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1.
J Clin Med ; 12(2)2023 Jan 11.
Article in English | MEDLINE | ID: mdl-36675528

ABSTRACT

Translational research in medicine, defined as the transfer of knowledge and discovery from the basic sciences to the clinic, is typically achieved through interactions between members across scientific disciplines to overcome the traditional silos within the community. Thus, translational medicine underscores 'Team Medicine', the partnership between basic science researchers and clinicians focused on addressing a specific goal in medicine. Here, we highlight this concept from a City of Hope perspective. Using cisplatin resistance in non-small cell lung cancer (NSCLC) as a paradigm, we describe how basic research scientists, clinical research scientists, and medical oncologists, in true 'Team Science' spirit, addressed cisplatin resistance in NSCLC and identified a previously approved compound that is able to alleviate cisplatin resistance in NSCLC. Furthermore, we discuss how a 'Team Medicine' approach can help to elucidate the mechanisms of innate and acquired resistance in NSCLC and develop alternative strategies to overcome drug resistance.

2.
Biochim Biophys Acta Rev Cancer ; 1877(5): 188803, 2022 09.
Article in English | MEDLINE | ID: mdl-36150564

ABSTRACT

Previously, we showed that knockout mice homozygous for deficiency of the mercapturic acid pathway (MAP) transporter protein, RLIP (RLIP-/-), are resistant to chemical carcinogenesis, inflammation, and metabolic syndrome (MetS). We also found that RLIP-/- mice are highly resistant to obesity caused by a high-fat diet (HFD). Interestingly, these studies showed that kinase, cytokine, and adipokine signaling that are characteristics of obesity were blocked despite the presence of increased oxidative stress in RLIP-/- mice. The deficiencies in obesity-inducing kinase, cytokine, and adipokine signaling were attributable to a lack of clathrin-dependent endocytosis (CDE), a process that is severely deficient in RLIP-/- mice. Because CDE is also necessary for carcinogenic signaling through EGF, WNT, TGFß and other cancer-specific peptide hormones, and because RLIP-/- mice are cancer-resistant, we reasoned that depletion of RLIP by an antisense approach should cause cancer regression in human cancer xenografts. This prediction has been confirmed in studies of xenografts from lung, kidney, prostate, breast, and pancreatic cancers and melanoma. Because these results suggested an essential role for RLIP in carcinogenesis, and because our studies have also revealed a direct interaction between p53 and RLIP, we reasoned that if RLIP played a central role in carcinogenesis, that development of lymphoma in p53-/- mice, which normally occurs by the time these mice are 6 months old, could be delayed or prevented by depleting RLIP. Recent studies described herein have confirmed this hypothesis, showing complete suppression of lymphomagenesis in p53-/- mice treated with anti-RLIP antisense until the age of 8 months. All control mice developed lymphoma in the thymus or testis as expected. These findings lead to a novel paradigm predicting that under conditions of increased oxidative stress, the consequent increased flux of metabolites in the MAP causes a proportional increase in the rate of CDE. Because CDE inhibits insulin and TNF signaling but promotes EGF, TGFß, and Wnt signaling, our model predicts that chronic stress-induced increases in RLIP (and consequently CDE) will induce insulin-resistance and enhance predisposition to cancer. Alternatively, generalized depletion of RLIP would antagonize the growth of malignant cells, and concomitantly exert therapeutic insulin-sensitizing effects. Therefore, this review focuses on how targeted depletion or inhibition of RLIP could provide a novel target for treating both obesity and cancer.


Subject(s)
Insulins , Neoplasms , Peptide Hormones , Acetylcysteine/metabolism , Adipokines/metabolism , Animals , Carcinogenesis/genetics , Carcinogens , Carrier Proteins/metabolism , Clathrin/metabolism , Cytokines/metabolism , Epidermal Growth Factor/metabolism , GTPase-Activating Proteins/metabolism , Humans , Infant , Insulins/metabolism , Male , Mice , Obesity/genetics , Oxidative Stress , Peptide Hormones/metabolism , Transforming Growth Factor beta/metabolism , Tumor Suppressor Protein p53/metabolism
3.
RSC Adv ; 9(58): 33602-33606, 2019 Oct 18.
Article in English | MEDLINE | ID: mdl-35528879

ABSTRACT

We report a facile, green synthesis of graphene/Ag/ZnO nanocomposites and their use as acetone sensors via a medicinal plant extraction assisted precipitation process. The choice of plant extract in combination with metal nitrates led to self-sustaining colloid chemistry. Along with the green synthesis strategy, structural, morphological and gas sensing properties are described.

6.
Asian J Neurosurg ; 16(4): 770-776, 2021.
Article in English | MEDLINE | ID: mdl-35071076

ABSTRACT

INTRODUCTION: Salivary gland hypofunction might be associated with various local and systemic conditions and is managed with a plethora of therapeutic options with associated side effects. Transcutaneous electrical nerve stimulation (TENS) is one such option with no known systemic side effects for dealing with this crippling condition. The present study was planned with a similar intent of assessing impact of TENS on salivary flow rates in normal healthy adults according to gender and age groups. MATERIALS AND METHODS: The present study was designed as a cross-sectional study on 130 healthy adults wherein unstimulated and stimulated saliva was collected for 5 min in graduated test tubes fitted with a funnel while mean salivary flow rates were calculated. The data were analyzed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). RESULTS: In the present study, differences between mean unstimulated and stimulated salivary flow rates with TENS were found to be statistically significant for both genders (P < 0.001). Furthermore, in relation to age groups included, maximum increase in salivary flow rate was seen in 20-29 years of age group, though significant results were seen in all three age groups included namely 20-29 years, 30-39 years, and 40-49 years (P < 0.001). CONCLUSIONS: Based on results from the present study, it could be concluded that TENS comes out to be a safer, nonpharmacological therapeutic option for treating patients with xerostomia.

7.
Cancers (Basel) ; 13(24)2021 Dec 20.
Article in English | MEDLINE | ID: mdl-34944997

ABSTRACT

Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox generates the pro-apoptotic Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE), we surmised that Ω-6 PUFAs would increase the effectiveness of dox chemotherapy. Since the mercapturic acid pathway enzyme RALBP1 (also known as RLIP76 or Rlip) that limits cellular accumulation of 4-HNE also mediates dox resistance, the combination of Ω-6 PUFAs and Rlip depletion could synergistically improve the efficacy of dox. Thus, we studied the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip knockdown on the antineoplastic activity of dox towards Her2-amplified breast cancer cell lines SK-BR-3, which is sensitive to Her2 inhibitors, and AU565, which is resistant. AA increased lipid peroxidation, 4-HNE generation, apoptosis, cellular dox concentration and dox cytotoxicity in both cell lines while sparing cultured immortalized cardiomyocyte cells. The known functions of Rlip including clathrin-dependent endocytosis and dox efflux were inhibited by AA. Our results support a model in which 4-HNE generated by AA overwhelms the capacity of Rlip to defend against apoptosis caused by dox or 4-HNE. We propose that Ω-6 PUFA supplementation could improve the efficacy of dox or Rlip inhibitors for treating Her2-amplified breast cancer.

8.
Chem Soc Rev ; 51(1): 293-328, 2022 Jan 04.
Article in English | MEDLINE | ID: mdl-34889926

ABSTRACT

This review provides a comprehensive overview of recent advances in the supramolecular organisation and hierarchical self-assembly of organo-functionalised hybrid polyoxometalates (hereafter referred to as hybrid POMs), and their emerging role as multi-functional building blocks in the construction of new nanomaterials. Polyoxometalates have long been studied as a fascinating outgrowth of traditional metal-oxide chemistry, where the unusual position they occupy between individual metal oxoanions and solid-state bulk oxides imbues them with a range of attractive properties (e.g. solubility, high structural modularity and tuneable properties/reactivity). Specifically, the capacity for POMs to be covalently coupled to an effectively limitless range of organic moieties has opened exciting new avenues in their rational design, while the combination of distinct organic and inorganic components facilitates the formation of complex molecular architectures and the emergence of new, unique functionalities. Here, we present a detailed discussion of the design opportunities afforded by hybrid POMs, where fine control over their size, topology and their covalent and non-covalent interactions with a range of other species and/or substrates makes them ideal building blocks in the assembly of a broad range of supramolecular hybrid nanomaterials. We review both direct self-assembly approaches (encompassing both solution and solid-state approaches) and the non-covalent interactions of hybrid POMs with a range of suitable substrates (including cavitands, carbon nanotubes and biological systems), while giving key consideration to the underlying driving forces in each case. Ultimately, this review aims to demonstrate the enormous potential that the rational assembly of hybrid POM clusters shows for the development of next-generation nanomaterials with applications in areas as diverse as catalysis, energy-storage and molecular biology, while providing our perspective on where the next major developments in the field may emerge.


Subject(s)
Nanostructures , Nanotubes, Carbon , Anions , Polyelectrolytes
10.
Cancers (Basel) ; 13(13)2021 Jul 02.
Article in English | MEDLINE | ID: mdl-34283045

ABSTRACT

We recently reported that loss of one or both alleles of Ralbp1, which encodes the stress-protective protein RLIP76 (Rlip), exerts a strong dominant negative effect on both the inherent cancer susceptibility and the chemically inducible cancer susceptibility of mice lacking one or both alleles of the tumor suppressor p53. In this paper, we examined whether congenital Rlip deficiency could prevent genetically-driven breast cancer in two transgenic mouse models: the MMTV-PyVT model, which expresses the polyomavirus middle T antigen (PyVT) under control of the mouse mammary tumor virus promoter (MMTV) and the MMTV-Erbb2 model which expresses MMTV-driven erythroblastic leukemia viral oncogene homolog 2 (Erbb2, HER2/Neu) and frequently acquires p53 mutations. We found that loss of either one or two Rlip alleles had a suppressive effect on carcinogenesis in Erbb2 over-expressing mice. Interestingly, Rlip deficiency did not affect tumor growth but significantly reduced the lung metastatic burden of breast cancer in the viral PyVT model, which does not depend on either Ras or loss of p53. Furthermore, spontaneous tumors of MMTV-PyVT/Rlip+/+ mice showed no regression following Rlip knockdown. Finally, mice lacking one or both Rlip alleles differentially expressed markers for apoptotic signaling, proliferation, angiogenesis, and cell cycling in PyVT and Erbb2 breast tumors. Our results support the efficacy of Rlip depletion in suppressing p53 inactivated cancers, and our findings may yield novel methods for prevention or treatment of cancer in patients with HER2 mutations or tumor HER2 expression.

11.
Mol Cancer Ther ; 20(10): 1820-1835, 2021 10.
Article in English | MEDLINE | ID: mdl-34253596

ABSTRACT

Protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of apoptosis, proliferation, and DNA-damage response, is overexpressed in many cancers, including small cell lung cancer (SCLC). Here we report that LB100, a small molecule inhibitor of PP2A, when combined with platinum-based chemotherapy, synergistically elicited an antitumor response both in vitro and in vivo with no apparent toxicity. Using inductively coupled plasma mass spectrometry, we determined quantitatively that sensitization via LB100 was mediated by increased uptake of carboplatin in SCLC cells. Treatment with LB100 alone or in combination resulted in inhibition of cell viability in two-dimensional culture and three-dimensional spheroid models of SCLC, reduced glucose uptake, and attenuated mitochondrial and glycolytic ATP production. Combining LB100 with atezolizumab increased the capacity of T cells to infiltrate and kill tumor spheroids, and combining LB100 with carboplatin caused hyperphosphorylation of the DNA repair marker γH2AX and enhanced apoptosis while attenuating MET signaling and invasion through an endothelial cell monolayer. Taken together, these data highlight the translational potential of inhibiting PP2A with LB100 in combination with platinum-based chemotherapy and immunotherapy in SCLC.


Subject(s)
Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Lung Neoplasms/drug therapy , Piperazines/pharmacology , Protein Phosphatase 2/antagonists & inhibitors , Small Cell Lung Carcinoma/drug therapy , Antineoplastic Agents/pharmacology , Apoptosis , Cell Proliferation , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Small Cell Lung Carcinoma/enzymology , Small Cell Lung Carcinoma/pathology , Tumor Cells, Cultured
12.
Cancer Lett ; 518: 10-22, 2021 10 10.
Article in English | MEDLINE | ID: mdl-34126193

ABSTRACT

The treatment of metastatic melanoma is greatly hampered by the simultaneous dysregulation of several major signaling pathways that suppress apoptosis and promote its growth and invasion. The global resistance of melanomas to therapeutics is also supported by a highly active mercapturic acid pathway (MAP), which is responsible for the metabolism and excretion of numerous chemotherapy agents. The relative importance of the MAP in melanoma survival was not recognized until demonstrated that B16 melanoma undergoes dramatic apoptosis and regression upon the depletion or inhibition of the MAP transporter protein RLIP. RLIP is a multi-functional protein that couples ATP hydrolysis with the movement of substances. As the rate-limiting step of the MAP, the primary function of RLIP in the plasma membrane is to catalyze the ATP-dependent efflux of unmetabolized drugs and toxins, including glutathione (GSH) conjugates of electrophilic toxins (GS-Es), which are the precursors of mercapturic acids. Clathrin-dependent endocytosis (CDE) is an essential mechanism for internalizing ligand-receptor complexes that promote tumor cell proliferation through autocrine stimulation (Wnt5a, PDGF, ßFGF, TNFα) or paracrine stimulation by hormones produced by fibroblasts (IGF1, HGF) or inflammatory cells (IL8). Aberrant functioning of these pathways appears critical for melanoma cell invasion, metastasis, and evasion of apoptosis. This review focuses on the selective depletion or inhibition of RLIP as a highly effective targeted therapy for melanoma that could cause the simultaneous disruption of the MAP and critical peptide hormone signaling that relies on CDE.


Subject(s)
Acetylcysteine/metabolism , Melanoma/metabolism , ATP-Binding Cassette Transporters/metabolism , Animals , Apoptosis/physiology , Endocytosis/physiology , Humans
13.
Sci Rep ; 11(1): 5023, 2021 Mar 03.
Article in English | MEDLINE | ID: mdl-33658543

ABSTRACT

Surface area and surface active sites are two important key parameters in enhancing the gas sensing as well as photocatalytic properties of the parent material. With this motivation, herein, we report a facile synthesis of Reduced Graphene Oxide/Tungsten Oxide RGO/WO3 hierarchical nanostructures via simple hydrothermal route, and their validation in accomplishment of improved H2S sensing and highly efficient solar driven photo-degradation of RhB Dye. The self-made RGO using modified Hummer's method, is utilized to develop the RGO/WO3 nanocomposites with 0.15, 0.3 and 0.5 wt% of RGO in WO3 matrix. As-developed nanocomposites were analyzed using various physicochemical techniques such as XRD, FE-SEM, TEM/HRTEM, and EDAX. The creation of hierarchic marigold frameworks culminated in a well affiliated mesoporous system, offering efficient gas delivery networks, leading to a significant increase in sensing response to H2S. The optimized sensor (RGO/WO3 with 0.3 wt% loading) exhibited selective response towards H2S, which is ~ 13 times higher (Ra/Rg = 22.9) than pristine WO3 (Ra/Rg = 1.78) sensor. Looking at bi-directional application, graphene platform boosted the photocatalytic activity (94% degradation of Rhodamine B dye in 210 min) under natural sunlight. The RGO's role in increasing the active surface and surface area is clarified by the H2S gas response analysis and solar-driven photo-degradation of RhB dye solution. The outcome of this study provides the new insights to RGO/WO3 based nanocomposites' research spreadsheet, in view of multidisciplinary applications.

14.
Carcinogenesis ; 42(5): 742-752, 2021 05 28.
Article in English | MEDLINE | ID: mdl-33623991

ABSTRACT

The incidence of malignant melanoma, a neoplasm of melanocytic cells, is increasing rapidly. The lymph nodes are often the first site of metastasis and can herald systemic dissemination, which is almost uniformly fatal. RLIP, a multi-specific ATP-dependent transporter that is over-expressed in several types of cancers, plays a central role in cancer cell resistance to radiation and chemotherapy. RLIP appears to be necessary for cancer cell survival because both in vitro cell culture and in vivo animal tumor studies show that the depletion or inhibition of RLIP causes selective toxicity to malignant cells. RLIP depletion/inhibition triggers apoptosis in cancer cells by inducing the accumulation of endogenously formed glutathione-conjugates. In our in vivo studies, we administered RLIP antibodies or antisense oligonucleotides to mice bearing subcutaneous xenografts of SKMEL2 and SKMEL5 melanoma cells and demonstrated that both treatments caused significant xenograft regression with no apparent toxic effects. Anti-RLIP antibodies and antisense, which respectively inhibit RLIP-mediated transport and deplete RLIP expression, showed similar tumor regressing activities, indicating that the inhibition of RLIP transport activity at the cell surface is sufficient to achieve anti-tumor activity. Furthermore, RLIP antisense treatment reduced levels of RLIP, pSTAT3, pJAK2, pSrc, Mcl-1 and Bcl2, as well as CDK4 and cyclin B1, and increased levels of Bax and phospho 5' AMP-activated protein kinase (pAMPK). These studies indicate that RLIP serves as a key effector in the survival of melanoma cells and is a valid target for cancer therapy. Overall, compounds that inhibit, deplete or downregulate RLIP will function as wide-spectrum agents to treat melanoma, independent of common signaling pathway mutations.


Subject(s)
ATP-Binding Cassette Transporters/genetics , GTPase-Activating Proteins/genetics , Janus Kinase 2/genetics , Melanoma/genetics , STAT3 Transcription Factor/genetics , ATP-Binding Cassette Transporters/antagonists & inhibitors , ATP-Binding Cassette Transporters/immunology , Animals , Antibodies, Anti-Idiotypic/pharmacology , Apoptosis/genetics , Cell Line, Tumor , Cell Survival/genetics , GTPase-Activating Proteins/antagonists & inhibitors , GTPase-Activating Proteins/immunology , Humans , Melanoma/pathology , Mice , Neoplasm Proteins/genetics , Signal Transduction/genetics , Xenograft Model Antitumor Assays
15.
Mol Carcinog ; 60(3): 213-223, 2021 03.
Article in English | MEDLINE | ID: mdl-33544936

ABSTRACT

The overexpression and amplification of the protooncogene neu (ERBB2) play an important role in the development of aggressive breast cancer (BC) in humans. Ral-interacting protein (RLIP), a modular stress-response protein with pleiotropic functions, is overexpressed in several types of cancer, including BC. Here, we show that blocking RLIP attenuates the deleterious effects caused by the loss of the tumor suppressor p53 and inhibits the growth of human BC both in vitro and in vivo in MMTV-neu mice. In addition, we show that treatment with the diet-derived, RLIP-targeting chemotherapeutic 2'-hydroxyflavanone (2HF), alone or in combination with RLIP-specific antisense RNA or antibodies, significantly reduced the cumulative incidence and/or burden of mammary hyperplasia and carcinoma in MMTV-neu mice. 2HF treatment correlated with reduced tumor cell proliferation and increased apoptosis, and the average number of Ki67-positive (proliferating) cells was significantly lower in the tumors of 2HF-treated mice than in the tumors of control mice. Furthermore, targeting RLIP also resulted in the overexpression of E-cadherin and the infiltration of CD3+ T cells into mammary tumors. Taken together, these results underscore the translational potential of RLIP-targeting agents and provide a strong rationale to validate them in the clinic.


Subject(s)
ATP-Binding Cassette Transporters/metabolism , Anticarcinogenic Agents/pharmacology , Breast Neoplasms/metabolism , GTPase-Activating Proteins/metabolism , Mammary Neoplasms, Experimental/prevention & control , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Flavanones/pharmacology , GTPase-Activating Proteins/genetics , Humans , Lymphocytes, Tumor-Infiltrating/drug effects , Mammary Glands, Animal/drug effects , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/pathology , Mice, Transgenic , Molecular Targeted Therapy , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptor, ErbB-2/metabolism
16.
Biochim Biophys Acta Rev Cancer ; 1875(2): 188512, 2021 04.
Article in English | MEDLINE | ID: mdl-33460725

ABSTRACT

Aberrations in RLIP, p53, and PKCα represent essentially the entire spectrum of all human neoplasms. Elevated PKCα expression, failure of the cell cycle checkpoint (p53 dysfunction), and abnormal glutathione (GSH) metabolism are fundamental hallmarks of carcinogenesis and drug/radiation resistance. However, a lack of investigations into the interactions between these important regulatory nodes has fundamentally limited our understanding of carcinogenesis and the development of effective interventions for cancer prevention and therapy. Loss of p53, perhaps the most powerful tumor suppressor gene, predisposes rodents to spontaneous cancer and humans to familial, as well as acquired, cancers. Until recently, no genetic manipulation of any oncogene had been reported to abrogate spontaneous carcinogenesis in p53-/- rodent models. However, the overexpression of RLIP, a GSH-electrophile conjugate (GS-E) transporter, has been found to enhance cancer cell proliferation and confer drug/radiation resistance, whereas its depletion causes tumor regression, suggesting its importance in cancer and drug/radiation resistance. Indeed, RLIP is an essential effector of p53 that is necessary for broad cancer-promoting epigenetic remodeling. Interestingly, through a haploinsufficiency mechanism, the partial depletion of RLIP in p53-/- mice provides complete protection from neoplasia. Furthermore, RLIP-/- mice exhibit altered p53 and PKCα function, marked deficiency in clathrin-dependent endocytosis (CDE), and almost total resistance to chemical carcinogenesis. Based on these findings, in this review, we present a novel and radical hypothesis that expands our understanding of the highly significant cross-talk between p53, PKCα, and GSH signaling by RLIP in multiple tumor models.


Subject(s)
ATP-Binding Cassette Transporters/metabolism , GTPase-Activating Proteins/metabolism , Neoplasms/metabolism , Protein Kinase C-alpha/metabolism , Tumor Suppressor Protein p53/metabolism , ATP-Binding Cassette Transporters/genetics , Animals , Drug Resistance, Neoplasm , Drug Tolerance , GTPase-Activating Proteins/genetics , Gene Expression Regulation, Neoplastic , Humans , Signal Transduction , Tumor Suppressor Protein p53/genetics
17.
Biosens Bioelectron ; 165: 112397, 2020 Oct 01.
Article in English | MEDLINE | ID: mdl-32729518

ABSTRACT

Stereochemical configuration of the drug is responsible for racemic switch with enantiomers in presence of chiral environment for human beings. Therefore, its determination in racemic and pharmaceutical samples becomes a challenge. Addressing this issue, an enantioselective electrochemical biomimetic sensor for discrimination of isomers of ethambutol (ETB) employing square wave voltammetry (SWV) is reported for the first time. For this purpose, a chiral host, ß-Cyclodextrin based copper metal organic framework (CD-CuMOF) was synthesized and used for chelate complexation of ETB isomers (SS-ETB/RR-ETB). A glassy carbon electrode (GCE) is chemically modified using CD-CuMOF and carbon nanofibers (CNF) composite material to construct a sensor in the form of (CD-CuMOF-CNF-GCE). The behaviour of CD-CuMOF for ETB isomers on GCE is postulated to be an artificial enzyme model (AEM) as it mimics the catalytic activity similar to enzyme alcohol dehydrogenase for ETB. The biosensor exhibits excellent peak potential difference (ΔEp (SS-RR) = 108 mV) between ETB isomers using SWV showing a clear distinction in the racemic mixture. It showed a linear response in the range of 1.0 x 10-7 to 1 x 10-4 M and 5.0 x 10-7 to 2.5 x 10-4 M with low detection limit of 3.10 x 10-8 M and 8.52 x 10-8 M for RR-ETB and SS-ETB isomers respectively. The sensor was applied for the estimation of ETB isomers in racemic mixture and real samples viz., blood, urine and pharmaceutical. The CD-CuMOF is a low-cost material with higher stability than enzyme and offers an advantage for sensing and catalysis in future.


Subject(s)
Biosensing Techniques , Metal-Organic Frameworks , Nanofibers , beta-Cyclodextrins , Biomimetics , Carbon , Copper , Electrochemical Techniques , Electrodes , Ethambutol , Humans
18.
Cancers (Basel) ; 12(6)2020 Jun 02.
Article in English | MEDLINE | ID: mdl-32498332

ABSTRACT

RLIP76 (RAL-binding protein-1, Rlip) is a stress-protective mercapturic-acid-pathway transporter protein that also plays a key role in regulating clathrin-dependent endocytosis as a Ral effector. Targeted inhibition or depletion of Rlip causes regression of xenografts of many cancers and is capable of abrogating tumor formation in p53-null mice. This is associated with the reversion of the abnormal methylomic profile of p53-null mice to wild-type. In a query of The Cancer Genome Atlas (TCGA) databases, we found that Rlip expression was associated with poor survival and with significant differences in the frequencies of PIK3CA mutation, MYC amplification, and CDKN2A/B deletion, which were the most commonly mutated, amplified, and deleted genes, respectively, among TCGA breast cancer patients. We conducted the present study to further examine the effects of Rlip inhibition and to evaluate the in vitro and in vivo efficacy in breast cancer. Using immunogold electron microscopy, we found that plasma-membrane Rlip was accessible to cell-surface antibodies in the MCF7 (ER+) breast cancer cell line. Rlip depletion resulted in decreased survival of MCF7 and MDA-MB-231 cells and increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity and DNA laddering, indicating apoptotic cell death. Additionally, in vitro knockdown of Rlip inhibited EGF endocytosis and WNT/MAPK signaling. Xenograft studies in nude mice showed regression of breast cancer via antisense-mediated depletion of Rlip mRNA as well as by anti-Rlip antibody. Finally, knockdown of Rlip by antisense locked nucleic acid oligonucleotides increased markers for apoptotic signaling and decreased markers for proliferation, angiogenesis, and cell cycling in MCF7 and MDA-MB-231luc xenografts. Our findings validate Rlip as an attractive target in breast cancer.

19.
Cancer Lett ; 484: 16-28, 2020 08 01.
Article in English | MEDLINE | ID: mdl-32387443

ABSTRACT

MicroRNAs (miRNAs/or miR) are a type of small, non-coding RNAs that regulate gene expression by binding to 3'-UTRs of the target genes. miRNAs can serve as oncogenes or tumor suppressors, and have prognostic and therapeutic values that may be directly applicable in the clinic. miR-216b is located on chromosome 2p16.1. Accumulating evidence suggests that it acts as a tumor suppressor and its downregulation may play a significant role in cancer biology through the dysregulation of various oncogenes and signaling pathways related to cancer cell proliferation, cell cycle progression, migration, invasion, apoptosis, and chemoresistance. In this review, we discuss the aberrant expression of miR-216b in cancer and its role in tumor pathogenesis, which will offer novel insights into its clinical applications.


Subject(s)
Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , MicroRNAs/genetics , Neoplasms/genetics , Apoptosis/genetics , Cell Proliferation/genetics , Humans , Neoplasms/classification , Neoplasms/therapy , Prognosis , Signal Transduction/genetics
20.
IDCases ; 20: e00778, 2020.
Article in English | MEDLINE | ID: mdl-32341910

ABSTRACT

People exposed to COVID-19 have a risk of developing disease, and health care workers are at risk at a time when they are badly needed during a health care crisis. Hydroxychloroquine and chloroquine have been used as treatment and are being considered as prophylaxis. Our patient developed COVID-19 while on hydroxychloroquine and although more work is needed, this calls into question the role of these medications as preventive therapy.

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