Cancer stem-like cells (CSLCs) play a pivotal role in acquiring multidrug resistant (MDR) phenoty... more Cancer stem-like cells (CSLCs) play a pivotal role in acquiring multidrug resistant (MDR) phenotypes. It has been established that pancreatic cancers overexpressing CD44 receptors (a target of hyaluronic acid; HA) is one of the major contributors for causing MDR. Therefore, targeted killing of CD44 expressing tumor cells using HA based active targeting strategies may be beneficial for eradicating MDR-pancreatic cancers. Here, we report the synthesis of a new HA conjugate of copoly(styrene maleic acid) (HA-SMA) that could be engineered to form nanomicelles with a potent anticancer agent, 3,4-difluorobenzylidene curcumin (CDF). The anticancer activity of CDF loaded nanomicelles against MiaPaCa-2 and AsPC-1 human pancreatic cancer cells revealed dose-dependent cell killing. Results of cellular internalization further confirmed better uptake of HA engineered nanomicelles in triple-marker positive (CD44+/CD133+/EpCAM+) pancreatic CSLCs compared with triple-marker negative (CD44-/CD133-/EpCAM-) counterparts. More importantly, HA-SMA-CDF exhibited superior anticancer response toward CD44+ pancreatic CSLCs. Results further confirmed that triple-marker positive cells treated with HA-SMA-CDF caused significant reduction in CD44 expression and marked inhibition of NF-κB that in-turn can mitigate their proliferative and invasive behavior. Conclusively, these results suggest that the newly developed CD44 targeted nanomicelles may have great implications in treating pancreatic cancers including the more aggressive pancreatic CSLCs.
Pancreatic cancer remains one of the most devastating diseases in terms of patient mortality rate... more Pancreatic cancer remains one of the most devastating diseases in terms of patient mortality rates for which current treatment options are very limited. 3,4-Difluorobenzylidene curcumin (CDF) is a nontoxic analog of curcumin (CMN) developed in our laboratory, which exhibits extended circulation half-life, while maintaining high anticancer activity and improved pancreas specific accumulation in vivo, compared with CMN. CDF however has poor aqueous solubility and its dose escalation for systemic administration remains challenging. We have engineered self-assembling nano-micelles of amphiphilic styrene-maleic acid copolymer (SMA) with CDF by non-covalent hydrophobic interactions. The SMA-CDF nano-micelles were characterized for size, charge, drug loading, release, serum stability, and in vitro anticancer activity. The SMA-CDF nano-micelles exhibited tunable CDF loading from 5 to 15% with excellent aqueous solubility, stability, favorable hemocompatibility and sustained drug release characteristics. The outcome of cytotoxicity testing of SMA-CDF nano-micelles on MiaPaCa-2 and AsPC-1 pancreatic cancer cell lines revealed pronounced antitumor response due to efficient intracellular trafficking of the drug loaded nano-micelles. Additionally, the nano-micelles are administrable via the systemic route for future in vivo studies and clinical translation. The currently developed SMA based nano-micelles thus portend to be a versatile carrier for dose escalation and targeted delivery of CDF, with enhanced therapeutic margin and safety.
Please cite this article in press as: Kesharwani, P., Iyer, A.K. Recent advances in dendrimer-bas... more Please cite this article in press as: Kesharwani, P., Iyer, A.K. Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery, Drug Discov Today (2015), http:// dx.
Reactive oxygen species (ROS), such as superoxide anion radicals (O z2 2 ) and hydrogen peroxide ... more Reactive oxygen species (ROS), such as superoxide anion radicals (O z2 2 ) and hydrogen peroxide (H 2 O 2 ) are potentially harmful by-products of normal cellular metabolism that directly affect cellular functions. ROS is generated by all aerobic organisms and it seems to be indispensable for signal transduction pathways that regulate cell growth and reduction -oxidation (redox) status. However, overproduction of these highly reactive oxygen metabolites can initiate lethal chain reactions, which involve oxidation and damage to structures that are crucial for cellular integrity and survival. In fact, many antitumor agents, such as vinblastine, cisplatin, mitomycin C, doxorubicin, camptothecin, inostamycin, neocarzinostatin and many others exhibit antitumor activity via ROS-dependent activation of apoptotic cell death, suggesting potential use of ROS as an antitumor principle. Thus, a unique anticancer strategy named "oxidation therapy" has been developed by inducing cytotoxic oxystress for cancer treatment. This goal could be achieved mainly by two methods, namely, (i) inducing the generation of ROS directly to solid tumors and (ii) inhibiting the antioxidative enzyme (defense) system of tumor cells. Since 1950s, many strategies have been employed based on the first method, namely, administration of ROS per se (e.g. H 2 O 2 ) or ROS generating enzyme to tumor bearing animals. However no successful and practical results were obtained probably because of the lack of tumor selective ROS delivery and hence resulting in subsequent induction of severe side effects. To overcome these obstacles, we developed polyethylene glycol (PEG) conjugated O z2 2 or H 2 O 2 -generating enzymes, xanthine oxidase (XO) and D-amino acid oxidase (DAO) (PEG -DAO) respectively. More recently, a pegylated (PEG) zinc protoporphyrin (PEG -ZnPP) and a highly water soluble micellar formulation of ZnPP based on amphiphilic styrene maleic acid (SMA) copolymer, SMA -ZnPP, are prepared, which are potent inhibitors of heme oxygenase-1 (HO-1). HO-1 is a major antioxidative enzyme of tumors, that is different in mechanism of catalase or superoxide dismutase (SOD). Consequently, both PEG-enzymes and PEG -ZnPP exhibited superior in vivo pharmacokinetics than their parental molecules, particularly in tumor delivery by taking advantage of the EPR effect of macromolecular nature, and thus showed remarkable antitumor effects suggesting the potentials of this anticancer therapeutic for clinical application. Furthermore, it has been well known that many antioxidative enzymes such as catalase, SOD are down-regulated in most solid tumors in vivo. On the contrary, HO-1 is highly upregulated and it plays a very important role of antioxidation, because HO-1 generates biliverdin, which being converted to bilirubin exhibits a very potent antioxidative effect, and hence antiapoptosis in tumors. Thus this oxidation therapy, by inhibiting this HO-1 dependent antioxidant (bilirubin) formation by ZnPP, and by enhancing ROS generation, is expected to offer a powerful therapeutic modality for future anticancer therapy.
Journal of Biomaterials Science, Polymer Edition, 2015
Worldwide, the cancer appeared as one of the most leading cause of morbidity and mortality. Among... more Worldwide, the cancer appeared as one of the most leading cause of morbidity and mortality. Among the various cancer types, brain tumors are most life threatening with low survival rate. Every year approximately 238,000 new cases of brain and other central nervous system tumors are diagnosed. The dendrimeric approaches have a huge potential for diagnosis and treatment of brain tumor with targeting abilities of molecular cargoes to the tumor sites and the efficiency of crossing the blood brain barrier and penetration to brain after systemic administration. The various generations of dendrimers have been designed as novel targeted drug delivery tools for new therapies including sustained drug release, gene therapy, and antiangiogenic activities. At present era, various types of dendrimers like PAMAM, PPI, and PLL dendrimers validated them as milestones for the treatment and diagnosis of brain tumor as well as other cancers. This review highlights the recent research, opportunities, advantages, and challenges involved in development of novel dendrimeric complex for the therapy of brain tumor.
Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeti... more Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeting and codelivery of small interfering RNA (siRNA) and doxorubicin, and to overcome multidrug resistance, we conjugated a cholic acid-polyethylenimine polymer with folic acid, forming CA-PEI-FA micelles. CA-PEI-FA exhibited a low critical micelle concentration (80 μM), small average particle size (150 nm), and positive zeta potential (+ 12 mV). They showed high entrapment efficiency for doxorubicin (61.2 ± 1.7%, w/w), forming D-CA-PEI-FA, and for siRNA, forming D-CA-PEI-FA-S. X-ray photoelectron spectroscopic analysis revealed the presence of external FA on D-CA-PEI-FA micelles. About 25% doxorubicin was released within 24 h at pH 7.4, while more than 30% release was observed at pH 5. The presence of FA enhanced micelle antitumor activity. The D-CA-PEI-FA and D-CA-PEI-FA-S micelles inhibited tumor growth in vivo. No significant differences between their in vitro cytotoxic activities or their in vivo antitumor effects were observed, indicating that the siRNA coloading did not significantly increase the antitumor activity. Histological analysis revealed that tumor tissues from mice treated with D-CA-PEI-FA or D-CA-PEI-FA-S showed the lowest cancer cell density and the highest levels of apoptosis and necrosis. Similarly, the livers of these mice exhibited the lowest level of dihydropyrimidine dehydrogenase among all treated groups. The lowest serum vascular endothelial growth factor level (VEGF) (24.4 pg/mL) was observed in mice treated with D-CA-PEI-FA-S micelles using siRNA targeting VEGF. These findings indicated that the developed CA-PEI-FA nanoconjugate has the potential to achieve targeted codelivery of drugs and siRNA.
In recent times, many real world applications have emerged that require estimates of class ratios... more In recent times, many real world applications have emerged that require estimates of class ratios in an unlabeled instance collection as opposed to labels of individual instances in the collection. In this paper we investigate the use of maximum mean discrepancy (MMD) in a reproducing kernel Hilbert space (RKHS) for estimating such ratios.
In the last two decades, dendrimers have proven their capabilities in drug delivery, physical sta... more In the last two decades, dendrimers have proven their capabilities in drug delivery, physical stabilization of the drug, solubility enhancement of the poorly soluble drugs and gene delivery. Key features of dendrimers like excellent control over molecular structure, nanoscopic size, availability of multiple functional groups at the periphery and narrow polydispersity index distinguish them amongst the available polymers. Diversity of bio-actives loaded in dendrimers due to covalent and non-covalent interactions, such as hydrogen bonding and hydrophobic interaction contribute to the physical forces for binding of bioactives. The key advantage of drug loaded dendrimers is the delayed and sustained release of bioactives because of the encapsulation of the drug in the hydrophobic cavities of the dendrimer that acts as a sink to retain the drug molecules for extended duration. Because of these features researchers are particularly excited about the potential application of dendrimers as ...
In the last couple of decades antioxidant agents have entered the health market as an easy and at... more In the last couple of decades antioxidant agents have entered the health market as an easy and attractive means of managing diseases. These agents are of enormous interest for an increasingly health-concerned society, and may be particularly relevant for prophylaxis of a number of diseases i.e. arthritis, cancer, metabolic and cardiovascular diseases, osteoporosis, cataracts, brain disorders, etc. Antioxidants are also favorable to vascular healthiness and symbolize useful compounds because they are able to diminish overall cardiovascular risk by acting analogous to first line therapy or as adjuvants in case of failure or in situations where first line therapy cannot be used. Furthermore, well-designed trials are indeed needed to improve the therapeutic efficacy and health benefits of antioxidants. Numerous in vivo proof-of-concepts studies are offered to underline the feasibility of nanostructure system in order to optimizing the delivery of cardiovascular drugs. The present review...
Clostridium taeniosporum is a Gram-positive, anaerobic, rod-shaped non-toxigenic organism isolate... more Clostridium taeniosporum is a Gram-positive, anaerobic, rod-shaped non-toxigenic organism isolated from Crimean lake silt. It is unique in forming spores from which about twelve large, flat, ribbon-like appendages emanate. These ribbon-like structures, about 4.5 mm long and 0.45 mm wide, are assembled from smaller fibrils with 5 nm diameter spherical heads attached to thin tails about 1-2 nm in diameter and about 40 nm in length. The appendages have four major components, a glycoprotein with a collagenlike region, two proteins each of which contains two conserved domains of unknown function, and an ortholog of the Bacillus subtilis spore morphogenetic protein SpoVM. Genes for three of these and other, possibly related proteins, cluster on two chromosome fragments. Here we report that C. taeniosporum is saccharolytic, non-proteolytic, and produces both acetic and butyric acid fermentation products. It synthesizes a-D-glucosidase and N-acetyl-b,D-glucoseaminidase constitutively. These physiological properties are similar to those of the C. botulinum Group II. Genotypically, C. taeniosporum is also closely related to the same Group II, based on 16S rDNA sequences. C. taeniosporum differs from typical C. botulinum Group II strains because it is non-toxigenic and in forming the ribbon-like spore appendages. These major differences among otherwise closely related organisms suggest lateral transfer of genes for appendage synthesis and for toxigenicity.
Proceedings of the fourth ACM international conference on Web search and data mining - WSDM '11, 2011
Automatic extraction of structured records from inconsistently formatted lists on the web is chal... more Automatic extraction of structured records from inconsistently formatted lists on the web is challenging: different lists present disparate sets of attributes with variations in the ordering of attributes; many lists contain additional attributes and noise that can confuse the extraction process; and formatting within a list may be inconsistent due to missing attributes or manual formatting on some sites.
2012 IEEE 12th International Conference on Data Mining, 2012
The goal of this work is to estimate the accuracy of a classifier on a large unlabeled dataset ba... more The goal of this work is to estimate the accuracy of a classifier on a large unlabeled dataset based on a small labeled set and a human labeler. We seek to estimate accuracy and select instances for labeling in a loop via a continuously refined stratified sampling strategy. For stratifying data we develop a novel strategy of learning r bit hash functions to preserve similarity in accuracy values. We show that our algorithm provides better accuracy estimates than existing methods for learning distance preserving hash functions. Experiments on a wide spectrum of real datasets show that our estimates achieve between 15% and 62% relative reduction in error compared to existing approaches. We show how to perform stratified sampling on unlabeled data that is so large that in an interactive setting even a single sequential scan is impractical. We present an optimal algorithm for performing importance sampling on a static index over the data that achieves close to exact estimates while reading three orders of magnitude less data.
In this paper a novel method for simulating unsteady incompressible viscous flow over a moving bo... more In this paper a novel method for simulating unsteady incompressible viscous flow over a moving boundary is described. The numerical model is based on a 2D Navier-Stokes incompressible flow in artificial compressibility formulation with Arbitrary Lagrangian Eulerian approach for moving grid and dual time stepping approach for time accurate discretization. A higher order unstructured finite volume scheme, based on a Harten Lax and van Leer with Contact (HLLC) type Riemann solver for convective fluxes, developed for steady incompressible flow in artificial compressibility formulation by Mandal and Iyer (AIAA paper 2009-3541), is extended to solve unsteady flows over moving boundary. Viscous fluxes are discretized in a central differencing manner based on Coirier's diamond path. An algorithm based on interpolation with radial basis functions is used for grid movements. The present numerical scheme is validated for an unsteady channel flow with a moving indentation. The present numerical results are found to agree well with experimental results reported in literature.
Objective. Advanced mast cell (MC) neoplasms are usually resistant to conventional therapy. There... more Objective. Advanced mast cell (MC) neoplasms are usually resistant to conventional therapy. Therefore, current research focuses on new targets in neoplastic MC and development of respective targeted drugs. Mastocytomas in dogs often behave as aggressive tumors. We report that heat-shock protein 32 (Hsp32), also known as heme oxygenase-1, is a survival-enhancing molecule and new target in canine mastocytoma cells. Materials and Methods. As assessed by reverse transcriptase polymerase chain reaction, Northern blotting, immunocytochemistry, and Western blotting, primary neoplastic dog MC, and the canine mastocytoma-derived cell line C2 expressed Hsp32 mRNA and the Hsp32 protein in a constitutive manner. Results. The KIT-targeting drug midostaurin inhibited expression of Hsp32, as well as survival in C2 cells. Confirming the functional role of Hsp32, the inhibitory effect of midostaurin on C2 cells was markedly reduced by the Hsp32-inductor hemin. Two pharmacologic Hsp32inhibitors, styrene maleic-acid micelle-encapsulated ZnPP (SMA-ZnPP) and pegylated zincprotoporphyrin (PEG-ZnPP) were applied. Both drugs were found to inhibit proliferation of C2 cells as well as growth of primary neoplastic canine MC. The growth-inhibitory effects of SMA-ZnPP and PEG-ZnPP were dose-and time-dependent (IC 50 : 1-10 mM) and found to be associated with induction of apoptosis. Conclusions. Hsp32 is an important survival factor and interesting new target in neoplastic canine MC. Trials with Hsp32-targeted drugs are now warranted to define the clinical efficacy of these drugs. Ó
Cancer stem-like cells (CSLCs) play a pivotal role in acquiring multidrug resistant (MDR) phenoty... more Cancer stem-like cells (CSLCs) play a pivotal role in acquiring multidrug resistant (MDR) phenotypes. It has been established that pancreatic cancers overexpressing CD44 receptors (a target of hyaluronic acid; HA) is one of the major contributors for causing MDR. Therefore, targeted killing of CD44 expressing tumor cells using HA based active targeting strategies may be beneficial for eradicating MDR-pancreatic cancers. Here, we report the synthesis of a new HA conjugate of copoly(styrene maleic acid) (HA-SMA) that could be engineered to form nanomicelles with a potent anticancer agent, 3,4-difluorobenzylidene curcumin (CDF). The anticancer activity of CDF loaded nanomicelles against MiaPaCa-2 and AsPC-1 human pancreatic cancer cells revealed dose-dependent cell killing. Results of cellular internalization further confirmed better uptake of HA engineered nanomicelles in triple-marker positive (CD44+/CD133+/EpCAM+) pancreatic CSLCs compared with triple-marker negative (CD44-/CD133-/EpCAM-) counterparts. More importantly, HA-SMA-CDF exhibited superior anticancer response toward CD44+ pancreatic CSLCs. Results further confirmed that triple-marker positive cells treated with HA-SMA-CDF caused significant reduction in CD44 expression and marked inhibition of NF-κB that in-turn can mitigate their proliferative and invasive behavior. Conclusively, these results suggest that the newly developed CD44 targeted nanomicelles may have great implications in treating pancreatic cancers including the more aggressive pancreatic CSLCs.
Pancreatic cancer remains one of the most devastating diseases in terms of patient mortality rate... more Pancreatic cancer remains one of the most devastating diseases in terms of patient mortality rates for which current treatment options are very limited. 3,4-Difluorobenzylidene curcumin (CDF) is a nontoxic analog of curcumin (CMN) developed in our laboratory, which exhibits extended circulation half-life, while maintaining high anticancer activity and improved pancreas specific accumulation in vivo, compared with CMN. CDF however has poor aqueous solubility and its dose escalation for systemic administration remains challenging. We have engineered self-assembling nano-micelles of amphiphilic styrene-maleic acid copolymer (SMA) with CDF by non-covalent hydrophobic interactions. The SMA-CDF nano-micelles were characterized for size, charge, drug loading, release, serum stability, and in vitro anticancer activity. The SMA-CDF nano-micelles exhibited tunable CDF loading from 5 to 15% with excellent aqueous solubility, stability, favorable hemocompatibility and sustained drug release characteristics. The outcome of cytotoxicity testing of SMA-CDF nano-micelles on MiaPaCa-2 and AsPC-1 pancreatic cancer cell lines revealed pronounced antitumor response due to efficient intracellular trafficking of the drug loaded nano-micelles. Additionally, the nano-micelles are administrable via the systemic route for future in vivo studies and clinical translation. The currently developed SMA based nano-micelles thus portend to be a versatile carrier for dose escalation and targeted delivery of CDF, with enhanced therapeutic margin and safety.
Please cite this article in press as: Kesharwani, P., Iyer, A.K. Recent advances in dendrimer-bas... more Please cite this article in press as: Kesharwani, P., Iyer, A.K. Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery, Drug Discov Today (2015), http:// dx.
Reactive oxygen species (ROS), such as superoxide anion radicals (O z2 2 ) and hydrogen peroxide ... more Reactive oxygen species (ROS), such as superoxide anion radicals (O z2 2 ) and hydrogen peroxide (H 2 O 2 ) are potentially harmful by-products of normal cellular metabolism that directly affect cellular functions. ROS is generated by all aerobic organisms and it seems to be indispensable for signal transduction pathways that regulate cell growth and reduction -oxidation (redox) status. However, overproduction of these highly reactive oxygen metabolites can initiate lethal chain reactions, which involve oxidation and damage to structures that are crucial for cellular integrity and survival. In fact, many antitumor agents, such as vinblastine, cisplatin, mitomycin C, doxorubicin, camptothecin, inostamycin, neocarzinostatin and many others exhibit antitumor activity via ROS-dependent activation of apoptotic cell death, suggesting potential use of ROS as an antitumor principle. Thus, a unique anticancer strategy named "oxidation therapy" has been developed by inducing cytotoxic oxystress for cancer treatment. This goal could be achieved mainly by two methods, namely, (i) inducing the generation of ROS directly to solid tumors and (ii) inhibiting the antioxidative enzyme (defense) system of tumor cells. Since 1950s, many strategies have been employed based on the first method, namely, administration of ROS per se (e.g. H 2 O 2 ) or ROS generating enzyme to tumor bearing animals. However no successful and practical results were obtained probably because of the lack of tumor selective ROS delivery and hence resulting in subsequent induction of severe side effects. To overcome these obstacles, we developed polyethylene glycol (PEG) conjugated O z2 2 or H 2 O 2 -generating enzymes, xanthine oxidase (XO) and D-amino acid oxidase (DAO) (PEG -DAO) respectively. More recently, a pegylated (PEG) zinc protoporphyrin (PEG -ZnPP) and a highly water soluble micellar formulation of ZnPP based on amphiphilic styrene maleic acid (SMA) copolymer, SMA -ZnPP, are prepared, which are potent inhibitors of heme oxygenase-1 (HO-1). HO-1 is a major antioxidative enzyme of tumors, that is different in mechanism of catalase or superoxide dismutase (SOD). Consequently, both PEG-enzymes and PEG -ZnPP exhibited superior in vivo pharmacokinetics than their parental molecules, particularly in tumor delivery by taking advantage of the EPR effect of macromolecular nature, and thus showed remarkable antitumor effects suggesting the potentials of this anticancer therapeutic for clinical application. Furthermore, it has been well known that many antioxidative enzymes such as catalase, SOD are down-regulated in most solid tumors in vivo. On the contrary, HO-1 is highly upregulated and it plays a very important role of antioxidation, because HO-1 generates biliverdin, which being converted to bilirubin exhibits a very potent antioxidative effect, and hence antiapoptosis in tumors. Thus this oxidation therapy, by inhibiting this HO-1 dependent antioxidant (bilirubin) formation by ZnPP, and by enhancing ROS generation, is expected to offer a powerful therapeutic modality for future anticancer therapy.
Journal of Biomaterials Science, Polymer Edition, 2015
Worldwide, the cancer appeared as one of the most leading cause of morbidity and mortality. Among... more Worldwide, the cancer appeared as one of the most leading cause of morbidity and mortality. Among the various cancer types, brain tumors are most life threatening with low survival rate. Every year approximately 238,000 new cases of brain and other central nervous system tumors are diagnosed. The dendrimeric approaches have a huge potential for diagnosis and treatment of brain tumor with targeting abilities of molecular cargoes to the tumor sites and the efficiency of crossing the blood brain barrier and penetration to brain after systemic administration. The various generations of dendrimers have been designed as novel targeted drug delivery tools for new therapies including sustained drug release, gene therapy, and antiangiogenic activities. At present era, various types of dendrimers like PAMAM, PPI, and PLL dendrimers validated them as milestones for the treatment and diagnosis of brain tumor as well as other cancers. This review highlights the recent research, opportunities, advantages, and challenges involved in development of novel dendrimeric complex for the therapy of brain tumor.
Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeti... more Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeting and codelivery of small interfering RNA (siRNA) and doxorubicin, and to overcome multidrug resistance, we conjugated a cholic acid-polyethylenimine polymer with folic acid, forming CA-PEI-FA micelles. CA-PEI-FA exhibited a low critical micelle concentration (80 μM), small average particle size (150 nm), and positive zeta potential (+ 12 mV). They showed high entrapment efficiency for doxorubicin (61.2 ± 1.7%, w/w), forming D-CA-PEI-FA, and for siRNA, forming D-CA-PEI-FA-S. X-ray photoelectron spectroscopic analysis revealed the presence of external FA on D-CA-PEI-FA micelles. About 25% doxorubicin was released within 24 h at pH 7.4, while more than 30% release was observed at pH 5. The presence of FA enhanced micelle antitumor activity. The D-CA-PEI-FA and D-CA-PEI-FA-S micelles inhibited tumor growth in vivo. No significant differences between their in vitro cytotoxic activities or their in vivo antitumor effects were observed, indicating that the siRNA coloading did not significantly increase the antitumor activity. Histological analysis revealed that tumor tissues from mice treated with D-CA-PEI-FA or D-CA-PEI-FA-S showed the lowest cancer cell density and the highest levels of apoptosis and necrosis. Similarly, the livers of these mice exhibited the lowest level of dihydropyrimidine dehydrogenase among all treated groups. The lowest serum vascular endothelial growth factor level (VEGF) (24.4 pg/mL) was observed in mice treated with D-CA-PEI-FA-S micelles using siRNA targeting VEGF. These findings indicated that the developed CA-PEI-FA nanoconjugate has the potential to achieve targeted codelivery of drugs and siRNA.
In recent times, many real world applications have emerged that require estimates of class ratios... more In recent times, many real world applications have emerged that require estimates of class ratios in an unlabeled instance collection as opposed to labels of individual instances in the collection. In this paper we investigate the use of maximum mean discrepancy (MMD) in a reproducing kernel Hilbert space (RKHS) for estimating such ratios.
In the last two decades, dendrimers have proven their capabilities in drug delivery, physical sta... more In the last two decades, dendrimers have proven their capabilities in drug delivery, physical stabilization of the drug, solubility enhancement of the poorly soluble drugs and gene delivery. Key features of dendrimers like excellent control over molecular structure, nanoscopic size, availability of multiple functional groups at the periphery and narrow polydispersity index distinguish them amongst the available polymers. Diversity of bio-actives loaded in dendrimers due to covalent and non-covalent interactions, such as hydrogen bonding and hydrophobic interaction contribute to the physical forces for binding of bioactives. The key advantage of drug loaded dendrimers is the delayed and sustained release of bioactives because of the encapsulation of the drug in the hydrophobic cavities of the dendrimer that acts as a sink to retain the drug molecules for extended duration. Because of these features researchers are particularly excited about the potential application of dendrimers as ...
In the last couple of decades antioxidant agents have entered the health market as an easy and at... more In the last couple of decades antioxidant agents have entered the health market as an easy and attractive means of managing diseases. These agents are of enormous interest for an increasingly health-concerned society, and may be particularly relevant for prophylaxis of a number of diseases i.e. arthritis, cancer, metabolic and cardiovascular diseases, osteoporosis, cataracts, brain disorders, etc. Antioxidants are also favorable to vascular healthiness and symbolize useful compounds because they are able to diminish overall cardiovascular risk by acting analogous to first line therapy or as adjuvants in case of failure or in situations where first line therapy cannot be used. Furthermore, well-designed trials are indeed needed to improve the therapeutic efficacy and health benefits of antioxidants. Numerous in vivo proof-of-concepts studies are offered to underline the feasibility of nanostructure system in order to optimizing the delivery of cardiovascular drugs. The present review...
Clostridium taeniosporum is a Gram-positive, anaerobic, rod-shaped non-toxigenic organism isolate... more Clostridium taeniosporum is a Gram-positive, anaerobic, rod-shaped non-toxigenic organism isolated from Crimean lake silt. It is unique in forming spores from which about twelve large, flat, ribbon-like appendages emanate. These ribbon-like structures, about 4.5 mm long and 0.45 mm wide, are assembled from smaller fibrils with 5 nm diameter spherical heads attached to thin tails about 1-2 nm in diameter and about 40 nm in length. The appendages have four major components, a glycoprotein with a collagenlike region, two proteins each of which contains two conserved domains of unknown function, and an ortholog of the Bacillus subtilis spore morphogenetic protein SpoVM. Genes for three of these and other, possibly related proteins, cluster on two chromosome fragments. Here we report that C. taeniosporum is saccharolytic, non-proteolytic, and produces both acetic and butyric acid fermentation products. It synthesizes a-D-glucosidase and N-acetyl-b,D-glucoseaminidase constitutively. These physiological properties are similar to those of the C. botulinum Group II. Genotypically, C. taeniosporum is also closely related to the same Group II, based on 16S rDNA sequences. C. taeniosporum differs from typical C. botulinum Group II strains because it is non-toxigenic and in forming the ribbon-like spore appendages. These major differences among otherwise closely related organisms suggest lateral transfer of genes for appendage synthesis and for toxigenicity.
Proceedings of the fourth ACM international conference on Web search and data mining - WSDM '11, 2011
Automatic extraction of structured records from inconsistently formatted lists on the web is chal... more Automatic extraction of structured records from inconsistently formatted lists on the web is challenging: different lists present disparate sets of attributes with variations in the ordering of attributes; many lists contain additional attributes and noise that can confuse the extraction process; and formatting within a list may be inconsistent due to missing attributes or manual formatting on some sites.
2012 IEEE 12th International Conference on Data Mining, 2012
The goal of this work is to estimate the accuracy of a classifier on a large unlabeled dataset ba... more The goal of this work is to estimate the accuracy of a classifier on a large unlabeled dataset based on a small labeled set and a human labeler. We seek to estimate accuracy and select instances for labeling in a loop via a continuously refined stratified sampling strategy. For stratifying data we develop a novel strategy of learning r bit hash functions to preserve similarity in accuracy values. We show that our algorithm provides better accuracy estimates than existing methods for learning distance preserving hash functions. Experiments on a wide spectrum of real datasets show that our estimates achieve between 15% and 62% relative reduction in error compared to existing approaches. We show how to perform stratified sampling on unlabeled data that is so large that in an interactive setting even a single sequential scan is impractical. We present an optimal algorithm for performing importance sampling on a static index over the data that achieves close to exact estimates while reading three orders of magnitude less data.
In this paper a novel method for simulating unsteady incompressible viscous flow over a moving bo... more In this paper a novel method for simulating unsteady incompressible viscous flow over a moving boundary is described. The numerical model is based on a 2D Navier-Stokes incompressible flow in artificial compressibility formulation with Arbitrary Lagrangian Eulerian approach for moving grid and dual time stepping approach for time accurate discretization. A higher order unstructured finite volume scheme, based on a Harten Lax and van Leer with Contact (HLLC) type Riemann solver for convective fluxes, developed for steady incompressible flow in artificial compressibility formulation by Mandal and Iyer (AIAA paper 2009-3541), is extended to solve unsteady flows over moving boundary. Viscous fluxes are discretized in a central differencing manner based on Coirier's diamond path. An algorithm based on interpolation with radial basis functions is used for grid movements. The present numerical scheme is validated for an unsteady channel flow with a moving indentation. The present numerical results are found to agree well with experimental results reported in literature.
Objective. Advanced mast cell (MC) neoplasms are usually resistant to conventional therapy. There... more Objective. Advanced mast cell (MC) neoplasms are usually resistant to conventional therapy. Therefore, current research focuses on new targets in neoplastic MC and development of respective targeted drugs. Mastocytomas in dogs often behave as aggressive tumors. We report that heat-shock protein 32 (Hsp32), also known as heme oxygenase-1, is a survival-enhancing molecule and new target in canine mastocytoma cells. Materials and Methods. As assessed by reverse transcriptase polymerase chain reaction, Northern blotting, immunocytochemistry, and Western blotting, primary neoplastic dog MC, and the canine mastocytoma-derived cell line C2 expressed Hsp32 mRNA and the Hsp32 protein in a constitutive manner. Results. The KIT-targeting drug midostaurin inhibited expression of Hsp32, as well as survival in C2 cells. Confirming the functional role of Hsp32, the inhibitory effect of midostaurin on C2 cells was markedly reduced by the Hsp32-inductor hemin. Two pharmacologic Hsp32inhibitors, styrene maleic-acid micelle-encapsulated ZnPP (SMA-ZnPP) and pegylated zincprotoporphyrin (PEG-ZnPP) were applied. Both drugs were found to inhibit proliferation of C2 cells as well as growth of primary neoplastic canine MC. The growth-inhibitory effects of SMA-ZnPP and PEG-ZnPP were dose-and time-dependent (IC 50 : 1-10 mM) and found to be associated with induction of apoptosis. Conclusions. Hsp32 is an important survival factor and interesting new target in neoplastic canine MC. Trials with Hsp32-targeted drugs are now warranted to define the clinical efficacy of these drugs. Ó
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Papers by Arun Iyer