing diploid, haploid, and primary cells. AE exhibited up to 73.0% efficiency for 1 Mb and 3.4% for 100 Mb duplications, respectively. Whole-genome sequencing and deep sequencing of the junctions of edited sequences confirm the precision of duplication. AE can create chromosomal microduplications within disease-relevant regions in embryonic stem cells, indicating its potential for generating cellular and animal models. AE is a precise and efficient tool for chromosomal engineering and DNA duplication, broadening the landscape of precision genome editing from an individual genetic locus to the chromosomal scale.

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future.

Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. SIGNIFICANCE STATEMENT: Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.

Efficient targeted insertion of large DNA fragments without DNA donors.

Targeted insertion of large DNA fragments holds great potential for treating genetic diseases. Prime editors can effectively insert short fragments (~44 bp) but not large ones. Here we developed GRAND editing to precisely insert large DNA fragments without DNA donors. In contrast to prime editors, which require reverse transcription templates hybridizing with the target sequence, GRAND editing employs a pair of prime editing guide RNAs, with reverse transcription templates nonhomologous to the target site but complementary to each other. This strategy exhibited an efficiency of up to 63.0% of a 150-bp insertion with minor by-products and 28.4% of a 250-bp insertion. It allowed insertions up to ~1 kb, although the efficiency remains low for fragments larger than 400 bp. We confirmed efficient insertion in multiple genomic loci of several cell lines and non-dividing cells, which expands the scope of genome editing to enable donor-free insertion of large DNA sequences.

Design and synthesis of hemicyanine-based NIRF probe for detecting Aß aggregates in Alzheimer's disease.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, has garnered increased attention due to its substantial economic burden and the escalating global aging phenomenon. Amyloid-ß deposition is a key pathogenic marker observed in the brains of Alzheimer's sufferers. Based on real-time, safe, low-cost, and commonly used, near-infrared fluorescence (NIRF) imaging technology have become an essential technique for the detection of AD in recent years. In this work, NIRF probes with hemicyanine structure were designed, synthesized and evaluated for imaging Aß aggregates in the brain. We use the hemicyanine structure as the parent nucleus to enhance the probe's optical properties. The introduction of PEG chain is to improve the probe's brain dynamice properties, and the alkyl chain on the N atom is to enhance the fluorescence intensity of the probe after binding to the Aß aggregates as much as possible. Among these probes, Z2, Z3, Z6, X3, X6 and T1 showed excellent optical properties and high affinity to Aß aggregates (Kd = 24.31 âˆ¼ 59.60 nM). In vitro brain section staining and in vivo NIRF imaging demonstrated that X6 exhibited superior discrimination between Tg mice and WT mice, and X6 has the best brain clearance rate. As a result, X6 was identified as the optimal probe. Furthermore, the docking theory calculation results aided in describing X6's binding behavior with Aß aggregates. As a high-affinity, high-selectivity, safe and effective probe of targeting Aß aggregates, X6 is a promising NIRF probe for in vivo detection of Aß aggregates in the AD brain.

Iterative Synthesis of Contorted Macromolecular Ladders for Fast-Charging and Long-Life Lithium Batteries.

We report here an iterative synthesis of long helical perylene diimide (hPDI[n]) nanoribbons with a length up to 16 fused benzene rings. These contorted, ladder-type conjugated, and atomically precise nanoribbons show great potential as organic fast-charging and long-lifetime battery cathodes. By tuning the length of the hPDI[n] oligomers, we can simultaneously modulate the electrical conductivity and ionic diffusivity of the material. The length of the ladders adjusts both the conjugation for electron transport and the contortion for lithium-ion transport. The longest oligomer, hPDI[6], when fabricated as the cathode in lithium batteries, features both high electrical conductivity and high ionic diffusivity. This electrode material exhibits a high power density and can be charged in less than 1 min to 66% of its maximum capacity. Remarkably, this material also has exceptional cycling stability and can operate for up to 10,000 charging-discharging cycles without any appreciable capacity decay. The design principles described here chart a clear path for organic battery electrodes that are sustainable, fast-charging, and long lasting.

Molecular targeting therapies for neuroblastoma: Progress and challenges.

There is an urgent need to identify novel therapies for childhood cancers. Neuroblastoma is the most common pediatric solid tumor, and accounts for ~15% of childhood cancer-related mortality. Neuroblastomas exhibit genetic, morphological and clinical heterogeneity, which limits the efficacy of existing treatment modalities. Gaining detailed knowledge of the molecular signatures and genetic variations involved in the pathogenesis of neuroblastoma is necessary to develop safer and more effective treatments for this devastating disease. Recent studies with advanced high-throughput "omics" techniques have revealed numerous genetic/genomic alterations and dysfunctional pathways that drive the onset, growth, progression, and resistance of neuroblastoma to therapy. A variety of molecular signatures are being evaluated to better understand the disease, with many of them being used as targets to develop new treatments for neuroblastoma patients. In this review, we have summarized the contemporary understanding of the molecular pathways and genetic aberrations, such as those in MYCN, BIRC5, PHOX2B, and LIN28B, involved in the pathogenesis of neuroblastoma, and provide a comprehensive overview of the molecular targeted therapies under preclinical and clinical investigations, particularly those targeting ALK signaling, MDM2, PI3K/Akt/mTOR and RAS-MAPK pathways, as well as epigenetic regulators. We also give insights on the use of combination therapies involving novel agents that target various pathways. Further, we discuss the future directions that would help identify novel targets and therapeutics and improve the currently available therapies, enhancing the treatment outcomes and survival of patients with neuroblastoma.

Foliar uptake and transport of atmospheric trace metals bounded on particulate matters in epiphytic Tillandsia brachycaulos.

Epiphytic Tillandsia species are uniquely suitable for the study of foliar uptake of atmospheric trace metals (ATM) because these plants can only rely on their leaves for this purpose. Therefore, we analyzed the uptake and transport of different metals (Fe, Al, Zn, Mn, Ba, Ti, Cu, Ni, Cr, Sn, Pb, Co, As, and Se) bounded on atmospheric particulate matters (APM) in Tillandsia brachycaulos Schltdl. The results showed that the metal contents inside leaves significantly (p < .05) increased after APM exposure. There was a significant (p < .05) positive correlation between the content of 14 trace metals accumulated on the leaf surface and inside the leaf, which indicated that APM is the main source of ATM uptake. The subcellular analysis showed that the Pb, Cu, Ni, Zn, and Cr absorbed by T. brachycaulos were stored primarily in the cell walls and organelles. After the removal of foliar trichomes of T. brachycaulos, the metal contents on the leaf surface decreased, whereas the contents of most metals inside the leaf increased. This is an evidence that foliar trichomes serve a protective function by intercepting ATM onto the leaf surface.Novelty statementsThere was a significant positive correlation between the contents of 14 trace metals accumulated on the leaf surface and in the leaf of T. brachycaulos, which indicated that atmospheric particulate matters are the main source of trace metals in the leaves.After the removal of foliar trichomes of T. brachycaulos, the trace metal contents on the leaf surface decreased, whereas the contents of most trace metals inside the leaf increased. This is an evidence that foliar trichomes serve a protective function by intercepting atmospheric trace metals onto the leaf surface.

Genomic Space of MGMT in Human Glioma Revisited: Novel Motifs, Regulatory RNAs, NRF1, 2, and CTCF Involvement in Gene Expression.

BACKGROUND: The molecular regulation of increased MGMT expression in human brain tumors, the associated regulatory elements, and linkages of these to its epigenetic silencing are not understood. Because the heightened expression or non-expression of MGMT plays a pivotal role in glioma therapeutics, we applied bioinformatics and experimental tools to identify the regulatory elements in the MGMT and neighboring EBF3 gene loci. RESULTS: Extensive genome database analyses showed that the MGMT genomic space was rich in and harbored many undescribed RNA regulatory sequences and recognition motifs. We extended the MGMT's exon-1 promoter to 2019 bp to include five overlapping alternate promoters. Consensus sequences in the revised promoter for (a) the transcriptional factors CTCF, NRF1/NRF2, GAF, (b) the genetic switch MYC/MAX/MAD, and (c) two well-defined p53 response elements in MGMT intron-1, were identified. A putative protein-coding or non-coding RNA sequence was located in the extended 3' UTR of the MGMT transcript. Eleven non-coding RNA loci coding for miRNAs, antisense RNA, and lncRNAs were identified in the MGMT-EBF3 region and six of these showed validated potential for curtailing the expression of both MGMT and EBF3 genes. ChIP analysis verified the binding site in MGMT promoter for CTCF which regulates the genomic methylation and chromatin looping. CTCF depletion by a pool of specific siRNA and shRNAs led to a significant attenuation of MGMT expression in human GBM cell lines. Computational analysis of the ChIP sequence data in ENCODE showed the presence of NRF1 in the MGMT promoter and this occurred only in MGMT-proficient cell lines. Further, an enforced NRF2 expression markedly augmented the MGMT mRNA and protein levels in glioma cells. CONCLUSIONS: We provide the first evidence for several new regulatory components in the MGMT gene locus which predict complex transcriptional and posttranscriptional controls with potential for new therapeutic avenues.

Targeting MDM2 for novel molecular therapy: Beyond oncology.

The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other nonmalignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these nonmalignant diseases. In addition, a better understanding of how MDM2 works in nonmalignant diseases may provide new biomarkers for their diagnosis, prognostic prediction, and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several nonmalignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker.

A Wide-Bandgap Conjugated Polymer Based on Quinoxalino[6,5-f ]quinoxaline for Fullerene and Non-Fullerene Polymer Solar Cells.

A wide-bandgap conjugated polymer, PNQx-2F2T, based on a ring-fused unit of quinoxalino[6,5-f ]quinoxaline (NQx), is synthesized for use as electron donor in polymer solar cells (PSCs). The polymer shows intense light absorption in the range from 300 to 740 nm and favorable energy levels of frontier molecular orbitals. The polymer has afforded decent device performance when blended with either fullerene-based acceptor [6,6]-phenyl-C71 -butylric acid methyl ester ([70]PCBM) or non-fullerene acceptor 3,9-bis(2-methylene-(3-(1,1-dicyanomethylene)-indanone-methyl))-5,5,11,11-tetrakis(4-n-hexylphenyl)-dithieno[2,3-d: 2',3'-d']-s-indaceno[1,2-b:5,6-b']dithiophene (IT-M). The highest PCEs of 7.9% and 7.5% have been achieved for [70]PCBM or IT-M based PSCs, respectively. Moreover, the influence of molecular weight of PNQx-2F2T on solar cell performance has been investigated. It is found that fullerene-based devices prefer higher polymer molecular weight, while non-fullerene devices are not susceptible to the molecular weight of PNQx-2F2T. The device results are extensively explained by electrical and morphological characterizations. This work not only evidences the potential of NQx for constructing high-performance photovoltaic polymers but also demonstrates a useful structure-performance relationship for efficiency enhancement of non-fullerene PSCs via the development of new conjugated polymers.

Prevention of prostate cancer by natural product MDM2 inhibitor GS25: in vitro and in vivo activities and molecular mechanisms.

Prostate cancer remains a major health problem in the USA and worldwide. There is an urgent need to develop novel approaches to preventing primary and metastatic prostate cancer. We have identified 25-OCH3-protopanaxadiol (GS25), the most active ginsenoside that has been identified so far; it has potent activity against human cancers, including prostate cancer. However, it has not been proven if GS25 could be a safe and effective agent for cancer prevention. In this study, we used the TRAMP model and clearly demonstrated that GS25 inhibited prostate tumorigenesis and metastasis with minimal host toxicity. Mechanistically, GS25 directly bound to the RING domain of MDM2, disrupted MDM2-MDMX binding and induced MDM2 protein degradation, resulting in strong inhibition of prostate cancer cell growth and metastasis, independent of p53 and androgen receptor status. In conclusion, our in vitro and in vivo data support the potential use of GS25 in prevention of primary and metastatic prostate cancer.

RNF185 modulates JWA ubiquitination and promotes gastric cancer metastasis.

Gastric cancer (GC) is one of the most common malignant cancers worldwide. Metastasis leads to poor prognoses in GC patients in advanced stages. Our previous studies have demonstrated that JWA functions as a tumour suppressor and that low expression of JWA in GC tissues is significantly correlated with shorter overall survival (OS) as well as with advanced clinicopathologic features in patients. However, the mechanism of dysregulation of JWA in cancers is not clear. In the present study, we found that an E3 ubiquitin ligase, RNF185, directly interacted with JWA and promoted its ubiquitination at the K158 site, resulting in subsequent degradation. Moreover, the protein level of RNF185 was negatively correlated with JWA in tumour tissues from GC patients. High RNF185 expression was significantly correlated with shorter OS. Additionally, increased RNF185 expression facilitated GC cell migration in vitro and promoted GC metastasis in vivo by downregulating JWA expression. However, this effect was reversed by replenishment of JWA. In conclusion, our findings highlight the following: (1) RNF185 promotes GC metastasis by mediating JWA degradation via a ubiquitin-proteasome pathway; (2) the K158 site of JWA is essential for its ubiquitination in GC cells. These findings suggest that RNF185 is a novel candidate prognostic marker and potential therapeutic target for GC.

Synthetic imaging through wavy water surface with centroid evolution.

Imaging through a wavy water surface is a challenging task, as the wavy water surface introduces anisoplanatism effects difficult to model and track. A typical recovery method is usually involving multiple-stage processing on a pre-acquired image sequence. A new progressive restoration scheme is demonstrated, it can run simultaneously with image acquisition and mitigate both distortion and blur progressively. This method extends the anisotropic evolution in lucky region fusion with a novel progressive optical flow based de-warping scheme, centroid evolution. A comparison has been made with other state-of-art techniques, the proposed method can create comparable results, even with much less frames acquired. Experiments with real through-water scenes have also proved the effectiveness of the method.

QSAR Studies of New Pyrido[3,4-b]indole Derivatives as Inhibitors of Colon and Pancreatic Cancer Cell Proliferation.

We have discovered a new class of pyrido[b]bindole derivatives that show potent and broad spectrum anticancer activity with IC50 values down to submicromolar levels. Structure-activity relationship data acquired with the compounds as antiproliferative agents against several cancer cell lines, i.e. human HCT116 colon cancer cell line, and HPAC, Mia-PaCa2 and Panc-1 pancreatic cancer cell lines, were subjected to two different QSAR modeling methods. A kernel-based partial least squares (KPLS) regression analysis with chemical 2D fingerprint descriptors, and a PHASE pharmacophore alignment with 3D-QSAR study. The KPLS method afforded successful predictive QSAR models for antiproliferative activity of the HCT116 colon cell line and on two of the pancreatic cancer cell lines HPAC and Mia-PaCa2, with the following statistics: R 2s of 0.99, 0.99 and 0.98, for training set coefficients of determination, and external test set predictive r 2s of 0.70, 0.58 and 0.70, respectively. The best 2D fingerprint descriptor for both the HCT116 and HPAC data out of the eight finger prints utilized was the atom triplet fingerprint; whereas the one that worked best for the Mia-PaCa2 data was the linear fingerprint descriptor. The PHASE pharmacophore based 3D-QSAR study afforded a four-point pharmacophore model comprising one hydrogen bond donor (D) and three ring (R) elements, which yielded a successful 3D-QSAR model only with the HCT116 cell line data with training set R 2 of 0.683, and an external test set predictive r 2 of 0.562. With the PHASE 3D-QSAR, the influence of electronic effects and hydrophobicity were visualized, and were in agreement with the observed SAR of substitutions, while the KPLS method the relative extent of contribution of each atom in a compound to the activity. These models will foster the lead optimization process for this potent series of anticancer pyrido [3,4-b]indole compounds.

Analysis of threshold current of uniaxially tensile stressed bulk Ge and Ge/SiGe quantum well lasers.

We propose and design uniaxially tensile stressed bulk Ge and Ge/SiGe quantum well lasers with the stress along <100> direction. The micro-bridge structure is adapted for introducing uniaxial stress in Ge/SiGe quantum well. To enhance the fabrication tolerance, full-etched circular gratings with high reflectivity bandwidths of ~500 nm are deployed in laser cavities. We compare and analyze the density of state, the number of states between Γ- and L-points, the carrier injection efficiency, and the threshold current density for the uniaxially tensile stressed bulk Ge and Ge/SiGe quantum well lasers. Simulation results show that the threshold current density of the Ge/SiGe quantum well laser is much higher than that of the bulk Ge laser, even combined with high uniaxial tensile stress owing to the larger number of states between Γ- and L- points and extremely low carrier injection efficiency. Electrical transport simulation reveals that the reduced effective mass of the hole and the small conduction band offset cause the low carrier injection efficiency of the Ge/SiGe quantum well laser. Our theoretical results imply that unlike III-V material, uniaxially tensile stressed bulk Ge outperforms a Ge/SiGe quantum well with the same strain level and is a promising approach for Si-compatible light sources.

Design and analysis of a CMOS-compatible distributed Bragg reflector laser based on highly uniaxial tensile stressed germanium.

We design a CMOS-compatible Distributed Bragg Reflector (DBR) laser based on highly uniaxial tensile stressed germanium. Our design first incorporates three critical elements including high uniaxial tensile stress, low loss optical resonator and heterojunction for electrical injection. A threshold current density of 80 kA/cm2 and an internal quantum efficiency of 8.5% are estimated when the Shockley-Reed-Hall (SRH) lifetime is chosen to be 3 ns. Furthermore, the performance of the DBR laser can be enhanced by improving the crystal quality and carefully designing the p-n junction. The simulation results also indicate that the limitation of the improvement of threshold current density and internal quantum efficiency are 29 kA/cm2 and 19.6%, resulting from the Auger recombination. The influences of strain and n-type doping on the threshold current density and the internal quantum efficiency are discussed. The proposed DBR laser offers a new approach to realize on-chip light source for silicon photonics.

Analysis of acousto-optic interaction based on forward stimulated Brillouin scattering in hybrid phononic-photonic waveguides.

We present the generation of forward stimulated Brillouin scattering (FSBS) in hybrid phononic-photonic waveguides. To confine the optical and acoustic waves simultaneously, a hybrid waveguide is designed by embedding the silicon line defect in the silicon nitride phononic crystal slab. By taking into account three kinds hybrid waveguide, the appropriate structural parameters are obtained to enhance the acousto-optic interaction. We fabricate the honeycomb hybrid waveguide with a CMOS compatible technology. The forward Brillouin frequency shift is measured up to 2.425 GHz and the acoustic Q-factor of the corresponding acoustic mode is 1100. The influences of pump power, acoustic loss, nonlinear optical loss and lattice constant on the acousto-optic interaction in FSBS are analyzed and discussed. The proposed approach has important potential applications in on-chip all-optical signal processing.

Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications.

Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial developmental and physiological processes in the cell. More recently, they have been found to play important roles in human carcinogenesis and cancer development and progression. The deregulation and dysfunction of PcG proteins often lead to blocking or inappropriate activation of developmental pathways, enhancing cellular proliferation, inhibiting apoptosis, and increasing the cancer stem cell population. Genetic and molecular investigations of PcG proteins have long been focused on their PcG functions. However, PcG proteins have recently been shown to exert non-classical-Pc-functions, contributing to the regulation of diverse cellular functions. We and others have demonstrated that PcG proteins regulate the expression and function of several oncogenes and tumor suppressor genes in a PcG-independent manner, and PcG proteins are associated with the survival of patients with cancer. In this review, we summarize the recent advances in the research on PcG proteins, including both the Pc-repressive and non-classical-Pc-functions. We specifically focus on the mechanisms by which PcG proteins play roles in cancer initiation, development, and progression. Finally, we discuss the potential value of PcG proteins as molecular biomarkers for the diagnosis and prognosis of cancer, and as molecular targets for cancer therapy.

Ribosomal proteins and human diseases: pathogenesis, molecular mechanisms, and therapeutic implications.

Ribosomes are essential components of the protein synthesis machinery. The process of ribosome biogenesis is well organized and tightly regulated. Recent studies have shown that ribosomal proteins (RPs) have extraribosomal functions that are involved in cell proliferation, differentiation, apoptosis, DNA repair, and other cellular processes. The dysfunction of RPs has been linked to the development and progression of hematological, metabolic, and cardiovascular diseases and cancer. Perturbation of ribosome biogenesis results in ribosomal stress, which triggers activation of the p53 signaling pathway through RPs-MDM2 interactions, resulting in p53-dependent cell cycle arrest and apoptosis. RPs also regulate cellular functions through p53-independent mechanisms. We herein review the recent advances in several forefronts of RP research, including the understanding of their biological features and roles in regulating cellular functions, maintaining cell homeostasis, and their involvement in the pathogenesis of human diseases. We also highlight the translational potential of this research for the identification of molecular biomarkers, and in the discovery and development of novel treatments for human diseases.

NFAT as cancer target: mission possible?

The NFAT signaling pathway regulates various aspects of cellular functions; NFAT acts as a calcium sensor, integrating calcium signaling with other pathways involved in development and growth, immune response, and inflammatory response. The NFAT family of transcription factors regulates diverse cellular functions such as cell survival, proliferation, migration, invasion, and angiogenesis. The NFAT isoforms are constitutively activated and overexpressed in several cancer types wherein they transactivate downstream targets that play important roles in cancer development and progression. Though the NFAT family has been conclusively proved to be pivotal in cancer progression, the different isoforms play distinct roles in different cellular contexts. In this review, our discussion is focused on the mechanisms that drive the activation of various NFAT isoforms in cancer. Additionally, we analyze the potential of NFAT as a valid target for cancer prevention and therapy.