Publications by authors named "Mohammad Aslam Khan"

29 Publications

  • Page 1 of 1

Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management.

Semin Cancer Biol 2021 Aug 18. Epub 2021 Aug 18.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, 36617, United States; Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, United States; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, United States. Electronic address:

Resistance to platinum-based chemotherapy is a major clinical challenge in ovarian cancer, contributing to the high mortality-to-incidence ratio. Management of the platinum-resistant disease has been difficult due to diverse underlying molecular mechanisms. Over the past several years, research has revealed several novel molecular targets that are being explored as biomarkers for treatment planning and monitoring of response. The therapeutic landscape of ovarian cancer is also rapidly evolving, and alternative therapies are becoming available for the recurrent platinum-resistant disease. This review provides a snapshot of platinum resistance mechanisms and discusses liquid-based biomarkers and their potential utility in effective management of platinum-resistant ovarian cancer.
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http://dx.doi.org/10.1016/j.semcancer.2021.08.005DOI Listing
August 2021

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

Sci Rep 2021 Jun 18;11(1):12901. Epub 2021 Jun 18.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, 36617, USA.

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.
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http://dx.doi.org/10.1038/s41598-021-92352-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213794PMC
June 2021

Extracellular Nanovesicles: From Intercellular Messengers to Efficient Drug Delivery Systems.

ACS Omega 2021 Jan 11;6(3):1773-1779. Epub 2021 Jan 11.

Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, United States.

Nanosized extracellular vesicles (nEV) are released by all the eukaryotic cells into the extracellular spaces. They serve as crucial mediators of intercellular communication, and their presence has been detected in a variety of body fluids. nEV carry nucleic acids, lipids, proteins, and metabolites from the donor cells and transfer them to the recipient cells in the vicinity or distant locations to cause changes in their biological phenotypes. This very property of nEV makes them a suitable carrier of the drugs for therapeutic applications. The use of nEV as a drug delivery system offers several advantages over synthetic nanoparticles, including biocompatibility, natural targeting ability, and long-term safety. Further, nEV can be isolated from various biological sources, quickly loaded with the drug of choice, and modified to further enhance their utility as targeted drug delivery vehicles. Here we review these aspects of nEV and discuss the parameters that should be kept in mind while choosing the nEV source, drug loading method, and surface modification strategies. We also discuss the challenges associated with the nEV-based drug delivery platforms that must be overcome before realizing their full potential in clinical applications.
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http://dx.doi.org/10.1021/acsomega.0c05539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841770PMC
January 2021

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

ACS Omega 2020 Sep 31;5(36):23299-23307. Epub 2020 Aug 31.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama 36617, United States.

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.
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http://dx.doi.org/10.1021/acsomega.0c03136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495913PMC
September 2020

Comprehensive Analysis of Expression, Clinicopathological Association and Potential Prognostic Significance of RABs in Pancreatic Cancer.

Int J Mol Sci 2020 Aug 4;21(15). Epub 2020 Aug 4.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL 36617, USA.

RAB proteins (RABs) represent the largest subfamily of Ras-like small GTPases that regulate a wide variety of endosomal membrane transport pathways. Their aberrant expression has been demonstrated in various malignancies and implicated in pathogenesis. Using The Cancer Genome Atlas (TCGA) database, we analyzed the differential expression and clinicopathological association of genes in pancreatic ductal adenocarcinoma (PDAC). Of the 62 genes analyzed, five and ) exhibited statistically significant upregulation, while five ( and ) were downregulated in PDAC as compared to the normal pancreas. Racially disparate expression was also reported for and . However, no clear trend of altered expression was observed with increasing stage and grade, age, and gender of the patients. PDAC from occasional drinkers had significantly higher expression of compared to daily or weekly drinkers, whereas expression was significantly higher in social drinkers, compared to occasional ones. The expression of was significantly reduced in PDAC from diabetic patients, whereas was significantly lower in pancreatitis patients. More importantly, a significant association of high expression of and , and low expression of and was observed with poorer survival of PC patients. Together, our study suggests potential diagnostic and prognostic significance of RABs in PDAC, warranting further investigations to define their functional and mechanistic significance.
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http://dx.doi.org/10.3390/ijms21155580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432855PMC
August 2020

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

Semin Cancer Biol 2020 May 26. Epub 2020 May 26.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.semcancer.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688484PMC
May 2020

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

J Biol Chem 2020 06 1;295(25):8413-8424. Epub 2020 May 1.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama

Pancreatic cancer (PC) remains a therapeutic challenge because of its intrinsic and extrinsic chemoresistance mechanisms. Here, we report that C--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 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.
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http://dx.doi.org/10.1074/jbc.RA119.011748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307206PMC
June 2020

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

J Proteome Res 2020 02 27;19(2):794-804. Epub 2020 Jan 27.

Department of Pathology, College of Medicine , University of South Alabama , Mobile , Alabama 36617 , United States.

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 ( < 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.
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http://dx.doi.org/10.1021/acs.jproteome.9b00641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700759PMC
February 2020

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

Cancer Lett 2020 03 7;473:176-185. Epub 2020 Jan 7.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, 36617, USA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.canlet.2020.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067140PMC
March 2020

Looking at cancer health disparities without the colored lenses.

Cancer Health Disparities 2019 19;3:e1-e9. Epub 2019 Aug 19.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.

Cancer health disparities (CHDs), defined as the adverse differences in cancer incidence and mortality, are prevalent in certain racial and ethnic groups. Underlying causes of CHDs are multi-factorial and debatable. While low socioeconomic status, geographical location, lifestyle and behavioral factors are mostly believed to contribute to CHDs, regardless of ethnic and racial background, significant data now also exist to support a genetic basis of such disparities as well. Clearly, CHDs could best be understood by studying the interplay of multiple (genetic and non-genetic) factors and then translating the resulting knowledge into effective approaches for reducing the existing disparity gaps. This review article highlights these aspects in brief and calls the people of different expertise to work together to make an impact and tackle the challenges associated with CHDs.
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http://dx.doi.org/10.9777/chd.2019.1004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705599PMC
August 2019

Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival.

J Cell Biochem 2020 01 12;121(1):828-839. Epub 2019 Aug 12.

Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.

Pancreatic tumors are highly desmoplastic and poorly-vascularized, and therefore must develop adaptive mechanisms to sustain their survival under hypoxic condition. Extracellular vesicles (EV) play vital roles in pancreatic tumor pathobiology by facilitating intercellular communication. Here we studied the effect of hypoxia on the release of EVs and examined their role in adaptive survival of pancreatic cancer (PC) cells. Hypoxia promoted the release of EV in PC cell lines, MiaPaCa and AsPC1, wherein former exhibited a far greater induction. Moreover, a time-dependent, measurable and significant increase was recorded for small EV (SEV) in both the cell lines with only minimal induction observed for medium (MEV) and large EVs (LEV). Similarly, noticeable changes in size distribution of SEV were also recorded with a shift toward smaller average size under extreme hypoxia. Thrombospondin (apoptotic bodies marker) was exclusively detected on LEVs, while Arf6 (microvesicles marker) was mostly present on MEV with some expression in LEV as well. However, CD9 and CD63 (exosome markers) were expressed in both SEV and MEVs with a decreased expression recorded under hypoxia. Among all subfractions, SEV was the most bioactive in promoting the survival of hypoxic PC cells and hypoxia-inducible factor-1α stabilization was involved in heightened EV release under hypoxia and for their potency to promote hypoxic cell survival. Altogether, our findings provide a novel mechanism for the adaptive hypoxic survival of PC cells and should serve as the basis for future investigations on broader functional implications of EV.
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http://dx.doi.org/10.1002/jcb.29328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878126PMC
January 2020

Comparative analysis of exosome isolation methods using culture supernatant for optimum yield, purity and downstream applications.

Sci Rep 2019 03 29;9(1):5335. Epub 2019 Mar 29.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.

Exosomes have received significant attention for their role in pathobiological processes and are being explored as a tool for disease diagnosis and management. Consequently, various isolation methods based on different principles have been developed for exosome isolation. Here we compared the efficacy of four kits from Invitrogen, 101Bio, Wako and iZON along with conventional ultracentrifugation-based method for exosome yield, purity and quality. Cell culture supernatant was used as an abundant source of exosomes, and exosome quantity, size-distribution, zeta-potential, marker-expression and RNA/protein quality were determined. The Invitrogen kit gave the highest yield but the preparation showed broader size-distribution likely due to microvesicle co-precipitation and had the least dispersion stability. Other preparations showed <150 nm size range and good stability. Preparation from iZON column; however, had a broader size-distribution in the lower size range suggestive of some impurities of non-vesicular aggregates. RNA quality from all preparations was comparable; however, proteins from Invitrogen method-based exosomal preparation showed polyethylene glycol (PEG) contamination in mass spectrometry. Chemical impurities from the precipitant could also be the cause of toxicity of Invitrogen method-based exosomal preparation in biological growth measurement assay. Together, these findings should serve as a guide to choose and further optimize exosome isolation methods for their desired downstream applications.
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http://dx.doi.org/10.1038/s41598-019-41800-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441044PMC
March 2019

Gemcitabine treatment promotes immunosuppressive microenvironment in pancreatic tumors by supporting the infiltration, growth, and polarization of macrophages.

Sci Rep 2018 08 10;8(1):12000. Epub 2018 Aug 10.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.

Chemotherapy-induced immunosuppression poses an additional challenge to its limited efficacy in pancreatic cancer (PC). Here we investigated the effect of gemcitabine on macrophages, which are the first line of immune-defense mechanisms. We observed an increased presence of macrophages in orthotopic human pancreatic tumor xenografts from mice treated with gemcitabine as compared to those from vehicle only-treated mice. Conditioned media from gemcitabine-treated PC cells (Gem-CM) promoted growth, migration and invasion of RAW264.7 macrophage. In addition, Gem-CM also induced upregulation of M2-polarized macrophage markers, arginase-1 and TGF-β1. Cytokine profiling of gemcitabine-treated PC cells identified IL-8 as the most differentially-expressed cytokine. Incubation of Gem-CM with IL-8 neutralizing antibody diminished its ability to induce growth, migration and invasion of RAW264.7 macrophages, but did not abrogate their M2 polarization. Together, our findings identify IL-8 as an important mediator in the gemcitabine-induced infiltration of macrophages within the pancreatic tumor microenvironment and suggest the requirement of additional mechanism(s) for macrophage polarization.
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http://dx.doi.org/10.1038/s41598-018-30437-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086900PMC
August 2018

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

Nutr Cancer 2017 Aug-Sep;69(6):932-942. Epub 2017 Jul 18.

a Department of Oncologic Sciences , Mitchell Cancer Institute, University of South Alabama , Mobile , Alabama , USA.

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.
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http://dx.doi.org/10.1080/01635581.2017.1339818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125781PMC
July 2018

Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward.

Int J Mol Sci 2017 Apr 6;18(4). Epub 2017 Apr 6.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.

Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies.
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http://dx.doi.org/10.3390/ijms18040779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412363PMC
April 2017

Cancer Chemoprevention by Phytochemicals: Nature's Healing Touch.

Molecules 2017 Mar 3;22(3). Epub 2017 Mar 3.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.

Phytochemicals are an important part of traditional medicine and have been investigated in detail for possible inclusion in modern medicine as well. These compounds often serve as the backbone for the synthesis of novel therapeutic agents. For many years, phytochemicals have demonstrated encouraging activity against various human cancer models in pre-clinical assays. Here, we discuss select phytochemicals-curcumin, epigallocatechin-3-gallate (EGCG), resveratrol, plumbagin and honokiol-in the context of their reported effects on the processes of inflammation and oxidative stress, which play a key role in tumorigenesis. We also discuss the emerging evidence on modulation of tumor microenvironment by these phytochemicals which can possibly define their cancer-specific action. Finally, we provide recent updates on how low bioavailability, a major concern with phytochemicals, is being circumvented and the general efficacy being improved, by synthesis of novel chemical analogs and nanoformulations.
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http://dx.doi.org/10.3390/molecules22030395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155418PMC
March 2017

Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK.

Br J Cancer 2017 Feb 2;116(5):609-619. Epub 2017 Feb 2.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.

Background: Chemoresistance is a significant clinical problem in pancreatic cancer (PC) and underlying molecular mechanisms still remain to be completely understood. Here we report a novel exosome-mediated mechanism of drug-induced acquired chemoresistance in PC cells.

Methods: Differential ultracentrifugation was performed to isolate extracellular vesicles (EVs) based on their size from vehicle- or gemcitabine-treated PC cells. Extracellular vesicles size and subtypes were determined by dynamic light scattering and marker profiling, respectively. Gene expression was examined by qRT-PCR and/or immunoblot analyses, and direct targeting of DCK by miR-155 was confirmed by dual-luciferase 3'-UTR reporter assay. Flow cytometry was performed to examine the apoptosis indices and reactive oxygen species (ROS) levels in PC cells using specific dyes. Cell viability was determined using the WST-1 assay.

Results: Conditioned media (CM) from gemcitabine-treated PC cells (Gem-CM) provided significant chemoprotection to subsequent gemcitabine toxicity and most of the chemoresistance conferred by Gem-CM resulted from its EVs fraction. Sub-fractionation grouped EVs into distinct subtypes based on size distribution and marker profiles, and exosome (Gem-Exo) was the only sub-fraction that imparted chemoresistance. Gene expression analyses demonstrated upregulation of SOD2 and CAT (ROS-detoxifying genes), and downregulation of DCK (gemcitabine-metabolising gene) in Gem-Exo-treated cells. SOD/CAT upregulation resulted, at least in part, from exosome-mediated transfer of their transcripts and they suppressed basal and gemcitabine-induced ROS production, and partly promoted chemoresistance. DCK downregulation occurred through exosome-delivered miR-155 and either the functional suppression of miR-155 or restoration of DCK led to marked abrogation of Gem-Exo-mediated chemoresistance.

Conclusions: Together, these findings establish a novel role of exosomes in mediating the acquired chemoresistance of PC.
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http://dx.doi.org/10.1038/bjc.2017.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344296PMC
February 2017

Epigenetic basis of cancer health disparities: Looking beyond genetic differences.

Biochim Biophys Acta Rev Cancer 2017 Aug 17;1868(1):16-28. Epub 2017 Jan 17.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA; Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL, USA. Electronic address:

Despite efforts at various levels, racial health disparities still exist in cancer patients. These inequalities in incidence and/or clinical outcome can only be explained by a multitude of factors, with genetic basis being one of them. Several investigations have provided convincing evidence to support epigenetic regulation of cancer-associated genes, which results in the differential transcriptome and proteome, and may be linked to a pre-disposition of individuals of certain race/ethnicity to early or more aggressive cancers. Recent technological advancements and the ability to quickly analyze whole genome have aided in these efforts, and owing to their relatively easy detection, methylation events are much well-characterized, than the acetylation events, across human populations. The early trend of investigating a pre-determined set of genes for differential epigenetic regulation is paving way for more unbiased screening. This review summarizes our current understanding of the epigenetic events that have been tied to the racial differences in cancer incidence and mortality. A better understanding of the epigenetics of racial diversity holds promise for the design and execution of novel strategies targeting the human epigenome for reducing the disparity gaps.
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http://dx.doi.org/10.1016/j.bbcan.2017.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513784PMC
August 2017

Glucose Metabolism Reprogrammed by Overexpression of IKKε Promotes Pancreatic Tumor Growth.

Cancer Res 2016 12 20;76(24):7254-7264. Epub 2016 Oct 20.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.

Aberrant expression of the kinase IKKε in pancreatic ductal adenocarcinoma (PDAC) has been associated with poor prognosis. In this study, we define a pathobiologic function for IKKε in reprogramming glucose metabolism and driving progression in PDAC. Silencing IKKε in PDAC cells, which overexpressed it endogenously, was sufficient to reduce malignant cell growth, clonogenic potential, glucose consumption, lactate secretion, and expression of genes involved in glucose metabolism, without impacting the basal oxygen consumption rate. IKKε silencing also attenuated c-Myc in a manner associated with diminished signaling through an AKT/GSK3β/c-MYC phosphorylation cascade that promoted MYC nuclear accumulation. In an orthotopic mouse model, IKKε-silenced PDAC exhibited a relative reduction in glucose uptake, tumorigenicity, and metastasis. Overall, our findings offer a preclinical mechanistic rationale to target IKKε to improve the therapeutic management of PDAC in patients. Cancer Res; 76(24); 7254-64. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161695PMC
December 2016

Racial disparities in prostate cancer: a molecular perspective.

Front Biosci (Landmark Ed) 2017 01 1;22:772-782. Epub 2017 Jan 1.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.

Prostate cancer incidence and mortality rates are remarkably higher in African-American men as compared to their European-Americans counterparts. Despite these recognitions, precise causes underlying such prevalent racial disparities remain poorly understood. Although socioeconomic factors could account for such differences up to a certain extent, it is now being increasingly realized that such disparity has a molecular basis. Indeed, several differences, including genetic polymorphism, gene mutations, epigenetic modifications, miRNAs alterations, . have been reported in malignant prostate tissues from patients of diverse racial backgrounds. Here, we attempt to provide a molecular perspective on prostate cancer racial disparities by gathering available information on these associated factors and discussing their potential significance in disproportionate incidence and clinical outcomes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242333PMC
http://dx.doi.org/10.2741/4515DOI Listing
January 2017

Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor-stromal cross-talk.

Carcinogenesis 2016 11;37(11):1052-1061

Department of Oncologic Sciences, Mitchell Cancer Institute.

The poor clinical outcome of pancreatic cancer (PC) is largely attributed to its aggressive nature and refractoriness to currently available therapeutic modalities. We previously reported antitumor efficacy of honokiol (HNK), a phytochemical isolated from various parts of Magnolia plant, against PC cells in short-term in vitro growth assays. Here, we report that HNK reduces plating efficiency and anchorage-independent growth of PC cells and suppresses their migration and invasiveness. Furthermore, significant inhibition of pancreatic tumor growth by HNK is observed in orthotopic mouse model along with complete-blockage of distant metastases. Histological examination suggests reduced desmoplasia in tumors from HNK-treated mice, later confirmed by immunohistochemical analyses of myofibroblast and extracellular matrix marker proteins (α-SMA and collagen I, respectively). At the molecular level, HNK treatment leads to decreased expression of sonic hedgehog (SHH) and CXCR4, two established mediators of bidirectional tumor-stromal cross-talk, both in vitro and in vivo . We also show that the conditioned media (CM) from HNK-treated PC cells have little growth-inducing effect on pancreatic stellate cells (PSCs) that could be regained by the addition of exogenous recombinant SHH. Moreover, pretreatment of CM of vehicle-treated PC cells with SHH-neutralizing antibody abolishes their growth-inducing potential on PSCs. Likewise, HNK-treated PC cells respond poorly to CM from PSCs due to decreased CXCR4 expression. Lastly, we show that the transfection of PC cells with constitutively active IKKβ mutant reverses the suppressive effect of HNK on nuclear factor-kappaB activation and partially restores CXCR4 and SHH expression. Taken together, these findings suggest that HNK interferes with tumor-stromal cross-talk via downregulation of CXCR4 and SHH and decreases pancreatic tumor growth and metastasis.
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http://dx.doi.org/10.1093/carcin/bgw096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091041PMC
November 2016

Pentoxifylline triggers autophagy via ER stress response that interferes with Pentoxifylline induced apoptosis in human melanoma cells.

Biochem Pharmacol 2016 Mar 12;103:17-28. Epub 2016 Jan 12.

Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology, Chandigarh 160 036, India. Electronic address:

Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor is known to inhibit the growth of various cancer cells including melanoma. Here in this study, we have found that PTX induces autophagy in human melanoma cell lines (A375 and MeWo). Induction of autophagy is associated with the increase in Atg5 expression as knockdown of Atg5 effectively inhibited PTX mediated autophagy. A decrease in mTOR activation was also observed after PTX treatment. We observed that autophagy was activated as a downstream effector mechanism of ER stress induced by PTX. ER stress response was confirmed by upregulation of IRE-1α, GRP78 and CHOP expression. PTX treatment also resulted in an increase in intracellular calcium (Ca(2+)) level. Ca(2+) is the central player as blocking Ca(2+) by intracellular calcium chelator (BAPTA-AM) effectively inhibited the PTX induced ER stress response as well as autophagy. Moreover, silencing of CHOP also resulted in autophagy inhibition with a decrease in Atg5 expression. Collectively, PTX triggers ER stress response followed by induction of autophagy via involvement of Ca(2+)→CHOP→Atg5 signalling cascade. Interestingly, inhibition of intracellular calcium level by BAPTA-AM significantly increased PTX mediated cell death by augmenting intrinsic apoptotic pathway. Inhibition of autophagy by the ATG5 siRNA and pharmacological inhibitor, chloroquine also enhances PTX induced cell death. Taken together, our results clearly indicate that activation of ER stress response and autophagy provides resistance to PTX mediated apoptosis, and thus, interferes with the anticancer activity of PTX in human melanoma cells.
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http://dx.doi.org/10.1016/j.bcp.2015.12.018DOI Listing
March 2016

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

Adv Exp Med Biol 2015 ;889:71-87

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL, 36604-1405, USA.

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.
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http://dx.doi.org/10.1007/978-3-319-23730-5_5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706654PMC
April 2016

Gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells: Therapeutic implications.

Oncotarget 2015 Nov;6(36):39140-50

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.

Pancreatic tumor microenvironment (TME) is characterized by poor tumor-vasculature and extensive desmoplasia that together contribute to poor response to chemotherapy. It was recently shown that targeting of TME to inhibit desmoplasiatic reaction in a preclinical model resulted in increased microvessel-density and intratumoral drug concentration, leading to improved therapeutic response. This approach, however, failed to generate a favorable response in clinical trial. In that regard, we have previously demonstrated a role of gemcitabine-induced CXCR4 signaling as a counter-defense mechanism, which also promoted invasiveness of pancreatic cancer (PC) cells. Here, we investigated the effect of gemcitabine on endothelial cell phenotype. Gemcitabine-treatment of human-umbilical-vein-endothelial-cells (HUVECs) did not promote the growth of HUVECs; however, it was induced when treated with conditioned media from gemcitabine-treated (Gem-CM) PC cells due to increased cell-cycle progression and apoptotic-resistance. Moreover, treatment of HUVECs with Gem-CM resulted in capillary-like structure (CLS) formation and promoted their ability to migrate and invade through extracellular-matrix. Gemcitabine-treatment of PC cells induced expression of various growth factors/cytokines, including IL-8, which exhibited greatest upregulation. Further, IL-8 depletion in Gem-CM diminished its potency to promote angiogenic phenotypes. Together, these findings suggest an indirect effect of gemcitabine on angiogenesis, which, in light of our previous observations, may hold important clinical significance.
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http://dx.doi.org/10.18632/oncotarget.3784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770762PMC
November 2015

Gambogic acid induced oxidative stress dependent caspase activation regulates both apoptosis and autophagy by targeting various key molecules (NF-κB, Beclin-1, p62 and NBR1) in human bladder cancer cells.

Biochim Biophys Acta 2014 Dec 12;1840(12):3374-84. Epub 2014 Sep 12.

Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology, Chandigarh 160 036, India. Electronic address:

Background: Gambogic acid is a potent anticancer agent and has been found effective against various types of cancer cells. The present study was addressed to explore the cytotoxic potential of Gambogic acid and the modulation of autophagy and apoptosis in bladder cancer cells T24 and UMUC3.

Methods: Bladder cancer cell lines T24 and UMUC3 were treated with Gambogic acid, apoptosis was checked by flow-cytometry and expression of various autophagy and apoptosis related proteins was monitored by Western blotting. Confocal microscope was used for colocalization of p62 and Beclin-1.

Results: Gambogic acid induces reactive oxygen species, and elicits a strong autophagic response by activating JNK at earlier time points, which is inhibited at later time points with the activation of caspases. Reactive oxygen species mediated caspase activation causes degradation of autophagic proteins, cleavage of molecular chaperones (Hsp90 and GRP-78) and adaptor proteins (p62 and NBR1). Gambogic acid treatment results in mitochondrial hyperpolarization and cytochrome c release and activates caspases involved in both extrinsic and intrinsic apoptotic pathways. Gambogic acid abrogates NF-κB activation by ROS mediated inhibition of IκB-α phosphorylation. Functionally Gambogic acid induced autophagy acts as a strong cell survival response and delays caspase activation.

Conclusion: Our study provides the new insights about the mechanism of Gambogic acid induced modulation of autophagy and apoptosis in bladder cancer cells. All the molecular events responsible for Gambogic acid induced autophagy and apoptosis are mediated by reactive oxygen species.

General Significance: Since Gambogic acid targets various cell survival molecules therefore, it may be considered as a potential anticancer agent against bladder cancer.
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http://dx.doi.org/10.1016/j.bbagen.2014.08.019DOI Listing
December 2014

IL-27 inhibits IFN-γ induced autophagy by concomitant induction of JAK/PI3 K/Akt/mTOR cascade and up-regulation of Mcl-1 in Mycobacterium tuberculosis H37Rv infected macrophages.

Int J Biochem Cell Biol 2014 Oct 4;55:335-47. Epub 2014 Sep 4.

Division of Cell Biology and Immunology, Institute of Microbial Technology (CSIR), Chandigarh 160036, India. Electronic address:

Interleukin-27 (IL-27), a key immunoregulatory cytokine plays an important role in host response to mycobacterial infection as neutralization of IL-27 augments intracellular killing of mycobacteria. Autophagy has a pivotal role in host immunity and is regulated by various cytokines. Here, we report that IL-27 inhibits IFN-γ and starvation induced autophagy and as a result blocks phagosome maturation and promotes intracellular survival of Mycobacterium tuberculosis H37Rv. Addition of exogenous IL-27 induces the activation of mTOR through JAK/PI3 K pathway and inhibits IFN-γ stimulated autophagy. Furthermore, blockade of JAKs obstructs the inhibitory effect of IL-27 on IFN-γ induced autophagy. Besides this, IL-27 also up-regulates Mcl-1 through PI3 K pathway. We further show that in mTOR or Mcl-1 silenced THP-1 cells, IL-27 could no longer inhibit IFN-γ mediated autophagy in M. tuberculosis H37Rv infected cells. Altogether, our study demonstrates that IL-27 by concurrent activation of JAK/PI3 K/Akt/mTOR cascade as well as up-regulation of Mcl-1 inhibits IFN-γ induced autophagy and elimination of intracellular mycobacteria in macrophages.
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http://dx.doi.org/10.1016/j.biocel.2014.08.022DOI Listing
October 2014

Oxidative stress induced by curcumin promotes the death of cutaneous T-cell lymphoma (HuT-78) by disrupting the function of several molecular targets.

Mol Cancer Ther 2012 Sep 31;11(9):1873-83. Epub 2012 May 31.

Division of Cell Biology and Immunology, Institute of Microbial Technology, CSIR, Chandigarh, India.

Curcumin is known to exert its anticancer effect either by scavenging or by generating reactive oxygen species (ROS). In this study, we report that curcumin-mediated rapid generation of ROS induces apoptosis by modulating different cell survival and cell death pathways in HuT-78 cells. Curcumin induces the activation of caspase-8, -2, and -9, alteration of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-3 and concomitant PARP cleavage, but the addition of caspase inhibitors only partially blocked the curcumin-mediated apoptosis. Curcumin also downregulates the expression of antiapoptotic proteins c-FLIP, Bcl-xL, cellular inhibitor of apoptosis protein, and X-linked IAP in a ROS-dependent manner. Curcumin disrupts the integrity of IKK and beclin-1 by degrading Hsp90. Degradation of IKK leads to the inhibition of constitutive NF-κB. Degradation of beclin-1 by curcumin leads to the accumulation of autophagy-specific marker, microtubule-associated protein-I light chain 3 (LC3), LC3-I. Our findings indicate that HuT-78 cells are vulnerable to oxidative stress induced by curcumin and as a result eventually undergo cell death.
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http://dx.doi.org/10.1158/1535-7163.MCT-12-0141DOI Listing
September 2012

Pentoxifylline augments TRAIL/Apo2L mediated apoptosis in cutaneous T cell lymphoma (HuT-78 and MyLa) by modulating the expression of antiapoptotic proteins and death receptors.

Biochem Pharmacol 2010 Dec 8;80(11):1650-61. Epub 2010 Sep 8.

Division of Cell Biology and Immunology, Institute of Microbial Technology (CSIR), Chandigarh 160036, India.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising anticancer agent but cutaneous T lymphoma cells (CTCL) are less sensitive to TRAIL-induced apoptosis. Here, we report that pentoxifylline (PTX), a phosphodiesterase inhibitor, augments TRAIL-mediated apoptosis in HuT-78 and MyLa cells through modulating extrinsic death receptors and intrinsic mitochondria dependent pathways. Our results clearly show that PTX augments TRAIL-mediated activation of caspase-8 and induces cleavage of Bid, although PTX alone cannot activate caspase-8. This is followed by cytochrome c release and subsequent, activation of caspase-9 and caspase-3 and cleavage of poly (ADP ribose) polymerase (PARP). Combined treatment downregulates the expression of various antiapoptotic proteins including c-FLIP, Bcl-xl, cIAP-1, cIAP-2 and XIAP. PTX induces the expression of death receptors DR4 and DR5 on cell surface of both the cell types where c-Jun NH2-terminal kinase (JNK) pathway plays an important role. Moreover, combined silencing of DR4 and DR5 by small interfering RNA abrogates the ability of PTX to induce TRAIL-mediated apoptosis. Thus, this is the first demonstration that PTX can potentiate TRAIL-mediated apoptosis through downregulation of cell survival gene products and upregulation of death receptors.
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http://dx.doi.org/10.1016/j.bcp.2010.08.018DOI Listing
December 2010

A university-sponsored home health nursing program in Karachi, Pakistan.

Home Healthc Nurse 2005 Nov;23(11):710-6

Department of Medicine, the Aga Khan University Medical College, Karachi, Pakistan.

This article describes a university-sponsored home health nursing program in a large urban center in Pakistan and details the essential elements needed in implementing such a program in a developing country. Compared to in-hospital treatment, home healthcare reduced hospital stay from 12.8 days to 3.9 days, and resulted in a net savings of Pakistani rupees (PRs) 5,374,135 (USD 89,569). A cost-effective home treatment program in a resource-limited country can be successfully implemented by using the hospital pharmacy as the central point for the preparation and distribution of medications and specialty nursing services.
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http://dx.doi.org/10.1097/00004045-200511000-00007DOI Listing
November 2005
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