The emerging regulatory roles of non-coding RNAs associated with glucose metabolism in breast cancer.

Altered energy metabolism is one of the hallmarks of tumorigenesis and essential for fulfilling the high demand for metabolic energy in a tumor through accelerating glycolysis and reprogramming the glycolysis metabolism through the Warburg effect. The dysregulated glucose metabolic pathways are coordinated not only by proteins coding genes but also by non-coding RNAs (ncRNAs) during the initiation and cancer progression. The ncRNAs are responsible for regulating numerous cellular processes under developmental and pathological conditions. Recent studies have shown that various ncRNAs such as microRNAs, circular RNAs, and long noncoding RNAs are extensively involved in rewriting glucose metabolism in human cancers. In this review, we demonstrated the role of ncRNAs in the progression of breast cancer with a focus on outlining the aberrant expression of glucose metabolic pathways. Moreover, we have discussed the existing and probable future applications of ncRNAs to regulate energy pathways along with their importance in the prognosis, diagnosis, and future therapeutics for human breast carcinoma.

AI-enhanced adsorption modeling: Challenges, applications, and bibliographic analysis.

Inorganic and organic contaminants, such as fertilisers, heavy metals, and dyes, are the primary causes of water pollution. The field of artificial intelligence (AI) has received significant interest due to its capacity to address challenges across various fields. The use of AI techniques in water treatment and desalination has recently shown useful for optimising processes and dealing with the challenges of water pollution and scarcity. The utilization of AI in the water treatment industry is anticipated to result in a reduction in operational expenditures through the lowering of procedure costs and the optimisation of chemical utilization. The predictive capabilities of artificial intelligence models have accurately assessed the efficacy of different adsorbents in removing contaminants from wastewater. This article provides an overview of the various AI techniques and how they can be used in the adsorption of contaminants during the water treatment process. The reviewed publications were analysed for their diversity in journal type, publication year, research methodology, and initial study context. Citation network analysis, an objective method, and tools like VOSviewer are used to find these groups. The primary issues that need to be addressed include the availability and selection of data, low reproducibility, and little proof of uses in real water treatment. The provision of challenges is essential to ensure the prospective success of AI associated with technologies. The brief overview holds importance to everyone involved in the field of water, encompassing scientists, engineers, students, and stakeholders.

Bacteria as a treasure house of secondary metabolites with anticancer potential.

Cancer stands in the frontline among leading killers worldwide and the annual mortality rate is expected to reach 16.4 million by 2040. Humans suffer from about 200 different types of cancers and many of them have a small number of approved therapeutic agents. Moreover, several types of major cancers are diagnosed at advanced stages as a result of which the existing therapies have limited efficacy against them and contribute to a dismal prognosis. Therefore, it is essential to develop novel potent anticancer agents to counteract cancer-driven lethality. Natural sources such as bacteria, plants, fungi, and marine microorganisms have been serving as an inexhaustible source of anticancer agents. Notably, over 13,000 natural compounds endowed with different pharmacological properties have been isolated from different bacterial sources. In the present article, we have discussed about the importance of natural products, with special emphasis on bacterial metabolites for cancer therapy. Subsequently, we have comprehensively discussed the various sources, mechanisms of action, toxicity issues, and off-target effects of clinically used anticancer drugs (such as actinomycin D, bleomycin, carfilzomib, doxorubicin, ixabepilone, mitomycin C, pentostatin, rapalogs, and romidepsin) that have been derived from different bacteria. Furthermore, we have also discussed some of the major secondary metabolites (antimycins, chartreusin, elsamicins, geldanamycin, monensin, plicamycin, prodigiosin, rebeccamycin, salinomycin, and salinosporamide) that are currently in the clinical trials or which have demonstrated potent anticancer activity in preclinical models. Besides, we have elaborated on the application of metagenomics in drug discovery and briefly described about anticancer agents (bryostatin 1 and ET-743) identified through the metagenomics approach.

A comprehensive review of the multifaceted role of the microbiota in human pancreatic carcinoma.

Pancreatic carcinoma is associated with one of the worst clinical outcomes throughout the globe because of its aggressive, metastatic, and drug-resistant nature. During the past decade, several studies have shown that oral, gut, and tumor microbiota play a critical role in the modulation of metabolism and immune responses. Growing pieces of evidence have proved beyond a doubt that the microbiota has a unique ability to influence the tumor microenvironment as well as the metabolism of chemotherapeutic agents or drugs. Given this, microbiota, known as the ecological community of microorganisms, stands to be an avenue of quality research. In this review, we provide detailed and critical information on the role of oral, gut, and pancreatic microbiota disruptions in the development of pancreatic carcinoma. Moreover, we comprehensively discuss the different types of microbiota, their potential role, and mechanism associated with pancreatic carcinoma. The microbiome provides the unique opportunity to enhance the effectiveness of chemotherapeutic agents and immunotherapies for pancreatic cancer by maintaining the right type of microbiota and holds a promising future to enhance the clinical outcomes of patients with pancreatic carcinoma.

Plant lectins and their usage in preparing targeted nanovaccines for cancer immunotherapy.

Plant lectins, a natural source of glycans with a therapeutic potential may lead to the discovery of new targeted therapies. Glycans extracted from plant lectins are known to act as ligands for C-type lectin receptors (CLRs) that are primarily present on immune cells. Plant-derived glycosylated lectins offer diversity in their N-linked oligosaccharide structures that can serve as a unique source of homogenous and heterogenous glycans. Among the plant lectins-derived glycan motifs, Man9GlcNAc2Asn exhibits high-affinity interactions with CLRs that may resemble glycan motifs of pathogens. Thus, such glycan domains when presented along with antigens complexed with a nanocarrier of choice may bewilder the immune cells and direct antigen cross-presentation - a cytotoxic T lymphocyte immune response mediated by CD8+ T cells. Glycan structure analysis has attracted considerable interest as glycans are looked upon as better therapeutic alternatives than monoclonal antibodies due to their cost-effectiveness, reduced toxicity and side effects, and high specificity. Furthermore, this approach will be useful to understand whether the multivalent glycan presentation on the surface of nanocarriers can overcome the low-affinity lectin-ligand interaction and thereby modulation of CLR-dependent immune response. Besides this, understanding how the heterogeneity of glycan structure impacts the antigen cross-presentation is pivotal to develop alternative targeted therapies. In the present review, we discuss the findings on structural analysis of glycans from natural lectins performed using GlycanBuilder2 - a software tool based on a thorough literature review of natural lectins. Additionally, we discuss how multiple parameters like the orientation of glycan ligands, ligand density, simultaneous targeting of multiple CLRs and design of antigen delivery nanocarriers may influence the CLR targeting efficacy. Integrating this information will eventually set the ground for new generation immunotherapeutic vaccine design for the treatment of various human malignancies.

Overexpression of laminin-5 gamma-2 promotes tumorigenesis of pancreatic ductal adenocarcinoma through EGFR/ERK1/2/AKT/mTOR cascade.

Pancreatic ductal adenocarcinoma (PDAC) is correlated with poor outcomes because of limited therapeutic options. Laminin-5 gamma-2 (LAMC2) plays a critical role in key biological processes. However, the detailed molecular mechanism and potential roles of LAMC2 in PDAC stay unexplored. The present study examines the essential role and molecular mechanisms of LAMC2 in the tumorigenesis of PDAC. Here, we identified that LAMC2 is significantly upregulated in microarray cohorts and TCGA RNA sequencing data of PDAC patients compared to non-cancerous/normal tissues. Patients with higher transcript levels of LAMC2 were correlated with clinical stages; dismal overall, as well as, disease-free survival. Additionally, we confirmed significant upregulation of LAMC2 in a panel of PDAC cell lines and PDAC tumor specimens in contrast to normal pancreatic tissues and cells. Inhibition of LAMC2 significantly decreased cell growth, clonogenic ability, migration and invasion of PDAC cells, and tumor growth in the PDAC xenograft model. Mechanistically, silencing of LAMC2 suppressed expression of ZEB1, SNAIL, N-cadherin (CDH2), vimentin (VIM), and induced E-cadherin (CDH1) expression leading to a reversal of mesenchymal to an epithelial phenotype. Interestingly, co-immunoprecipitation experiments demonstrated LAMC2 interaction with epidermal growth factor receptor (EGFR). Further, stable knockdown of LAMC2 inhibited phosphorylation of EGFR, ERK1/2, AKT, mTOR, and P70S6 kinase signaling cascade in PDAC cells. Altogether, our findings suggest that silencing of LAMC2 inhibited PDAC tumorigenesis and metastasis through repression of epithelial-mesenchymal transition and modulation of EGFR/ERK1/2/AKT/mTOR axis and could be a potential diagnostic, prognostic, and therapeutic target for PDAC.

Arsenicum album Induces Cell Cycle Arrest and Apoptosis, and Inhibits Epithelial-Mesenchymal Transition in Hormone-Dependent MCF7 Breast Cancer Cells.

BACKGROUND: Arsenic trioxide (As2O3) has been in therapeutic use since the 18th century for various types of cancers including skin and breast; however, it gained popularity following FDA approval for its use against acute promyelocytic leukemia. This present work was designed to evaluate the anti-cancer potential of a homeopathic potency of arsenic trioxide (Arsenicum album 6C) in hormone-dependent breast cancer. METHODS: Breast cancer cells (MCF7) were treated with Arsenicum album (Ars 6C) to evaluate its anti-proliferative and apoptotic potential. We examined the effect of Ars 6C on the cell cycle, wound healing, reactive oxygen species (ROS) generation, and modulation of expression of key genes which are aberrant in cancer. RESULTS: Treating breast cancer cells with Ars 6C halted the cell cycle at the sub-G0 and G2/M phases, which could be attributed to DNA damage induced by the generation of ROS. Apoptotic induction was associated with upregulation of Bax expression, with concurrent downregulation of the Bcl-2 gene. Ars 6C was also seen to reverse epithelial to mesenchymal transition and reduce the migration of breast cancer cells. CONCLUSION: The findings suggest that Ars has significant anti-proliferative and apoptotic potential against breast cancer cells. Further studies are required to elucidate the mechanism by which Ars exerts its effect in the in vivo setting.

A practical evaluation on integrated role of biochar and nanomaterials in soil remediation processes.

Soil decontamination and restoration continue to be a key environmental concern around the globe. The degradation of soil resources due to the presence of potentially toxic elements (PTEs) has a substantial influence on agricultural production, food security, and human well-being, and as a result, urgent action is required. PTEs pollution is not a threat to the agroecosystems but also a serious concern to human health; thereby, it needs to be addressed timely and effectively. Hence, the development of improved and cost-effective procedures to remove PTEs from polluted soils is imperative. With this context in mind, current review is designed to distinctly envisage the PTEs removal potential by the single and binary applications of biochar (BC) and nanomaterials (NMs).2 Recently, BC, a product of high-temperature biomass pyrolysis with high specific surface area, porosity, and distinctive physical and chemical properties has become one of the most used and economic adsorbent materials. Also, biochar's application has generated interest in a variety of fields and environments as a modern approach against the era of urbanization, industrialization, and climate change. Likewise, several NMs including metals and their oxides, carbon materials, zeolites, and bimetallic-based NMs have been documented as having the potential to remediate PTEs-polluted environments. However, both techniques have their own set of advantages and disadvantages, therefore combining them can be a more effective strategy to address the growing concern over the rapid accumulation and release of PTEs into the environment.

Investigating the Biochemical Responses in Wheat Cultivars Exposed to Thermal Power Plant Emission.

The current study aimed to assess how high concentrations of ozone (O3) and suspended particulate matter (SPM) alter biochemical properties of high yielding wheat cultivars (i.e., HD3086 and HD2967) grown under 10 km radius in 8 villages, located around Thermal Power Plant (TPP), Auraiya, Uttar Pradesh, India. Significant foliar damage was brought on by O3 and SPM exposure in both wheat cultivars and noted for consecutive 2 years as per emission patterns, air movement and biochemical defense capabilities. The detected air pollutants at the chosen experimental site ranged from 34 to 46 ppb O3 and 139-189 µg/m3 SPM. Range of biochemical parameter for both cultivars are as pH 6.6-7.1, relative water content (RWC) 44-62%, chlorophyll 0.23-0.35 mg/g, ascorbic acid (AA) 54-68 mg/g and air pollution tolerance index (APTI) 47-72. It has been observed that SPM deposition had a meaningful impact (P-value = 0.05) on the chlorophyll, pH, RWC and APTI.

Repurposing of drugs: An attractive pharmacological strategy for cancer therapeutics.

Human malignancies are one of the major health-related issues though out the world and anticipated to rise in the future. The development of novel drugs/agents requires a huge amount of cost and time that represents a major challenge for drug discovery. In the last three decades, the number of FDA approved drugs has dropped down and this led to increasing interest in drug reposition or repurposing. The present review focuses on recent concepts and therapeutic opportunities for the utilization of antidiabetics, antibiotics, antifungal, anti-inflammatory, antipsychotic, PDE inhibitors and estrogen receptor antagonist, Antabuse, antiparasitic and cardiovascular agents/drugs as an alternative approach against human malignancies. The repurposing of approved non-cancerous drugs is an effective strategy to develop new therapeutic options for the treatment of cancer patients at an affordable cost in clinics. In the current scenario, most of the countries throughout the globe are unable to meet the medical needs of cancer patients because of the high cost of the available cancerous drugs. Some of these drugs displayed potential anti-cancer activity in preclinic and clinical studies by regulating several key molecular mechanisms and oncogenic pathways in human malignancies. The emerging pieces of evidence indicate that repurposing of drugs is crucial to the faster and cheaper discovery of anti-cancerous drugs.

The multidimensional role of the Wnt/ß-catenin signaling pathway in human malignancies.

Several signaling pathways have been identified as important for developmental processes. One of such important cascades is the Wnt/ß-catenin signaling pathway, which can regulate various physiological processes such as embryonic development, tissue homeostasis, and tissue regeneration; while its dysregulation is implicated in several pathological conditions especially cancers. Interestingly, deregulation of the Wnt/ß-catenin pathway has been reported to be closely associated with initiation, progression, metastasis, maintenance of cancer stem cells, and drug resistance in human malignancies. Moreover, several genetic and experimental models support the inhibition of the Wnt/ß-catenin pathway to answer the key issues related to cancer development. The present review focuses on different regulators of Wnt pathway and how distinct mutations, deletion, and amplification in these regulators could possibly play an essential role in the development of several cancers such as colorectal, melanoma, breast, lung, and leukemia. Additionally, we also provide insights on diverse classes of inhibitors of the Wnt/ß-catenin pathway, which are currently in preclinical and clinical trial against different cancers.

Long noncoding RNAs: A novel insight in the leukemogenesis and drug resistance in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a common hematological disorder with heterogeneous nature that resulted from blocked myeloid differentiation and an enhanced number of immature myeloid progenitors. During several decades, different factors, including cytogenetic, genetic, and epigenetic have been reported to contribute to the pathogenesis of AML by inhibiting the differentiation and ensuring the proliferation of myeloid blast cells. Recently, long noncoding RNAs (lncRNAs) have been considered as potential diagnostic, therapeutic, and prognostic factors in different human malignancies including AML. Altered expression of lncRNAs is correlated with the transformation of hematopoietic stem and progenitor cells into leukemic blast cells because of their distinct role in the key cellular processes. We discuss the significant role of lncRNAs in the proliferation, survival, differentiation, leukemic stem cells in AML and their involvement in different molecular pathways (insulin-like growth factor type I receptor, FLT3, c-KIT, Wnt, phosphatidylinositol 3-kinase/protein kinase-B, microRNAs), and associated mechanisms such as autophagy, apoptosis, and glucose metabolism. In addition, we aim to highlight the role of lncRNAs as reliable biomarkers for diagnosis, prognosis, and drug resistance for precision medicine in AML.

Transcriptome analysis identifies TODL as a novel lncRNA associated with proliferation, differentiation, and tumorigenesis in liposarcoma through FOXM1.

Liposarcoma, the most common soft tissue sarcoma, is a group of fat cell mesenchymal tumors with different histological subtypes. The dysregulation of long non-coding RNAs (lncRNAs) has been observed in human cancers including a few studies in sarcoma. However, the global transcriptome analysis and potential role of lncRNAs remain unexplored in liposarcoma. The present investigation uncovers the transcriptomic profile of liposarcoma by RNA sequencing to gain insight into the global transcriptional changes in liposarcoma. Our RNA sequencing analysis has identified that many oncogenic lncRNAs are differentially expressed in different subtypes of liposarcoma including MALAT1, PVT1, SNHG15, LINC00152, and MIR210HG. Importantly, we identified a highly overexpressed, unannotated, and novel lncRNA in dedifferentiated liposarcomas. We have named it TODL, transcript overexpressed in dedifferentiated liposarcoma. TODL lncRNA displayed significantly higher expression in dedifferentiated liposarcoma cell lines and patient samples. Interestingly, functional studies revealed that TODL lncRNA has an oncogenic function in liposarcoma cells by regulating proliferation, cell cycle, apoptosis, differentiation, and tumorigenesis in the murine model. Silencing of TODL lncRNA highlighted the enrichment of several key oncogenic signaling pathways including cell cycle, transcriptional misregulation, FOXM1 network, p53 signaling, PLK1 signaling, FoxO, and signaling Aurora signaling pathways. RNA pull-down assay revealed the binding of TODL lncRNA with FOXM1, an oncogenic transcription factor, and the key regulator of the cell cycle. Silencing of TODL lncRNA also induces adipogenesis in dedifferentiated liposarcomas. Altogether, our finding indicates that TODL could be utilized as a novel, specific diagnostic biomarker, and a pharmacological target for therapeutic development in controlling aggressive and metastatic dedifferentiated liposarcomas.

Fabrication and characterization of high-performance forward-osmosis membrane by introducing manganese oxide incited graphene quantum dots.

Forward osmosis (FO) is the futuristic membrane desalination technology as it transcends the disadvantages of other pressure-driven techniques. But, there still remain critical challenges like fabrication of highly permeable membrane with ideal structures maintaining high rejection rates that need to be addressed for implementation as a practical technology. In this work, novel thin-film composite (TFC) membranes were fabricated by means of incorporating manganese oxide (MnO2) incited graphene quantum dots (GQDs) nanocomposite into a cellulose acetate (CA) suspension followed by phase inversion (PI) for enhanced FO performance. The surface morphology and chemical structure of fabricated membranes were studied using various characterization techniques like XRD, FT-IR, SEM-EDS, Mapping, AFM, and TGA. The structural parameters, water flux, reverse salt flux and salt rejection was estimated on the basis of data obtained from four varying initial draw solution concentrations. At high nanocomposites stacking, the hydrophilicity of the casting blend increase, and subsequently, the PI exchange rate additionally increases, which brings about noticeable difference in the surface morphology. The membrane with 0.5 wt% nanocomposite exhibited superior FO separation performance with osmotic water flux of 18.89, 34.49, 41.76 and 42.34 in L.m-2.h-1 with variable concentrations of NaCl salt solution (0.25M, 0.5M, 1M, and 2M), respectively. Also, the porosity of the membrane was increased to 47.23% with 96.87% salt rejection. The results indicate that the hydrophilicity of the nanocomposite drives them to the interface among CA and water during PI process leading to solid hydrogen bonding to achieve high water permeability.

Venom peptides in cancer therapy: An updated review on cellular and molecular aspects.

Based on the high incidence and mortality rates of cancer, its therapy remains one of the most vital challenges in the field of medicine. Consequently, enhancing the efficacy of currently applied treatments and finding novel strategies are of great importance for cancer treatment. Venoms are important sources of a variety of bioactive compounds including salts, small molecules, macromolecules, proteins, and peptides that are defined as toxins. They can exhibit different pharmacological effects, and in recent years, their anti-tumor activities have gained significant attention. Several different compounds are responsible for the anti-tumor activity of venoms, and peptides are one of them. In the present review, we discuss the possible anti-tumor activities of venom peptides by highlighting molecular pathways and mechanisms through which these molecules can act effectively. Venom peptides can induce cell death in cancer cells and can substantially enhance the efficacy of chemotherapy and radiotherapy. Also, the venom peptides can mitigate the migration of cancer cells via suppression of angiogenesis and epithelial-to-mesenchymal transition. Notably, nanoparticles have been applied in enhancing the bioavailability of venom peptides and providing targeted delivery, thereby leading to their elevated anti-tumor activity and potential application for cancer therapy.

The multifaceted role of reactive oxygen species in tumorigenesis.

Redox homeostasis is an essential requirement of the biological systems for performing various normal cellular functions including cellular growth, differentiation, senescence, survival and aging in humans. The changes in the basal levels of reactive oxygen species (ROS) are detrimental to cells and often lead to several disease conditions including cardiovascular, neurological, diabetes and cancer. During the last two decades, substantial research has been done which clearly suggests that ROS are essential for the initiation, progression, angiogenesis as well as metastasis of cancer in several ways. During the last two decades, the potential of dysregulated ROS to enhance tumor formation through the activation of various oncogenic signaling pathways, DNA mutations, immune escape, tumor microenvironment, metastasis, angiogenesis and extension of telomere has been discovered. At present, surgery followed by chemotherapy and/or radiotherapy is the major therapeutic modality for treating patients with either early or advanced stages of cancer. However, the majority of patients relapse or did not respond to initial treatment. One of the reasons for recurrence/relapse is the altered levels of ROS in tumor cells as well as in cancer-initiating stem cells. One of the critical issues is targeting the intracellular/extracellular ROS for significant antitumor response and relapse-free survival. Indeed, a large number of FDA-approved anticancer drugs are efficient to eliminate cancer cells and drug resistance by increasing ROS production. Thus, the modulation of oxidative stress response might represent a potential approach to eradicate cancer in combination with FDA-approved chemotherapies, radiotherapies as well as immunotherapies.

Natural products and phytochemicals as potential anti-SARS-CoV-2 drugs.

The current pandemic responsible for the crippling of the health care system is caused by the novel SARS-CoV-2 in 2019 and leading to coronavirus disease 2019 (COVID-19). The virus enters into humans by attachment of its Spike protein (S) to the ACE receptor present on the lung epithelial cell surface followed by cleavage of S protein by the cellular transmembrane serine protease (TMPRSS2). After entry, the SARS-CoV-2 RNA genome is released into the cytosol, where it highjacks host replication machinery for viral replication, assemblage, as well as the release of new viral particles. The major drug targets that have been identified for SARS-CoV-2 through host-virus interaction studies include 3CLpro, PLpro, RNA-dependent RNA polymerase, and S proteins. Several reports of natural compounds along with synthetic products have displayed promising results and some of them are Tripterygium wilfordii, Pudilan Xiaoyan Oral Liquid, Saponin derivates, Artemisia annua, Glycyrrhiza glabra L., Jinhua Qinggan granules, Xuebijing, and Propolis. This review attempts to disclose the natural products identified as anti-SARS-CoV-2 based on in silico prediction and the effect of a variety of phytochemicals either alone and/or in combination with conventional treatments along with their possible molecular mechanisms involved for both prevention and treatment of the SARS-CoV-2 disease.

Response surface methodology and artificial neural network modelling for the performance evaluation of pilot-scale hybrid nanofiltration (NF) & reverse osmosis (RO) membrane system for the treatment of brackish ground water.

Artificial neural network (ANN) and response surface methodology (RSM) were employed to develop models for process optimisation of pilot scale nanofiltration (NF) and reverse osmosis (RO) membrane filtration system for the treatment of brackish groundwater. The process variables for this study were feed concentration, temperature, pH and pressure. The performance of NF/RO was assessed in terms of permeate flux, water recovery, salt rejection and specific energy consumption, which were considered as responses. The experimental design was employed to develop both RSM and ANN models. RSM model was validated for the whole range of experimental levels, while the ANN model was considered for the whole range of experimental design. RSM and ANN models were statistically analysed using analysis of variance (ANOVA). Further, the models were graphically compared for its predictive capacity. Numerical optimisation of NF and RO pilot plant to determine the optimum conditions were verified. Finally, using the optimum conditions, three hybrid configurations of NF and RO were studied to determine the best mode for the treatment of brackish groundwater. It was found that parallel NF-RO had a recovery of 57.18% and rejection of 44.89%, for RO-concentrate-NF (RO-C-NF) recovery was 49.55% and rejection of 38.64% & for NF-concentrate-RO (NF-C-RO), the recovery of 39.53% and rejection of 49.66% was obtained. Results obtained also suggested that the mode of configurations and the feed concentration affect the performance of the hybrid system.

The pleiotropic role of transcription factor STAT3 in oncogenesis and its targeting through natural products for cancer prevention and therapy.

Signal transducer and activator of transcription 3 (STAT3) is one of the crucial transcription factors, responsible for regulating cellular proliferation, cellular differentiation, migration, programmed cell death, inflammatory response, angiogenesis, and immune activation. In this review, we have discussed the classical regulation of STAT3 via diverse growth factors, cytokines, G-protein-coupled receptors, as well as toll-like receptors. We have also highlighted the potential role of noncoding RNAs in regulating STAT3 signaling. However, the deregulation of STAT3 signaling has been found to be associated with the initiation and progression of both solid and hematological malignancies. Additionally, hyperactivation of STAT3 signaling can maintain the cancer stem cell phenotype by modulating the tumor microenvironment, cellular metabolism, and immune responses to favor drug resistance and metastasis. Finally, we have also discussed several plausible ways to target oncogenic STAT3 signaling using various small molecules derived from natural products.

Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse.

Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A-transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone.