bims-myxlip Biomed News
on Myxoid liposarcoma
Issue of 2020‒12‒27
thirty-four papers selected by
Laura Mannarino
Mario Negri Institute

  1. Semin Cancer Biol. 2020 Dec 17. pii: S1044-579X(20)30272-8. [Epub ahead of print]
      Epithelial to mesenchymal transition (EMT) is a cellular process in which cells composing epithelial tissue lose requirements for physical contact with neighboring cells and acquire mesenchymal characteristics consisting of increased migratory and invasive behaviors. EMT is a fundamental process that is required for initial and later events during embryogenesis. Cancer stem cells (CSCs) possess multipotency sufficient for their differentiation into bulk tumor cells and also have the capacity to undergo EMT. When CSCs initiate EMT programs the resulting cancerous mesenchymal cells become invasive and this migratory behavior also poises them for metastatic activity. Long noncoding RNAs (lncRNAs) are functional RNA molecules that do not encode proteins, yet regulate the expression of protein-coding genes through recruitment or sequestration of gene-regulatory proteins and microRNAs. lncRNA exhibit tissue-specific patterns of gene expression during development and specific sets of lncRNAs are also involved in various cancer types. This review considers the interplay between lncRNAs and the biogenesis of CSCs. We also review function of lncRNAs in EMT in CSCs. In addition, we discuss the utility of lncRNAs as biomarkers of cancer progression, and their potential use as therapeutic targets for treatment of cancer.
    Keywords:  cancer stem cell; epithelial-mesenchymal transition (EMT); lncRNA
  2. J Mol Diagn. 2020 Dec 17. pii: S1525-1578(20)30586-9. [Epub ahead of print]
      Histology does not reliably distinguish benign lipomas from atypical lipomatous tumor / well differentiated liposarcoma, nor dedifferentiated liposarcoma from other pleomorphic sarcomas, entities with different prognosis and management. Molecular confirmation of pathognomonic 12q13-15 amplifications leading to overexpression of MDM2 is a diagnostic gold standard. Currently the most commonly used assay for this purpose is Fluorescent In-Situ Hybridization (FISH), but this is labor-intensive. We assessed if newer NanoString-based technology could allow for more rapid and cost-efficient diagnosis of liposarcomas on standard formalin-fixed tissues through gene expression. Leveraging large-scale transcriptome data from The Cancer Genome Atlas, we identified 20 genes, most derived from the 12q13-15 amplicon, that distinguish dedifferentiated liposarcoma from other sarcomas and can be measured within a single NanoString assay. Using 21 cases of histologically-ambiguous low grade adipocytic tumors with available MDM2 amplification status, we built a machine learning based analytical pipeline that assigns a given sample as negative or positive for liposarcoma based on quantitative gene expression. We validated the assay's effectiveness on an independent set of 100 sarcoma samples (including 40 incident prospective cases), where histology was considered insufficient for clinical diagnosis. The NanoString assay had a 93% technical success rate, and an accuracy of 97.8% versus an MDM2 amplification FISH gold standard. Turnaround time at our institution with NanoString was considerably faster and less expensive than FISH.
  3. Expert Opin Ther Pat. 2020 Dec 21.
      INTRODUCTION: DNA-dependent protein kinase (DNA-PK) plays a crucial role in the repair of DSBs via non-homologous end joining (NHEJ). Several DNA-PK inhibitors are being investigated for potential anticancer treatment in clinical trials.AREA COVERED: This review aims to give an overview of patents published since 2010 aiming to analyze the patent space and structure features of scaffolds used in those patents. It also discusses the recent clinical developments and provides perspectives on future challenges and directions of developing DNA-PK inhibitor drugs for cancer treatment.
    EXPERT OPINION: As a key component of the DNA damage response (DDR) pathway, DNA-PK appears to be a viable drug target for anticancer therapy. The clinical investigation of a DNA-PK inhibitor employs both a monotherapy and a combination strategy. In the combination strategy, a DNA-PK inhibitor is typically combined with a DSB inducer, radiation, a chemotherapy agent, or a PARP inhibitor etc. Patent analyses suggest that diverse structures comprising different scaffolds from mono- heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl are capable to achieve good DNA-PK inhibitory activity and good DNA-PK selectivity over other closely related enzymes. Several DNA-PK inhibitors are currently being evaluated in clinics, with the hope to get approval in the near future.
    Keywords:  DNA damage response (DDR); DNA double strand breaks (DSBs); DNA-PK; cancer therapy; inhibitor; patent review
  4. Fertil Steril. 2020 Dec 16. pii: S0015-0282(20)32511-5. [Epub ahead of print]
      OBJECTIVE: To examine whether subcutaneous (SC) abdominal adipose stem cell differentiation into adipocytes in vitro predicts insulin sensitivity (Si) in vivo in normal-weight women with polycystic ovary syndrome (PCOS) and controls.DESIGN: Prospective cohort study.
    SETTING: Academic medical center.
    PATIENT(S): Eight normal-weight women with PCOS and 8 age- and body mass index-matched controls.
    INTERVENTION(S): Women underwent circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total-body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy.
    MAIN OUTCOME MEASURE(S): PPARγ and CEBPa gene expression and lipid content of adipocytes matured in vitro were compared between women with PCOS and control women, and correlated with patient characteristics, systemic Si, and adipose insulin resistance (adipose-IR).
    RESULT(S): Serum androgen levels, adipose-IR, and percentage of android fat were greater in women with PCOS than control women. Stem cell PPARγ and CEBPa gene expression increased maximally by day 12 without a female-type effect. In control cells, gene expression positively correlated with fasting serum insulin levels (both genes) and adipose-IR (CEBPa) and negatively correlated with Si (CEBPa). Conversely, CEBPa gene expression in PCOS cells negatively correlated with adipose-IR and serum free testosterone, whereas total lipid accumulation in these cells positively corelated with Si.
    CONCLUSION: In normal-weight women with PCOS, accelerated SC abdominal adipose stem cell differentiation into adipocytes in vitro favors Si in vivo, suggesting a role for hyperandrogenism in the evolution of metabolic thrift to enhance fat storage through increased cellular glucose uptake.
    Keywords:  Adipose; adipocyte; hyperandrogenism; polycystic ovary syndrome; stem cell
  5. World J Surg Oncol. 2020 Dec 21. 18(1): 332
      BACKGROUND: This novel study compared the use of tumor necrosis factor (TNF)-alpha and melphalan-based isolated limb perfusion (TM-ILP) to the standard treatment of locally recurrent soft tissue extremity sarcoma. The aim was to assess whether TM-ILP positively influences the recurrence-free survival of locally recurrent high-grade soft tissue sarcoma (STS) of the extremities.METHODS: We retrospectively analyzed our clinical database for patients with STS. Variables were analyzed using chi-square test or Mann-Whitney rank-sum test. Furthermore, Kaplan-Meier survival plots were calculated and a proportional hazard regression model was developed.
    RESULTS: Out of 448 patients with extraabdominal STS treated between August 2012 and December 2015, 52 cases involving 47 patients had locally recurrent STS. Twenty-eight of these patients were treated with TM-ILP prior to surgical resection (TM-ILP-group), and 24 were treated with standard therapy (without TM-ILP). The 3-year recurrence-free survival for the TM-ILP-group was estimated at 75% (95% confidence interval (CI), 71.5-78.5). Local recurrence-free survival in the standard group was significantly lower (LRFS: 43.4%, 95% CI 38.7-48.1, p = 0.026). Multivariable analysis revealed resection with negative margins, lower number of previous recurrences, and TM-ILP as positive predictors for recurrence-free survival.
    CONCLUSIONS: TM-ILP and consecutive resection of residual tumor with negative resection margins significantly improves local recurrence-free survival for patients with a first local recurrence of high-grade STS in the extremities.
  6. Mol Omics. 2020 Dec 21.
      With the advancement of next-generation sequencing and mass spectrometry, there is a growing need for the ability to merge biological features in order to study a system as a whole. Features such as the transcriptome, methylome, proteome, histone post-translational modifications and the microbiome all influence the host response to various diseases and cancers. Each of these platforms have technological limitations due to sample preparation steps, amount of material needed for sequencing, and sequencing depth requirements. These features provide a snapshot of one level of regulation in a system. The obvious next step is to integrate this information and learn how genes, proteins, and/or epigenetic factors influence the phenotype of a disease in context of the system. In recent years, there has been a push for the development of data integration methods. Each method specifically integrates a subset of omics data using approaches such as conceptual integration, statistical integration, model-based integration, networks, and pathway data integration. In this review, we discuss considerations of the study design for each data feature, the limitations in gene and protein abundance and their rate of expression, the current data integration methods, and microbiome influences on gene and protein expression. The considerations discussed in this review should be regarded when developing new algorithms for integrating multi-omics data.
  7. Pathol Res Pract. 2020 Dec 04. pii: S0344-0338(20)32169-5. [Epub ahead of print]217 153314
      Cancer cells are able to undergo aerobic glycolysis and metabolize glucose to lactate instead of oxidative phosphorylation, which is known as Warburg effect. Accumulating evidence has revealed that microRNAs regulate cancer cell metabolism, which manifest a higher rate of glucose metabolism. Various signaling pathways along with glycolytic enzymes are responsible for the emergence of glycolytic dependence. MicroRNAs are a class of non-coding RNAs that are not translated into proteins but regulate target gene expression or in other words function pre-translationally and post-transcriptionally. MicroRNAs have been shown to be involved in various biological processes, including glucose metabolism via targeting major transcription factors, enzymes, oncogenes or tumor suppressors alongside the oncogenic signaling pathways. In this review, we describe the regulatory role of microRNAs of cancer cell glucose metabolism, including in the glucose uptake, glycolysis, tricarboxylic acid cycle and several signaling pathways and further suggest that microRNA-based therapeutics can be used to inhibit the process of glucose metabolism reprogramming in cancer cells and thus suppressing cancer progression.
    Keywords:  Cancer; Glucose; Metabolism; MicroRNA
  8. Cancers (Basel). 2020 Dec 17. pii: E3802. [Epub ahead of print]12(12):
      Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely on a robust infiltration of T-cells into the tumor microenvironment (TME) for an effective response. While early efforts relied on quantifying tumor infiltrating lymphocytes (TIL) in the TME, characterizing the functional quality and degree of TIL exhaustion correlates more strongly with ICI response. Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance. This review will explore these biochemical pathways linked to immune cell dysfunction in the TME and highlight potential adjunctive therapies to be used alongside current IMT.
    Keywords:  cellular energetics; immunometabolism; immunotherapy
  9. Front Endocrinol (Lausanne). 2020 ;11 587189
      Carbohydrate response element-binding protein (ChREBP) plays an important role in the development of type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, as well as tumorigenesis. ChREBP is highly expressed in lipogenic organs, such as liver, intestine, and adipose tissue, in which it regulates the production of acetyl CoA from glucose by inducing Pklr and Acyl expression. It has recently been demonstrated that ChREBP plays a role in the conversion of gut microbiota-derived acetate to acetyl CoA by activating its target gene, Acss2, in the liver. ChREBP regulates fatty acid synthesis, elongation, and desaturation by inducing Acc1 and Fasn, elongation of long-chain fatty acids family member 6 (encoded by Elovl6), and Scd1 expression, respectively. ChREBP also regulates the formation of very low-density lipoprotein by inducing the expression of Mtp. Furthermore, it plays a crucial role in peripheral lipid metabolism by inducing Fgf21 expression, as well as that of Angptl3 and Angptl8, which are known to reduce peripheral lipoprotein lipase activity. In addition, ChREBP is involved in the production of palmitic-acid-5-hydroxystearic-acid, which increases insulin sensitivity in adipose tissue. Curiously, ChREBP is indirectly involved in fatty acid β-oxidation and subsequent ketogenesis. Thus, ChREBP regulates whole-body lipid metabolism by controlling the transcription of lipogenic enzymes and liver-derived cytokines.
    Keywords:  carbohydrate response element-binding protein (Chrebp); fatty acid synthesis; gut microbiota; ketogenesis; lipoprotein metabolism; β-oxidation
  10. Cancer Treat Res Commun. 2020 Dec 11. pii: S2468-2942(20)30110-6. [Epub ahead of print]26 100275
      INTRODUCTION: Sarcomas are uncommon malignancies. No advances have been recently achieved despite multiple efforts. Pazopanib is a safe and effective tyrosine kinase inhibitor used in managing soft tissue sarcomas (STS) after chemotherapy failure. However, its use is limited in developing countries and no efficacy data exist from our region. We aimed to study the efficacy of pazopanib in our population, characterized by response rates of patients with chemotherapy-refractory advanced STS receiving pazopanib. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity profile.MATERIALS AND METHODS: 15 patients (age≥18 year) diagnosed with advanced STS, refractory to first-line chemotherapy, receiving pazopanib as ≥second-line therapy in one tertiary center in Lebanon were included between January 1st, 2014 and October 31st, 2018. Patient and disease characteristics, disease evaluation, as well as tolerance to treatment, were extracted from charts retrospectively. Statistical analysis was done using SPSS version 24.
    RESULTS: The mean age was 48.6 [19-66] years. Eleven patients (73.3%) received pazopanib in second-line, whereas four patients (26.7%) received it in third-line. Thirteen patients (86.7%) progressed, and two patients (13.3%) had stable disease. The median PFS was three months [1-19] and the mean OS was 25.4 months [17.2-33.6]. Five patients required dose-reductions due to poor tolerance.
    CONCLUSION: Conclusions cannot be drawn due to small patient numbers. However, given the 3-month PFS, 13% of patients maintaining stable disease, and tolerable safety profile, it is reasonable to incorporate pazopanib in STS treatment. More focused studies with larger patient populations need to be done in Lebanon.
    Keywords:  Adverse events; Outcomes; Pazopanib; Safety; Soft tissue sarcoma
  11. Obesity (Silver Spring). 2020 Dec 20.
      OBJECTIVE: Adipose tissue macrophages (ATMs) play critical roles in obesity-associated inflammation that contributes to metabolic dysfunction. Talabostat (TB) exerts some therapeutic effects on tumors and obesity. However, it remains unknown whether the metabolic benefits of TB on obesity is dependent on ATM-mediated adipose inflammation.METHODS: Male C57BL/6J mice were fed a normal chow diet (NCD) or a high-fat diet for 12 weeks, and mice were orally administered TB daily at a low dose (0.5 mg/kg).
    RESULTS: Administration of TB to mice fed a high-fat diet significantly improved adiposity and obesity-associated metabolic dysfunction, including glucose intolerance and insulin resistance, hyperlipidemia and hepatic steatosis, which were accompanied by increased whole-body energy expenditure. RNA sequencing analysis revealed extensive alterations in the transcriptome profiles associated with lipid metabolism and immune responses in adipose tissue of obese mice. Notably, TB treatment led to a significant reduction in ATM accumulation and a shift of the activation state of ATMs from the proinflammatory M1-like to the anti-inflammatory M2-like phenotype. Moreover, depletion of ATMs significantly abolished the TB-induced metabolic benefits.
    CONCLUSIONS: Our study demonstrates that TB at a low dose could increase energy expenditure and control ATM-mediated adipose inflammation in obese mice, thereby alleviating obesity and its associated metabolic dysfunction.
  12. Cancers (Basel). 2020 Dec 17. pii: E3801. [Epub ahead of print]12(12):
      Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes in cancer, promote resistance to therapy, and are associated with metastasis. In solid tumor cancers, tumor epithelia, immune cells, cancer-associated fibroblasts, endothelial cells and blood vessels, extracellular matrix, and hypoxia all support a CSC phenotype characterized by drug resistance, recurrence, and metastasis. Recently, studies have shown that DCLK1-positive CSCs are associated with epithelial-mesenchymal transition, angiogenesis, and immune checkpoint. Emerging data concerning targeting DCLK1 with small molecular inhibitors, monoclonal antibodies, and chimeric antigen receptor T-cells shows promising effects on inhibiting tumor growth and regulating the tumor immune microenvironment. Overall, DCLK1 is reaching maturity as an anti-cancer target and therapies directed against it may have potential against CSCs directly, in remodeling the tumor microenvironment, and as immunotherapies.
    Keywords:  DCLK1; cancer stem cells; immunotherapies; microenvironment; tuft cells
  13. Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Dec 17. pii: S1388-1981(20)30263-8. [Epub ahead of print] 158871
      Inducible beige adipocytes are emerging as an interesting issue in obesity and metabolism research. There is a neglected possibility that brown adipocytes are equally activated when external stimuli induce the formation of beige adipocytes. Thus, the question is whether beige adipocytes have the same functions as brown adipocytes when brown adipose tissue (BAT) is lacking. This question has not been well studied. Therefore we determine the beneficial effects of beige adipocytes upon cold challenge or CL316243 treatments in animal models of interscapular BAT (iBAT) ablation by surgical denervation. We found that denervated iBAT were activated by cold exposure and CL316243 treatments. The data show that beige adipocytes partly contribute to the improvement of impaired glucose metabolism resulting from denervated iBAT. Thus, we further used iBAT-removal animal models to abolish iBAT functions completely. We found that beige adipocytes upon cold exposure or CL316243 treatments improved impaired glucose metabolism and enhanced glucose uptake in iBAT-removal mice. The insulin signaling was activated in iBAT-removal mice upon cold exposure. Both the activation of insulin signaling and up-regulation of glucose transporter expression were observed in iBAT-removal mice with CL316243 treatments. The data show that inducible beige adipocytes may have different mechanisms to improve impaired glucose metabolism. Inducible beige adipocytes can also enhance energy expenditure and lipolytic activity of white adipose tissues when iBAT is lacking. We provide direct evidences for the beneficial effect of inducible beige adipocytes in glucose metabolism and energy expenditure in the absence of iBAT in vivo.
    Keywords:  energy expenditure; glucose tolerance; glucose transporter genes; removal; surgical denervation
  14. Cancer Genet. 2020 Dec 09. pii: S2210-7762(20)30291-X. [Epub ahead of print]252-253 6-24
      Cancer genome instability arises from diverse defects in DNA-repair machinery, which make cancer cells more susceptible to DNA targeting agents. The interrelation between DNA repair deficiency and the increased effect of DNA targeting agents highlights the double-strand break (DSB) repair, which comprises the homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. The DNA targeting agents are classified into two major groups: non-covalent DNA binding agents and covalent DNA-reactive agents. Although these agents have well-known limitations, such as resistance and secondary carcinogenesis risk, they are extremely important in today's real-life cancer therapy in combination with targeted therapy and immunotherapy. Indeed, DNA targeting drugs are promising therapeutics with a precise application through the background of cancer-specific DNA repair failure. In the current review, the mechanisms of action of diversified DNA-targeting agents, as well as the modulation of DNA repair pathways to increase the DNA-damaging drugs efficacy are presented. Finally, DNA-targeting-based therapies are discussed considering risks, resistance and its uses in the medicine precision era.
    Keywords:  Cancer; Carcinogenesis; Chemotherapy; DNA damage; DNA repair
  15. Cancer Treat Res Commun. 2020 Dec 10. pii: S2468-2942(20)30103-9. [Epub ahead of print]26 100268
      INTRODUCTION: Lymph node metastasis (LNM) in soft tissue sarcomas (STS) are uncommon, occurring in only 3% - 5% of all sarcomas, and are classified as Stage IV, along with distant metastasis (DM). This paper compares the prognosis of patients with lymphatic and DM, in extremity STS (eSTS).METHODS: A retrospective study was carried out in a high-volume sarcoma center; 853 patients with eSTS sarcomas were identified and classified from January 1, 1997 to December 31, 2017. Cases with pathological confirmation of LNM were included. Five-year survival rates were analyzed using the Kaplan-Meier method and the Cox proportional hazards model.
    RESULTS: LNM was present in 46 of the cases (5.4%), with an overall survival of 21 months (95% confidence interval [CI], 16.7 - 25.2), compared to 18 months (95% confidence interval [CI], 14.2 - 21.7) in those with only DM. Median recurrence-free survival was 21 months (95% confidence interval [CI], 19.7 - 22.4), vs. 20 months (95% confidence interval [CI], 16.2- 23.7), respectively. LNM only and DM only had also a similar OS of 21 months (95% CI 16.7-25.2) vs 18 months (95% CI 14.2-21.7. N1M1 cases had the worse median OS with 15 months (95% confidence interval [CI], 10.9-19.7) CONCLUSIONS: Overall survival and recurrence free survival in patients with lymph node disease and metastatic disease are similar. However prognosis is worse in N1M1. Use of systemic treatment in patients with LNM is not as common as in metastatic cases, this difference in treatment and the fact that prognosis is similar suggests that both biological behavior and effect of treatment have been underestimated. A subclassification of clinical stage IV might be the next step.
    Keywords:  Disease-free survival; Metastatic lymph nodes; Overall survival; Soft tissue sarcoma
  16. Clin Exp Pharmacol Physiol. 2020 Dec 21.
      Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme for nicotinamide adenine dinucleotide (NAD) synthesis and is involved in cancer cell proliferation through regulation of energy production pathways. Therefore, NAMPT inhibitors are promising drugs for cancer therapy by limiting energy supply of tumours. Herein, we demonstrated that the NAMPT inhibitor FK866 ((E)-N-(4-(1-Benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) dose-dependently inhibited growth and cell motility of DU-145 prostate tumour spheroids and decreased the intracellular ATP concentration. The apoptosis marker cleaved caspase-3 remained unchanged, but the autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) was upregulated. Growth inhibition was reversed upon co-administration of NAD to the cell culture medium. FK866 decreased calcein as well as pheophorbide A efflux from tumour spheroids and increased doxorubicin toxicity, indicating interference with function of drug efflux transporters. DU-145 multicellular tumour spheroids expressed the stem cell associated markers CD133, CD44, Oct4, Nanog, Sox2, and drug transporters ABCB1, ABCG2, and ABCC1 which are associated with stem cell properties in cancer cells. The ABCB1 inhibitor zosuquidar, the ABCG2 inhibitor Ko143, and the ABCC1 inhibitor MK571 increased calcein retention. Neither protein expression of stem cell markers, nor drug transporters was significantly changed upon FK866 treatment. In conclusion, our data suggest that FK866 inhibits prostate cancer cell proliferation by interference with the energy metabolism, and function of drug efflux transporters.
    Keywords:  ABCB1; ABCC1; ABCG2; autophagy; cancer stem cells; multidrug resistance; nicotinamide phosphoribosyltransferase; prostate tumour spheroid
  17. Front Pharmacol. 2020 ;11 596239
      Epithelial-mesenchymal Transition (EMT) is a de-differentiation process in which epithelial cells lose their epithelial properties to acquire mesenchymal features. EMT is essential for embryogenesis and wound healing but is aberrantly activated in pathological conditions like fibrosis and cancer. Tumor-associated EMT contributes to cancer cell initiation, invasion, metastasis, drug resistance and recurrence. This dynamic and reversible event is governed by EMT-transcription factors (EMT-TFs) with epigenetic complexes. In this review, we discuss recent advances regarding the mechanisms that modulate EMT in the context of epigenetic regulation, with emphasis on epigenetic drugs, such as DNA demethylating reagents, inhibitors of histone modifiers and non-coding RNA medication. Therapeutic contributions that improve epigenetic regulation of EMT will translate the clinical manifestation as treating cancer progression more efficiently.
    Keywords:  cell migration; epigenetic modification; epithelial-mesenchymal transition; inhibitor; metastasis
  18. Biochim Biophys Acta Rev Cancer. 2020 Dec 17. pii: S0304-419X(20)30214-6. [Epub ahead of print] 188495
      Receptor Tyrosine Kinases (RTK) are an important family involved in numerous signaling pathways essential for proliferation, cell survival, transcription or cell-cycle regulation. Their role and involvement in cancer cell survival have been widely described in the literature, and are generally associated with overexpression and/or excessive activity in the cancer pathology. Because of these characteristics, RTKs are relevant targets in the fight against cancer. In the last decade, increasingly numerous works describe the role of RTK signaling in the modulation of DNA repair, thus providing evidence of the relationship between RTKs and the protein actors in the repair pathways. In this review, we propose a summary of RTKs described as potential modulators of double-stranded DNA repair pathways in order to put forward new lines of research aimed at the implementation of new therapeutic strategies targeting both DNA repair pathways and RTK-mediated signaling pathways.
    Keywords:  Cancer; DNA repair; Inhibition; Receptor tyrosine kinase
  19. Cell Syst. 2020 Dec 14. pii: S2405-4712(20)30463-4. [Epub ahead of print]
      Transcription factors (TFs) bind regulatory DNA to control gene expression, and mutations to either TFs or DNA can alter binding affinities to rewire regulatory networks and drive phenotypic variation. While studies have profiled energetic effects of DNA mutations extensively, we lack similar information for TF variants. Here, we present STAMMP (simultaneous transcription factor affinity measurements via microfluidic protein arrays), a high-throughput microfluidic platform enabling quantitative characterization of hundreds of TF variants simultaneously. Measured affinities for ∼210 mutants of a model yeast TF (Pho4) interacting with 9 oligonucleotides (>1,800 Kds) reveal that many combinations of mutations to poorly conserved TF residues and nucleotides flanking the core binding site alter but preserve physiological binding, providing a mechanism by which combinations of mutations in cis and trans could modulate TF binding to tune occupancies during evolution. Moreover, biochemical double-mutant cycles across the TF-DNA interface reveal molecular mechanisms driving recognition, linking sequence to function. A record of this paper's Transparent Peer Review process is included in the Supplemental Information.
    Keywords:  DNA specificity; bHLH; basic helix-loop-helix; binding affinity; conformational selection; double-mutant cycle; microfluidics; protein-DNA binding; scanning mutagenesis; transcription factor; transcriptional regulation
  20. J Enzyme Inhib Med Chem. 2021 Dec;36(1): 307-318
      New piperazine-chalcone hybrids and related pyrazoline derivatives have been designed and synthesised as potential vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. The National Cancer Institute (NCI) has selected six compounds to evaluate their antiproliferative activity in vitro against 60 human cancer cells lines. Preliminary screening of the examined compounds indicated promising anticancer activity against number of cell lines. The enzyme inhibitory activity against VEGFR-2 was evaluated and IC50 of the tested compounds ranged from 0.57 µM to 1.48 µM. The most potent derivatives Vd and Ve were subjected to further investigations. A cell cycle analysis showed that both compounds mainly arrest HCT-116 cell cycle in the G2/M phase. Annexin V-FITC apoptosis assay showed that Vd and Ve induced an approximately 18.7-fold and 21.2-fold total increase in apoptosis compared to the control. Additionally, molecular docking study was performed against VEGFR (PDB ID: 4ASD) using MOE 2015.10 software and Sorafenib as a reference ligand.
    Keywords:  antitumor; molecular docking; vascular endothelial growth factor receptor
  21. J Cell Mol Med. 2020 Dec 21.
      microRNA-126 (miR-126), an endothelial-specific miRNA, is associated with vascular homeostasis and angiogenesis. However, the efficiency of miR-126-based treatment is partially compromised due to the low efficiency of miRNA delivery in vivo. Lately, exosomes have emerged as a natural tool for therapeutic molecule delivery. Herein, we investigated whether exosomes derived from bone marrow mesenchymal stem cells (BMMSCs) can be utilized to deliver miR-126 to promote angiogenesis. Exosomes were isolated from BMMSCs overexpressed with miR-126 (Exo-miR-126) by ultracentrifugation. In vitro study, Exo-miR-126 treatment promoted the proliferation, migration and angiogenesis of human umbilical vein endothelial cells (HUVECs). Furthermore, the gene/protein expression of angiogenesis-related vascular endothelial growth factor (VEGF) and angiotensin-1 (Ang-1) were up-regulated after incubation with Exo-miR-126. Additionally, the expression level of phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) showed an inverse correlation with miR-126 in HUVECs. Particularly, the Exo-miR-126 treatment contributed to enhanced angiogenesis of HUVECs by targeting PIK3R2 to activate the PI3K/Akt signalling pathway. Similarly, Exo-miR-126 administration profoundly increased the number of newly formed capillaries in wound sites and accelerated the wound healing in vivo. The results demonstrate that exosomes derived from BMMSCs combined with miR-126 may be a promising strategy to promote angiogenesis.
    Keywords:  angiogenesis; bone marrow mesenchymal stem cells; exosomes; microRNA-126
  22. Ann Pharmacother. 2020 Dec 21. 1060028020983014
      OBJECTIVE: To assess the clinical application of lurbinectedin and its role in the therapy of small-cell lung cancer (SCLC).DATA SOURCES: PubMed database and were utilized to perform a comprehensive literature search from August 2011 to mid-November 2020 with the terms lurbinectedin and PM01183.
    STUDY SELECTION AND DATA EXTRACTION: English-language clinical trials of lurbinectedin were evaluated.
    DATA SYNTHESIS: Lurbinectedin, as second-line therapy in SCLC, demonstrated an overall response (OR) rate of 35.2% and median overall survival of 9.3 months. Phase II studies in multiple cancers revealed myelosuppression (>95%), increased liver enzymes (>70%), nausea (up to 80%), vomiting (54%), and fatigue (>50%) as the most common adverse events associated with lurbinectedin. CYP3A4 drug interactions affect lurbinectedin exposure (severe pancytopenia occurred after coadministration with aprepitant), and protein binding can affect its clearance. Patients with cardiac comorbidities were not included in published lurbinectedin trials because of cardiotoxicity associated with trabectedin.
    RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Lurbinectedin is an option in SCLC after failure of a platinum-based regimen. Dose adjustments, drug interactions, antiemetic regimen choice, and patient comorbidities are important clinical considerations with lurbinectedin use. Likewise, its place in therapy in the era of immune checkpoint inhibitors requires further exploration.
    CONCLUSIONS: With a promising OR compared with other second-line options, lurbinectedin should be considered in patients who have failed first-line therapy. Studies are ongoing with lurbinectedin in combination with other agents in SCLC, and a phase III trial is assessing use in combination with doxorubicin compared with other second-line regimens.
    Keywords:  Zepzelca; extensive-stage; limited-stage; lurbinectedin; small-cell lung cancer
  23. Biomed Pharmacother. 2020 Dec 16. pii: S0753-3322(20)31284-1. [Epub ahead of print]134 111091
      The marine environment is an enormous source of marine-derived natural products (MNPs), and future investigation into anticancer drug discovery. Current progress in anticancer drugs offers a rise in isolation and clinical validation of numerous innovative developments and advances in anticancer therapy. However, only a limited number of FDA-approved marine-derived anticancer drugs are available due to several challenges and limitations highlighted here. The use of chitosan in developing marine-derived drugs is promising in the nanotech sector projected for a prolific anticancer drug delivery system (DDS). The cGAS-STING-mediated immune signaling pathway is crucial, which has not been significantly investigated in anticancer therapy and needs further attention. Additionally, a small range of anticancer mediators is currently involved in regulating various JAK/STAT signaling pathways, such as immunity, cell death, and tumor formation. This review addressed critical features associated with MNPs, origin, and development of anticancer drugs. Moreover, recent advances in the nanotech delivery of anticancer drugs and understanding into cancer immunity are detailed for improved human health.
    Keywords:  Anticancer drugs; Drug delivery system; JAK/STAT immune pathway; Marine-derived products; Nanotechnology; cGAS-STING
  24. Biochem Pharmacol. 2020 Dec 18. pii: S0006-2952(20)30620-1. [Epub ahead of print] 114384
      The uncontrolled growth and spread of abnormal cells because of activating protooncogenes and/or inactivating tumor suppressor genes are the hallmarks of cancer. The PI3K/Akt signaling is one of the most frequently activated pathways in cancer cells responsible for the regulation of cell survival and proliferation in stress and hypoxic conditions during oncogenesis. Non-coding RNAs are a large family of RNAs that are not involved in protein-coding, and microRNAs (miRNAs) are a sub-set of non-coding RNAs with a single strand of 18-25 nucleotides. miRNAs are extensively involved in the post-transcriptional regulation of gene expression and play an extensive role in the regulatory mechanisms including cell differentiation, proliferation, apoptosis, and tumorigenesis. The impact of cancer on mRNA stability and translation efficiency is extensive and therefore, cancerous tissues exhibit drastic alterations in the expression of miRNAs. miRNAs can be modulated by utilizing techniques such as miRNA mimics, miRNA antagonists, or CRISPR/Cas9. In addition to their capacity as potential targets in cancer therapy, they can be used as reliable biomarkers to diagnose the disease at the earliest stage. Recent evidence indicates that microRNA-mediated gene regulation intersects with the Akt pathway, forming an Akt-microRNA regulatory network. miRNAs and Akt in this network operate together to exert their cellular tasks. In the current review, we discuss the Akt-regulated miRNAs in several cancers, their molecular regulation, and how this newly emerging knowledge may contribute greatly to revolutionize cancer therapy.
    Keywords:  Akt; Biomarkers; Cancer; MicroRNAs; RNA-Therapeutics
  25. Mol Cell Endocrinol. 2020 Dec 18. pii: S0303-7207(20)30424-X. [Epub ahead of print] 111122
      Nonalcoholic fatty liver diseases (NAFLDs) are characterized by excessive triacylglycerol (TAG) accumulation in the liver which contributes to hepatocyte dysfunction, inflammation, and fibrosis. Patatin-like phospholipase domain-containing 3 (PNPLA3; also known as adiponutrin) has emerged as an important enzyme leading to hepatic TAG hydrolysis. Because the I148M substitution in the PNPLA3 gene markedly reduces hepatic TAG hydrolase activity, this genetic variation is strongly associated with increased hepatic TAG in the full spectrum of NAFLDs. The Retinoic acid-related orphan receptor α (RORα) regulates various target genes related to lipid metabolism. Here, we investigated the role of RORα on PNPLA3-mediated hepatic lipid hydrolysis. With blockade of lipid esterification and β-oxidation, RORα enhanced TAG hydrolysis, resulting in increased free glycerol levels. We found a putative RORα response element on the upstream of PNPLA3 gene that was activated by RORα. Furthermore, the inhibitory action of cJUN on the RORα/PNPLA3 axis was enhanced under lipid stress and contributed to hepatic lipid accumulation. In summary, we showed for the first time that RORα activates the transcription of PNPLA3, which suggests that RORα and its ligands represent potential precision therapeutic approaches for NAFLDs.
    Keywords:  Lipolysis; Nonalcoholic fatty liver disease; PNPLA3; RORα; Triacylglycerol
  26. Brief Bioinform. 2020 Dec 22. pii: bbaa389. [Epub ahead of print]
      Despite gene expression programs being notoriously complex, RNA abundance is usually assumed as a proxy for transcriptional activity. Recently developed approaches, able to disentangle transcriptional and post-transcriptional regulatory processes, have revealed a more complex scenario. It is now possible to work out how synthesis, processing and degradation kinetic rates collectively determine the abundance of each gene's RNA. It has become clear that the same transcriptional output can correspond to different combinations of the kinetic rates. This underscores the fact that markedly different modes of gene expression regulation exist, each with profound effects on a gene's ability to modulate its own expression. This review describes the development of the experimental and computational approaches, including RNA metabolic labeling and mathematical modeling, that have been disclosing the mechanisms underlying complex transcriptional programs. Current limitations and future perspectives in the field are also discussed.
    Keywords:  RNA degradation; RNA metabolic labeling; RNA processing; RNA synthesis; mathematical modeling; nascent RNA
  27. Physiol Genomics. 2020 Dec 21.
      Circulating cell-free DNA (cfDNA) and RNA (cfRNA) hold enormous potential as a new class of biomarkers for the development of non-invasive liquid biopsies in many diseases and conditions. In recent years, cfDNA and cfRNA have been studied intensely as tools for non-invasive prenatal testing, solid organ transplantation, cancer screening, and monitoring of tumors. In obesity, higher cfDNA concentration indicates accelerated cellular turnover of adipocytes during expansion of adipose mass and may be directly involved in the development of adipose tissue insulin resistance by inducing inflammation. Furthermore, cfDNA and cfRNA have promising diagnostic value in a range of obesity-related metabolic disorders, such as non-alcoholic fatty liver disease, type 2 diabetes, and diabetic complications. Here, we review the current and future applications of cfDNA and cfRNA within clinical diagnostics, discuss technical and analytical challenges in the field, and summarise the opportunities of using cfDNA and cfRNA in the diagnostics and prognostics of obesity-related metabolic disorders.
    Keywords:  Cell-free DNA; cell-free RNA; diagnostics; metabolic disorders; obesity
  28. Biomed Pharmacother. 2020 Dec 16. pii: S0753-3322(20)31308-1. [Epub ahead of print]134 111115
      Glioblastoma (GBM) is the most common primary malignant tumor in adults, and its morbidity and mortality are very high. Although progress has been achieved in the treatment of GBM, such as surgery, chemotherapy and radiotherapy, in recent years, the prognosis of patients with GBM has not improved significantly. MicroRNAs (miRNAs) are endogenous noncoding single-stranded RNAs consisting of approximately 20-22 nucleotides that regulate gene expression at the posttranscriptional level by binding to target protein-encoding mRNAs. Notably, miRNAs regulate various carcinogenic pathways, one of which is the epidermal growth factor receptor (EGFR) signaling pathway, which controls cell proliferation, invasion, migration, angiogenesis and apoptosis. In this review, we summarize the novel discoveries of roles for miRNAs targeting the factors in the EGFR signaling pathway in the occurrence and development of GBM. In addition, we describe their potential roles as biomarkers for the diagnosis and prognosis of GBM and for determining the treatment resistance of GBM and the efficacy of therapeutic drugs.
    Keywords:  EGFR signaling pathway; Glioblastoma; Predictive biomarkers; Treatment; microRNAs
  29. Arch Med Res. 2020 Dec 17. pii: S0188-4409(19)30912-9. [Epub ahead of print]
      BACKGROUND: Osteosarcoma (OS) is commonly known as a bone malignancy, causing a mass of lethality worldwide. Long coding RNAs (lncRNAs) have been widely reported by documents that they exert important functions in the development of cancers. However, the relative mechanism of lncRNA SOX21-AS1 needs to be fully discovered in OS, as it has never been studied in the past.AIM OF THE STUDY: To find out how SOX21-AS1 materializes its function in OS.
    METHODS: qRT-PCR detected RNA expression, and western blot tested the protein level. CCK8 and TUNEL assays were performed to assess cell viability and apoptosis. Next, Transwell analyses were applied to identify OS cell migration and invasion. Luciferase reporter, RIP and RNA pull-down experiments were employed for investigating the relationships among RNAs.
    RESULTS: SOX21-AS1 had high expression in OS, and its presence accelerated OS cell proliferation, migration and invasion. Interestingly, we evidenced that SOX21-AS1 sponged miR-7-5p, which then targeted IRS2 in OS cells. SOX21-AS1 competed with IRS2 in binding to miR-7-5p, which formulated the ceRNA signaling in OS. SOX21-AS1 could negatively regulate miR-7-5p expression. Rescue experiments certified that the enhancement of IRS2 would neutralize the inhibition of SOX21-AS1 depletion on OS cell proliferation and metastasis.
    CONCLUSIONS: SOX21-AS1 enhances IRS2 level by absorbing miR-7-5p, so as to boost the progression of OS.
    Keywords:  IRS2; Osteosarcoma; SOX21-AS1; miR-7-5p
  30. Nucleic Acids Res. 2020 Dec 21. pii: gkaa1219. [Epub ahead of print]
      An abnormally high rate of UV-light related mutations appears at transcription factor binding sites (TFBS) across melanomas. The binding of transcription factors (TFs) to the DNA impairs the repair of UV-induced lesions and certain TFs have been shown to increase the rate of generation of these lesions at their binding sites. However, the precise contribution of these two elements to the increase in mutation rate at TFBS in these malignant cells is not understood. Here, exploiting nucleotide-resolution data, we computed the rate of formation and repair of UV-lesions within the binding sites of TFs of different families. We observed, at certain dipyrimidine positions within the binding site of TFs in the Tryptophan Cluster family, an increased rate of formation of UV-induced lesions, corroborating previous studies. Nevertheless, across most families of TFs, the observed increased mutation rate within the entire DNA region covered by the protein results from the decreased repair efficiency. While the rate of mutations across all TFBS does not agree with the amount of UV-induced lesions observed immediately after UV exposure, it strongly agrees with that observed after 48 h. This corroborates the determinant role of the impaired repair in the observed increase of mutation rate.
  31. Front Genet. 2020 ;11 595550
      Cancer is characterized by dysregulation at multiple levels, such as gene transcription. Enhancers are well-studied transcription regulators that can enhance target transcripts through DNA loop formation mediated by chromosome folding. The gain or loss of the interaction between an enhancer and its target gene has a critical effect on gene expression. In this study, we analyzed GRO-seq data to identify active enhancers from seven common cancer cell lines and studied the function of these enhancers across multiple cancer types. By constructing an "enhancer effect score" (EES), we found a significant correlation between EES and tumor-infiltrating lymphocytes (TILs) in prostate cancer. Further analysis revealed that androgen receptor (AR) plays an important role in regulating the immune checkpoint gene PVR via its enhancer. These results suggest that AR contributes to prostate cancer aggressiveness by promoting cancer cell immune evasion.
    Keywords:  GRO-seq; androgen receptor; enhancer; immune evading; prostate cancer
  32. Brief Bioinform. 2020 Dec 22. pii: bbaa357. [Epub ahead of print]
      Drug repositioning has received increased attention since the past decade as several blockbuster drugs have come out of repositioning. Computational approaches are significantly contributing to these efforts, of which, network-based methods play a key role. Various structural (topological) network measures have thereby contributed to uncovering unintuitive functional relationships and repositioning candidates in drug-disease and other networks. This review gives a broad overview of the topic, and offers perspectives on the application of topological measures for network analysis. It also discusses unexplored measures, and draws attention to a wider scope of application efforts, especially in drug repositioning.
    Keywords:  computational methods; drug repositioning; networks; topological network measures; topology
  33. Transl Oncol. 2020 Dec 15. pii: S1936-5233(20)30475-7. [Epub ahead of print]14(2): 100983
      Radiotherapy (RT) has been used to control tumors by physically damaging DNA and inducing apoptosis; it also promotes antitumor immune responses via neoantigens release and augmenting immune-oncology agents to elicit systemic response. Tumor regression after RT can recruit inflammatory cells, such as tumor-associated macrophages and CD11b+ myeloid cell populations, a major subset of which may actually be immunosuppressive. However, these inflammatory cells also express Toll-like receptors (TLRs) that can be stimulated to reverse suppressive characteristics and promote systemic antitumor outcomes. Here, we investigated the effects of adding CMP-001, a CpG-A oligodeoxynucleotide TLR9 agonist delivered in a virus-like particle (VLP), to RT in two murine models (344SQ metastatic lung adenocarcinoma and CT26 colon carcinoma). High-dose RT (12Gy x 3 fractions) significantly increased the percentages of plasmacytoid dendritic cells within the tumor islets 3- and 5-days post-RT; adding CMP-001 after RT also enhanced adaptive immunity by increasing the proportion of CD4+ and CD8+ T cells. RT plus CMP-001-mediated activation of the immune system led to significant inhibition of tumor growth at both primary and abscopal tumor sites, thereby suggesting a new combinatorial treatment strategy for systemic disease.
    Keywords:  Abscopal effect; CMP-001; Cancer; Radiotherapy; TLR9 agonist
  34. Nucleic Acids Res. 2020 Dec 21. pii: gkaa1155. [Epub ahead of print]
      Chromatin immunoprecipitation (IP) followed by sequencing (ChIP-seq) is the gold standard to detect transcription-factor (TF) binding sites in the genome. Its success depends on appropriate controls removing systematic biases. The predominantly used controls, i.e. DNA input, correct for uneven sonication, but not for nonspecific interactions of the IP antibody. Another type of controls, 'mock' IP, corrects for both of the issues, but is not widely used because it is considered susceptible to technical noise. The tradeoff between the two control types has not been investigated systematically. Therefore, we generated comparable DNA input and mock IP experiments. Because mock IPs contain only nonspecific interactions, the sites predicted from them using DNA input indicate the spurious-site abundance. This abundance is highly correlated with the 'genomic activity' (e.g. chromatin openness). In particular, compared to cell lines, complex samples such as whole organisms have more spurious sites-probably because they contain multiple cell types, resulting in more expressed genes and more open chromatin. Consequently, DNA input and mock IP controls performed similarly for cell lines, whereas for complex samples, mock IP substantially reduced the number of spurious sites. However, DNA input is still informative; thus, we developed a simple framework integrating both controls, improving binding site detection.