MYB sustains hypoxic survival of pancreatic cancer cells by facilitating metabolic reprogramming.

Extensive desmoplasia and poor vasculature renders pancreatic tumors severely hypoxic, contributing to their aggressiveness and therapy resistance. Here, we identify the HuR/MYB/HIF1α axis as a critical regulator of the metabolic plasticity and hypoxic survival of pancreatic cancer cells. HuR undergoes nuclear-to-cytoplasmic translocation under hypoxia and stabilizes MYB transcripts, while MYB transcriptionally upregulates HIF1α. Upon MYB silencing, pancreatic cancer cells fail to survive and adapt metabolically under hypoxia, despite forced overexpression of HIF1α. MYB induces the transcription of several HIF1α-regulated glycolytic genes by directly binding to their promoters, thus enhancing the recruitment of HIF1α to hypoxia-responsive elements through its interaction with p300-dependent histone acetylation. MYB-depleted pancreatic cancer cells exhibit a dramatic reduction in tumorigenic ability, glucose-uptake and metabolism in orthotopic mouse model, even after HIF1α restoration. Together, our findings reveal an essential role of MYB in metabolic reprogramming that supports pancreatic cancer cell survival under hypoxia.

Biphasic transcriptional and posttranscriptional regulation of MYB by androgen signaling mediates its growth control in prostate cancer.

MYB, a proto-oncogene, is overexpressed in prostate cancer (PCa) and promotes its growth, aggressiveness, and resistance to androgen-deprivation therapy. Here, we examined the effect of androgen signaling on MYB expression and delineated the underlying molecular mechanisms. Paralleling a dichotomous effect on growth, low-dose androgen induced MYB expression at both transcript and protein levels, whereas it was suppressed in high-dose androgen-treated PCa cells. Interestingly, treatment with both low- and high-dose androgen transcriptionally upregulated MYB by increasing the binding of androgen receptor to the MYB promoter. In a time-course assay, androgen induced MYB expression at early time points followed by a sharp decline in high-dose androgen-treated cells due to decreased stability of MYB mRNA. Additionally, profiling of MYB-targeted miRNAs demonstrated significant induction of miR-150 in high-dose androgen-treated PCa cells. We observed a differential binding of androgen receptor on miR-150 promoter with significantly greater occupancy recorded in high-dose androgen-treated cells than those treated with low-dose androgen. Functional inhibition of miR-150 relieved MYB suppression by high-dose androgen, while miR-150 mimic abolished MYB induction by low-dose androgen. Furthermore, MYB-silencing or miR-150 mimic transfection suppressed PCa cell growth induced by low-dose androgen, whereas miR-150 inhibition rescued PCa cells from growth repression by high-dose androgen. Similarly, we observed that MYB silencing suppressed the expression of androgen-responsive, cell cycle-related genes in low-dose androgen-treated cells, while miR-150 inhibition increased their expression in cells treated with high-dose androgen. Overall, these findings reveal novel androgen-mediated mechanisms of MYB regulation that support its biphasic growth control in PCa cells.

Site-Specific Emulation of Neuronal Synaptic Behavior in Au Nanoparticle-Decorated Self-Organized TiOx Surface.

Neuromorphic computing is a potential approach for imitating massive parallel processing capabilities of a bio-synapse. To date, memristors have emerged as the most appropriate device for designing artificial synapses for this purpose due to their excellent analog switching capacities with high endurance and retention. However, to build an operational neuromorphic platform capable of processing high-density information, memristive synapses with nanoscale footprint are important, albeit with device size scaled down, retaining analog plasticity and low power requirement often become a challenge. This paper demonstrates site-selective self-assembly of Au nanoparticles on a patterned TiOx layer formed as a result of ion-induced self-organization, resulting in site-specific resistive switching and emulation of bio-synaptic behavior (e.g., potentiation, depression, spike rate-dependent and spike timing-dependent plasticity, paired pulse facilitation, and post tetanic potentiation) at nanoscale. The use of local probe-based methods enables nanoscale probing on the anisotropic films. With the help of various microscopic and spectroscopic analytical tools, the observed results are attributed to defect migration and self-assembly of implanted Au atoms on self-organized TiOx surfaces. By leveraging the site-selective evolution of gold-nanostructures, the functionalized TiOx surface holds significant potential in a multitude of fields for developing cutting-edge neuromorphic computing platforms and Au-based biosensors with high-density integration.

Study on damage of Gd2O3-CeO2 under electronic energy loss: comparison between bulk-like and nanostructure.

To understand the physical phenomena responsible for radiation damage of the materials used in nuclear reactors, and thus study their operation life and/or efficiency, it is required to simulate the conditions by exposing the materials to energetic ions. Ceria (CeO2) has been proposed as one of the inert matrices for the transmutation of minor actinides in the futuristic inert matrix fuel (IMF) concept. The inert matrix should also contain burnable poison to compensate for the initial reactivity of fuel. In this context, gadolinium (Gd) is an excellent burnable poison with a high neutron absorption cross-section. In view of this, Gd2O3-CeO2 nano-powders were synthesized and sintered at 800 °C and 1300 °C to obtain different grain sizes and morphologies. FESEM and TEM were carried out to study the grain size of pristine pellets. The sintered pellets were irradiated with 80-MeV Ag ions (electronic energy loss (Se) regime) at room temperature to emulate the effect of fission fragments. For analysis of the effect of grain size on the irradiation-induced structural degradation at different fluences, GIXRD and Raman spectroscopy were performed. Significantly large damage has been observed for the smaller grain-sized samples (sintered at 800 °C) as compared to the large grain-sized sample (sintered at 1300 °C). Neither of the samples amorphized under the present experimental conditions as indicated by the presence of the Raman-active T2g mode (centred at 462 cm-1) and all the XRD peaks of fluorite cubic structure up to the highest fluence employed (1 × 1014 ions cm-2). X-ray photoelectron spectroscopy results demonstrate that Ce4+ to Ce3+ and vacancy-related isolated clusters are the main defects produced in the systems. The radiation tolerance behaviour of the samples is understood with the help of thermal spike simulation, which indicates higher transient lattice temperatures with longer duration in the smaller grain-sized sample upon irradiation. Gd-doped ceria thus possesses good radiation stability in the Se regime, indicating its potential for application in IMFs.

Modulation of the tumor microenvironment by natural agents: implications for cancer prevention and therapy.

The development of cancer is not just the growth and proliferation of a single transformed cell, but its surrounding environment also coevolves with it. Indeed, successful cancer progression depends on the ability of the tumor cells to develop a supportive tumor microenvironment consisting of various types of stromal cells. The interactions between the tumor and stromal cells are bidirectional and mediated through a variety of growth factors, cytokines, metabolites, and other biomolecules secreted by these cells. Tumor-stromal crosstalk creates optimal conditions for the tumor growth, metastasis, evasion of immune surveillance, and therapy resistance, and its targeting is being explored for clinical management of cancer. Natural agents from plants and marine life have been at the forefront of traditional medicine. Numerous epidemiological studies have reported the health benefits imparted on the consumption of certain fruits, vegetables, and their derived products. Indeed, a significant majority of anti-cancer drugs in clinical use are either naturally occurring compounds or their derivatives. In this review, we describe fundamental cellular and non-cellular components of the tumor microenvironment and discuss the significance of natural compounds in their targeting. Existing literature provides hope that novel prevention and therapeutic approaches will emerge from ongoing scientific efforts leading to the reduced tumor burden and improve clinical outcomes in cancer patients.

One-pot liquid-phase synthesis of MoS2-WS2van der waals heterostructures for broadband photodetection.

Two dimensional (2D) van der Waals heterostructures (vdWHs) have unique potential in facilitating the stacking of layers of different 2D materials for optoelectronic devices with superior characteristics. However, the fabrication of large area all-2D heterostructures is still challenging towards realizing practical devices at a reduced cost. In the present work, we have demonstrated a rapid yet simple, impurity-free and efficient sonication-assisted chemical exfoliation approach to synthesize hybrid vdWHs based on 2D molybdenum disulphide (MoS2) and tungsten disulphide (WS2), with high yield. Microscopic and spectroscopic studies have confirmed the successful exfoliation of layered 2D materials and formation of their hybrid heterostructures. The co-existence of 2D MoS2and WS2in the vdWH hybrids is established by optical absorption and Raman shift measurements along with their chemical stiochiometry determined by x-ray photoelectron spectroscopy. The spectral response of the vdWH/Si (2D/3D) heterojunction photodetector fabricated using the as-synthesized material is found to exhibit broadband photoresponse compared to that of the individual 2D MoS2and WS2devices. The peak responsivity and detectivity are found to be as high as ∼2.15 A W-1and 2.05 × 1011Jones, respectively for an applied bias of -5 V. The ease of fabrication with appreciable performance of the chemically synthesized vdWH-based devices have revealed their potential use for large area optoelectronic applications on Si-compatible CMOS platforms.

MYB interacts with androgen receptor, sustains its ligand-independent activation and promotes castration resistance in prostate cancer.

BACKGROUND: Aberrant activation of androgen receptor signalling following castration therapy is a common clinical observation in prostate cancer (PCa). Earlier, we demonstrated the role of MYB overexpression in androgen-depletion resistance and PCa aggressiveness. Here, we investigated MYB-androgen receptor (AR) crosstalk and its functional significance. METHODS: Interaction and co-localization of MYB and AR were examined by co-immunoprecipitation and immunofluorescence analyses, respectively. Protein levels were measured by immunoblot analysis and enzyme-linked immunosorbent assay. The role of MYB in ligand-independent AR transcriptional activity and combinatorial gene regulation was studied by promoter-reporter and chromatin immunoprecipitation assays. The functional significance of MYB in castration resistance was determined using an orthotopic mouse model. RESULTS: MYB and AR interact and co-localize in the PCa cells. MYB-overexpressing PCa cells retain AR in the nucleus even when cultured under androgen-deprived conditions. AR transcriptional activity is also sustained in MYB-overexpressing cells in the absence of androgens. MYB binds and promotes AR occupancy to the KLK3 promoter. MYB-overexpressing PCa cells exhibit greater tumorigenicity when implanted orthotopically and quickly regain growth following castration leading to shorter mice survival, compared to those carrying low-MYB-expressing prostate tumours. CONCLUSIONS: Our findings reveal a novel MYB-AR crosstalk in PCa and establish its role in castration resistance.

Drone-Based Environmental Monitoring and Image Processing Approaches for Resource Estimates of Private Native Forest.

This paper investigated the utility of drone-based environmental monitoring to assist with forest inventory in Queensland private native forests (PNF). The research aimed to build capabilities to carry out forest inventory more efficiently without the need to rely on laborious field assessments. The use of drone-derived images and the subsequent application of digital photogrammetry to obtain information about PNFs are underinvestigated in southeast Queensland vegetation types. In this study, we used image processing to separate individual trees and digital photogrammetry to derive a canopy height model (CHM). The study was supported with tree height data collected in the field for one site. The paper addressed the research question "How well do drone-derived point clouds estimate the height of trees in PNF ecosystems?" The study indicated that a drone with a basic RGB camera can estimate tree height with good confidence. The results can potentially be applied across multiple land tenures and similar forest types. This informs the development of drone-based and remote-sensing image-processing methods, which will lead to improved forest inventories, thereby providing forest managers with recent, accurate, and efficient information on forest resources.

Co-targeting of CXCR4 and hedgehog pathways disrupts tumor-stromal crosstalk and improves chemotherapeutic efficacy in pancreatic cancer.

Pancreatic cancer (PC) remains a therapeutic challenge because of its intrinsic and extrinsic chemoresistance mechanisms. Here, we report that C-X-C motif chemokine receptor 4 (CXCR4) and hedgehog pathways cooperate in PC chemoresistance via bidirectional tumor-stromal crosstalk. We show that when PC cells are co-cultured with pancreatic stellate cells (PSCs) they are significantly more resistant to gemcitabine toxicity than those grown in monoculture. We also demonstrate that this co-culture-induced chemoresistance is abrogated by inhibition of the CXCR4 and hedgehog pathways. Similarly, the co-culture-induced altered expression of genes in PC cells associated with gemcitabine metabolism, antioxidant defense, and cancer stemness is also reversed upon CXCR4 and hedgehog inhibition. We have confirmed the functional impact of these genetic alterations by measuring gemcitabine metabolites, reactive oxygen species production, and sphere formation in vehicle- or gemcitabine-treated monocultures and co-cultured PC cells. Treatment of orthotopic pancreatic tumor-bearing mice with gemcitabine alone or in combination with a CXCR4 antagonist (AMD3100) or hedgehog inhibitor (GDC-0449) displays reduced tumor growth. Notably, we show that the triple combination treatment is the most effective, resulting in nearly complete suppression of tumor growth. Immunohistochemical analysis of Ki67 and cleaved caspase-3 confirm these findings from in vivo imaging and tumor measurements. Our findings provide preclinical and mechanistic evidence that a combination of gemcitabine treatment with targeted inhibition of both the CXCR4 and hedgehog pathways improves outcomes in a PC mouse model.

Current and Futuristic Roadmap of Ovarian Cancer Management: An Overview.

Ovarian cancer (OC) is the most lethal gynecological malignancy among women worldwide. In most cases, it is diagnosed late at an advanced stage and does not respond well to existing therapies leading to its poor prognosis. In addition, other factors including epidemiological, complex histological diversity, multiple molecular alterations, and overlapping signaling pathways are also important contributors to poor disease outcome. Efforts have continued to develop a deeper understanding of the molecular pathogenesis and altered signaling nodes that provide hope for better clinical management through the development of novel approaches for early diagnosis, disease subtyping, prognosis, and therapy. In this chapter, we provide a detailed overview of OC and its histological subtypes and discuss prevalent molecular aberrations and active signaling pathways that drive OC progression. We also summarize various diagnostic and prognostic markers and therapeutic approaches currently being employed and discuss emerging findings that hold the potential to change the future course of OC management.

Proteomic Analysis of MYB-Regulated Secretome Identifies Functional Pathways and Biomarkers: Potential Pathobiological and Clinical Implications.

Earlier we have shown important roles of MYB in pancreatic tumor pathobiology. To better understand the role of MYB in the tumor microenvironment and identify MYB-associated secreted biomarker proteins, we conducted mass spectrometry analysis of the secretome from MYB-modulated and control pancreatic cancer cell lines. We also performed in silico analyses to determine MYB-associated biofunctions, gene networks, and altered biological pathways. Our data demonstrated significant modulation (p < 0.05) of 337 secreted proteins in MYB-silenced MiaPaCa cells, whereas 282 proteins were differentially present in MYB-overexpressing BxPC3 cells, compared to their respective control cells. Alteration of several phenotypes such as cellular movement, cell death and survival, inflammatory response, protein synthesis, etc. was associated with MYB-induced differentially expressed proteins (DEPs) in secretomes. DEPs from MYB-silenced MiaPaCa PC cells were suggestive of the downregulation of genes primarily associated with glucose metabolism, PI3K/AKT signaling, and oxidative stress response, among others. DEPs from MYB-overexpressing BxPC3 cells suggested the enhanced release of proteins associated with glucose metabolism and cellular motility. We also observed that MYB positively regulated the expression of four proteins with potential biomarker properties, i.e., FLNB, ENO1, ITGB1, and INHBA. Mining of publicly available databases using Oncomine and UALCAN demonstrated that these genes are overexpressed in pancreatic tumors and associated with reduced patient survival. Altogether, these data provide novel avenues for future investigations on diverse biological functions of MYB, specifically in the tumor microenvironment, and could also be exploited for biomarker development.

Hydroxytyrosol Induces Apoptosis and Cell Cycle Arrest and Suppresses Multiple Oncogenic Signaling Pathways in Prostate Cancer Cells.

SCOPE: Hydroxytyrosol (HT), a polyphenol from olives, is a potential anticancer agent. This study was designed to evaluate the anticancer activity of HT against prostate cancer cells, and the mechanism thereof. METHODS AND RESULTS: Treatment of LNCaP and C4-2 prostate cancer cells with HT resulted in a dose-dependent inhibition of proliferation. This was in contrast to HT's ineffectiveness against normal prostate epithelial cells RWPE1 and PWLE2, suggesting cancer-cell-specific effect. HT induced G1/S cell cycle arrest, with inhibition of cyclins D1/E and cdk2/4 and induction of inhibitory p21/p27. HT also induced apoptosis, as confirmed by flow cytometry, caspase activation, PARP cleavage, and BAX/Bcl-2 ratio. It inhibited the phosphorylation of Akt/STAT3, and induced cytoplasmic retention of NF-κB, which may explain its observed effects. Finally, HT inhibited androgen receptor (AR) expression and the secretion of AR-responsive prostate-specific antigen. CONCLUSION: Castration-resistant prostate cancers retain AR signaling and are often marked by activated Akt, NF-κB, and STAT3 signaling. Our results establish a pleiotropic activity of HT against these oncogenic signaling pathways. Combined with its nontoxic effects against normal cells, our results support further testing of HT for prostate cancer therapy.

Insights into the Role of microRNAs in Pancreatic Cancer Pathogenesis: Potential for Diagnosis, Prognosis, and Therapy.

Pancreatic cancer is a highly lethal malignancy and a fourth leading cause of cancer-related death in the United States. Poor survival of pancreatic cancer patients is largely because of its asymptomatic progression to advanced stage against which no effective therapy is currently available. Over the years, we have developed significant knowledge of molecular progression of pancreatic cancer and identified several genetic and epigenetic aberrations to be involved in its etiology and aggressive behavior. In that regard, recent lines of evidence have suggested important roles of microRNAs (miRNAs/miRs) in pancreatic cancer pathogenesis. microRNAs belonging to a family of small, noncoding RNAs are able to control diverse biological processes due to their ability to regulate gene expression at the posttranscriptional level. Accordingly, dysregulation of miRNAs can lead to several disease conditions, including cancer. There is a long list of microRNAs that exhibit aberrant expression in pancreatic cancer and serve as key microplayers in its initiation, progression, metastasis, and chemoresistance. These findings have suggested that microRNAs could be exploited as novel biomarkers for diagnostic and prognostic assessments of pancreatic cancer and as targets for therapy. This book chapter describes clinical problems associated with pancreatic cancer, roles that microRNAs play in various aspects of pancreatic cancer pathogenesis, and envision opportunities for potential use of microRNAs in pancreatic cancer management.

Controllable physicochemical properties of WOx thin films grown under glancing angle.

In this work, various physicochemical properties are investigated in nanostructured WOx thin films prepared by radio-frequency magnetron sputtering for optoelectronic applications. A glancing angle of 87° is employed to grow films of different thicknesses, which are then exposed to post-growth annealing. Detailed local probe analyses in terms of morphology and work function of WOx films are carried out to investigate thickness-dependent property modulations of the as-deposited and annealed films. The analyses show a reasonably good correlation with photoelectron spectroscopic measurements on the films and the bulk I-V characteristics acquired on a series of WOx/p-Si heterojunction diodes. The presence of a critical WOx thickness is identified to regulate the rectification ratio values at the WOx/p-Si heterostructures and increase in series resistance within the bulk of the films. The present study provides valuable insights to correlate optical, electrical, and structural properties of WOx thin films, which will be beneficial for fabricating WOx-based optoelectronic devices, including photovoltaic cells.

Non-synonymous single nucleotide polymorphisms in genes for immunoregulatory galectins: association of galectin-8 (F19Y) occurrence with autoimmune diseases in a Caucasian population.

BACKGROUND: Galectins are potent immune regulators, with galectin-8 acting as a pro-apoptotic effector on synovial fluid cells and thymocytes and stimulator on T-cells. To set a proof-of-principle example for risk assessment in autoimmunity, and for a mutation affecting physiological galectin sensor functions, a polymorphism in the coding region of the galectin-8 gene (rs2737713; F19Y) was studied for its association with two autoimmune disorders, i.e. rheumatoid arthritis and myasthenia gravis. METHODS: A case-control analysis and a related quantitative trait-association study were performed to investigate the association of this polymorphism in patients (myasthenia gravis 149, rheumatoid arthritis 214 and 134 as primary and repetitive cohorts, respectively) and 365 ethnically matched (Caucasian) healthy controls. Distribution was also investigated in patients grouped according to their antibody status and age at disease onset. Comparative testing for lectin activity was carried out in ELISA/ELLA-based binding tests with both wild-type and F19Y mutant galectin-8 from peripheral blood mononuclear cell lysates of healthy individuals with different genotypes as well as with recombinant wild-type and F19Y mutant galectin-8 proteins. RESULTS: A strong association was found for rheumatoid arthritis, and a mild one with myasthenia gravis. Furthermore, the presence of the sequence deviation also correlated with age at disease onset in the case of rheumatoid arthritis. The F19Y substitution did not appear to affect carbohydrate binding in solid-phase assays markedly. GENERAL SIGNIFICANCE: This is the first report of an association between a galectin-based polymorphism leading to a mutant protein and autoimmune diseases, with evidence for antagonistic pleiotropy.

Atomic-Scale Imaging and Nano-Scale Mapping of Cubic α-CsPbI3 Perovskite Nanocrystals for Inverted Perovskite Solar Cells.

Colloidal synthesized cubic α-CsPbI3 perovskite nanocrystals having a smaller lattice constant (a = 6.2315 Å) compared to the standard structure, and nanoscale mapping of their surfaces are reported to achieve superior photovoltaic performance under 45-55% humidity conditions. Atomic scale transmission electron microscopic images have been utilized to probe the precise arrangement of Cs, Pb, and I atoms in a unit cell of α-CsPbI3 NCs, which is well supported by the VESTA structure. Theoretical calculation using density functional theory of our experimental structure reveals the realization of direct band to band transition with a lower band gap, a higher absorption coefficient, and stronger covalent bonding between the Pb and I atoms in the [PbI6]4- octahedral, as compared to reported standard structure. Nanoscale surface mapping using Kelvin probe force microscopy yielding contact potential difference (CPD) and conductive atomic force microscopy for current mapping have been employed on α-CsPbI3 NCs films deposited on different DMSO doped PEDOT:PSS layers. The difference of CPD value under dark and light illumination suggests that the hole injection strongly depends on the interfaces with PEDOT:PSS layer. The carrier transport through grain interiors and grain boundaries in α-CsPbI3 probed by the single-point c-AFM measurements reveal the excellent photosensitivity under the light conditions. Finally, inverted perovskite solar cells, employing α-CsPbI3 NCs film as an absorber layer and PEDOT:PSS layer as a hole transport layer, have been optimized to achieve the highest power conversion efficiency of 10.6%, showing their potential for future earth abundant, low cost, and air stable inverted perovskite photovoltaic devices.

Resistin Induces LIN28A-Mediated Let-7a Repression in Breast Cancer Cells Leading to IL-6 and STAT3 Upregulation.

Downregulation of the Let-7 family of microRNAs (miRNAs) has been reported in several cancers, including breast malignancy; however, underlying mechanisms are not completely understood. Resistin is an important component of the tumor microenvironment, having a functional impact on the tumor cell phenotypes. Here, we examined the role of resistin in the regulation of Let-7 miRNAs and studied its downstream consequences. We found that resistin treatment led to the reduced expression of Let-7 family miRNAs in breast cancer (BC) cells, with the highest downregulation reported for Let-7a. Furthermore, resistin induced the expression of LIN28A, and its silencing abrogated resistin-mediated Let-7a suppression. Let-7a restoration or LIN28A silencing abolished the resistin-induced growth, clonogenicity, and sphere-forming ability of BC cells. Restoration of Let-7a also suppressed the resistin-induced expression of genes associated with growth, survival, and stemness. Pathway analysis suggested STAT3 as a putative central node associated with Let-7a-mediated gene regulation. In silico analysis identified STAT3 and its upstream modifier, IL-6, as putative Let-7a gene targets, which were later confirmed by 3'UTR-reporter assays. Together, our findings demonstrate a novel resistin/LIN28A/Let-7a/IL-6/STAT3 signaling axis supporting the growth and stemness of BC cells.

Clinicopathologic significance and race-specific prognostic association of MYB overexpression in ovarian cancer.

Late diagnosis, unreliable prognostic assessment, and poorly-guided therapeutic planning result in dismal survival of ovarian cancer (OC) patients. Therefore, identifying novel functional biomarker(s) is highly desired for improved clinical management. MYB is an oncogenic transcription factor with emerging functional significance in OC. Here we examined its clinicopathologic significance by immunohistochemistry and TCGA/GTex data analyses. Aberrant MYB expression was detected in 94% of OC cases (n = 373), but not in the normal ovarian tissues (n = 23). MYB was overexpressed in all major epithelial OC histological subtypes exhibiting the highest incidence (~ 97%) and overall expression in serous and mucinous carcinomas. MYB expression correlated positively with tumor grades and stages. Moreover, MYB exhibited race-specific prognostic association. Moderate-to-high MYB levels were significantly associated with both poor overall- (p = 0.02) and progression-free (p = 0.02) survival in African American (AA), but not in the Caucasian American (CA) patients. Consistent with immunohistochemistry data, we observed significantly higher MYB transcripts in OC cases (n = 426) than normal ovary (n = 88). MYB transcripts were significantly higher in all epithelial OC subtypes, compared to normal, and its greater levels predicted poor survival in AA OC, but not CA OC, patients. Thus, MYB appears to be a useful clinical biomarker for prognostication, especially in AA patients.

Dysregulation of metabolic enzymes in tumor and stromal cells: Role in oncogenesis and therapeutic opportunities.

Altered cellular metabolism is a hallmark of cancer. Metabolic rewiring in cancer cells occurs due to the activation of oncogenes, inactivation of tumor suppressor genes, and/or other adaptive changes in cell signaling pathways. Furthermore, altered metabolism is also reported in tumor-corrupted stromal cells as a result of their interaction with cancer cells or due to their adaptation in the dynamic tumor microenvironment. Metabolic alterations are associated with dysregulation of metabolic enzymes and tumor-stromal metabolic crosstalk is vital for the progressive malignant journey of the tumor cells. Therefore, several therapies targeting metabolic enzymes have been evaluated and/or are being investigated in preclinical and clinical studies. In this review, we discuss some important metabolic enzymes that are altered in tumor and/or stromal cells, and focus on their role in supporting tumor growth. Moreover, we also discuss studies carried out in various cancers to target these metabolic abnormalities for therapeutic exploitation.

Exosomal Formulation Escalates Cellular Uptake of Honokiol Leading to the Enhancement of Its Antitumor Efficacy.

Honokiol is a phytochemical isolated from the Magnolia plant. It exhibits significant antitumor activity against a variety of cancer cell types via targeting of critical mediators of tumor progression, stromal remodeling, and chemoresistance. However, poor bioavailability and inefficient tumor uptake remain some of the hurdles in its translation as a therapeutically useful drug. Here, we developed a nanoformulation of honokiol using mesenchymal stem cell-derived exosomes, which are nonimmunogenic and express surface markers to support their tumor-targeted delivery. Maximum entrapment of honokiol occurred when it was mixed in a 1:4 weight ratio with exosomes and subjected to six cycles of sonication. Dynamic light scattering analysis demonstrated that the average size (∼175.3 nm), polydispersity (∼0.11), and integrity (∼12.9 mV) of exosomes remained in the desirable range post honokiol encapsulation. Exosome-encapsulated honokiol exhibited significantly higher therapeutic efficacy over the free honokiol in WST-1 growth and long-term clonogenicity assays. Flow cytometry-based cell cycle and live/dead cell assay, respectively, confirmed the enhanced effect of exosomal honokiol formulation on cell cycle arrest and apoptosis induction. More significant alterations in the expression of cell cycle- and survival-associated proteins were also observed in cancer cells treated with exosomal honokiol over free honokiol. Higher intracellular accumulation of honokiol was recorded in cancer cells treated with equivalent doses of honokiol as compared to the free honokiol. Together, our work is the first demonstration of exosomal encapsulation of honokiol and its improved antitumor efficacy resulting from improved cellular uptake.