Lignin Reinforced Rubber Composites

Lignin is the country's second most abundant renewable biomass resource next to cellulose. The pulp and paper industries produce very large quantities of lignin, most of those are burned to recover energy, pulping chemicals, enzymatic or acid hydrolysis to sugars followed by fermentation to alcohols. Another emerging technology where the lignin being used is in the adhesives and asphalts. For the former, lignin partly replaces phenol in phenol-formaldehyde formulations, for the latter lignin is used as an extender. Lignin in polyurethanes is for good mechanical properties and reactions of lignin such as grafting and crosslinking agent are also well known. Novolak-hexamine based phenolic resins are commonly used as reinforcing and processing aids in nitrile rubber (NBR) compounds. Not only the oil and petrol resistances increase significantly , resin loading is also found to offer better heat resistant properties than carbon blacks. For seals, valves and gasket applications addition of phenolic resins provides superior abrasion resistance, ageing and negligible hardening effects at elevated temperatures. Poor tackiness of NBR compounds can easily be eliminated by using phenolic resin in place of carbon black. The study presented here is to explore the possibility of employing lignin into some value -added rubber based composites . Lignin, gymnosperms, angiosperms and glass varieties, contain alcohol and phenolic groups and also double bonds in their structural moiety and therefore, could resinify into prepolymer in presence of hexamine.Varied proportions of lignin upto 50 parts with respect to total rubber plus hexamine,have been incorporated in medium acrylonitrile (37%) NBR and studied for their processing characteristics and physico-mechanical properties e.g. reinforcement, oil and fuel resistances, ageing and thermal stability. Efficacy of lignin has been found to be superior to either phenolic resin-hexamine or carbon black filled compounds. Finally, attempt has also been made to modify the surface chemistry incorporating CO,> C=O etc. groups by additions of dicumyl peroxide and this modified lignin was found to offer improved rubber-filler adhesion, tackiness and physical properties

Gemcitabine Combination Nano Therapies for Pancreatic Cancer

Pancreatic cancer is one of the deadliest causes of cancer-related death in the United States, with a 5-year overall survival rate of 6 to 8%. These statistics suggest that immediate medical attention is needed. Gemcitabine (GEM) is the gold standard first-line single chemotherapy agent for pancreatic cancer but, after a few months, cells develop chemoresistance. Multiple clinical and experimental investigations have demonstrated that a combination or co-administration of other drugs as chemotherapies with GEM lead to superior therapeutic benefits. However, such combination therapies often induce severe systemic toxicities. Thus, developing strategies to deliver a combination of chemotherapeutic agents more securely to patients is needed. Nanoparticle-mediated delivery can offer to load a cocktail of drugs, increase stability and availability, on-demand and tumor-specific delivery while minimizing chemotherapy-associated adverse effects. This review discusses the available drugs being co-administered with GEM and the limitations associated during the process of co-administration. This review also helps in providing knowledge of the significant number of delivery platforms being used to overcome problems related to gemcitabine-based co-delivery of other chemotherapeutic drugs, thereby focusing on how nanocarriers have been fabricated, considering the modes of action, targeting receptors, pharmacology of chemo drugs incorporated with GEM, and the differences in the physiological environment where the targeting is to be done. This review also documents the focus on novel mucin-targeted nanotechnology which is under development for pancreatic cancer therapy

Antibody-Drug Conjugates for Cancer Therapy: Chemistry to Clinical Implications

Chemotherapy is one of themajor therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal tissue selectivity and specificity in chemotherapy. Considering its importance in cancer treatment, we aim to review recent efforts for the design and development of ADCs. ADCs are mainly composed of an antibody, a cytotoxic payload, and a linker, which can offer selectivity against tumors, anti-cancer activity, and stability in systemic circulation. Therefore, we have reviewed recent updates and principal considerations behind ADC designs, which are not only based on the identification of target antigen, cytotoxic drug, and linker, but also on the drug-linker chemistry and conjugation site at the antibody. Our review focuses on site-specific conjugation methods for producing homogenous ADCs with constant drug-antibody ratio (DAR) in order to tackle several drawbacks that exists in conventional conjugation methods

Novel Paclitaxel Nanoformulation Impairs De Novo Lipid Synthesis in Pancreatic Cancer Cells and Enhances Gemcitabine Efficacy

Pancreatic cancer (PanCa) is a highly lethal disease with a poor 5 year survival rate, less than 7%. It has a dismal prognosis, and more than 50% of cases are detected at an advanced and metastatic stage. Gemcitabine (GEM) is a gold standard chemotherapy used for PanCa treatment. However, GEM-acquired resistance in cancer cells is considered as a major setback for its continued clinical implementation. This phenomenon is evidently linked to de novo lipid synthesis. PanCa cells rely on de novo lipid synthesis, which is a prime event in survival and one of the key drivers for tumorigenesis, cancer progression, and drug resistance. Thus, the depletion of lipogenesis or lipid metabolism can not only improve treatment outcomes but also overcome chemoresistance, which is an unmet clinical need. Toward this effort, our study reports a unique paclitaxel−poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PPNPs) formulation which can target lipid metabolism and improve anticancer efficacy of GEM in PanCa cells. PPNPs inhibit excessive lipid formation and alter membrane stability with compromised membrane integrity, which was confirmed by Fourier transform infrared and zeta potential measurements. The effective interference of PPNPs in lipid metabolic signaling was determined by reduction in the expression of FASN, ACC, lipin, and Cox-2 proteins. This molecular action profoundly enhances efficacy of GEM as evident through enhanced inhibitory effects on the tumorigenic and metastasis assays in PanCa cells. These data clearly suggest that the ablation of lipid metabolism might offer an innovative approach for the improved therapeutic outcome in PanCa patients

Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.The malaria parasite Plasmodium obligatorily infects and replicates inside hepatocytes surrounded by a parasitophorous vacuole membrane (PVM), which is decorated by the host-cell derived autophagy protein LC3. We have previously shown that the parasite-derived, PVM-resident protein UIS3 sequesters LC3 to avoid parasite elimination by autophagy from hepatocytes. Here we show that a small molecule capable of disrupting this interaction triggers parasite elimination in a host cell autophagy-dependent manner. Molecular docking analysis of more than 20 million compounds combined with a phenotypic screen identified one molecule, C4 (4-{[4-(4-{5-[3-(trifluoromethyl) phenyl]-1,2,4-oxadiazol-3-yl}benzyl)piperazino]carbonyl}benzonitrile), capable of impairing infection. Using biophysical assays, we established that this impairment is due to the ability of C4 to disrupt UIS3–LC3 interaction, thus inhibiting the parasite’s ability to evade the host autophagy response. C4 impacts infection in autophagy-sufficient cells without harming the normal autophagy pathway of the host cell. This study, by revealing the disruption of a critical host–parasite interaction without affecting the host’s normal function, uncovers an efficient anti-malarial strategy to prevent this deadly disease.This work was supported by grants from Institut Mérieux (MRG_20052016 to M.M.M). S.S. and A.F.C. were recipients of Fundação para a Ciência e Tecnologia fellowships SFRH/BPD/116451/2016 and SFRH/BPD/112009/2015, respectively. H.R. and V.S. were supported by core funds from NCBS-TIFR. A.L. was supported by Sanofi-Institut Pasteur 2018 Prize to M.M.M.info:eu-repo/semantics/publishedVersio

MicroRNA-145 replacement as a therapeutic tool to Improve TRAIL therapy

Pancreatic cancer (PanCa) is a third leading cause of cancer related deaths in US. Unlike other cancers, PanCa is highly resistant to TNF-related apoptosis-inducing ligand (TRAIL) that emerges as one of the most-promising therapy in clinical trials. Our group has previously identified microRNA-145 (miR-145) is downregulated in PanCa, the restoration of which inhibits tumor growth and enhances gemcitabine sensitivity. In this study, we have observed that miR-145 restoration in PanCa cells renders them sensitive to TRAIL treatment. Therefore, we have engineered unique superparamagnetic nanoparticles (SPs) for co-delivering miR-145 and TRAIL in PanCa for improving their therapeutic response to TRAIL. The results in this study demonstrate that acquired resistance to TRAIL in PanCa cells can overcome with the replacement of lost levels of miR-145 expression. Our SP nanoparticles were engineered to co-deliver miR-145 and TRAIL to PanCa cells, which resulted in simultaneous restoration of miR-145 and inhibition of acquired resistance to TRAIL. Combined actions of miR-145 and TRAIL markedly improve TRAIL-induced apoptotic effects in PanCa cells through the activation of an extrinsic apoptosis pathway pathway as indicated by activation of DR5, FLIP, FADD and enhanced expression of caspase-8/3. The co-delivery of miR-145 and TRAIL using SP nanoparticles inhibited tumorigenic characteristics of PanCa cells, which include proliferation, invasion, migration and clonogenicity. The results were reciprocated and got further confirmed with the inhibition of tumorsphere formation and in vivo tumorigencity in xenograft mice. Immunohistochemical staining of excised tumor tissues demonstrate an activation of death receptor pathway and subsequent expression of apoptotic markers. The study provides novel insights on two facades- how resistance of cancer cells to TRAIL-based pro-apoptotic therapies can be tackled, and how efficient intracellular delivery of TRAIL can be achieved. Our results suggest that acquired resistance to TRAIL can be overcome by co-delivery of miR-145 and pEGFP-TRAIL using SP nanoparticles

Therapeutic Intervention Using Autologous Exosomes for Treatment of Early-Stage Pancreatic Cancer

Background: Pancreatic cancer (PanCa) is the third deadliest cancer in United States with a poor survival rate. Despite extensive research efforts, there is not any substantial progress in cancer therapeutics; major challenges lie with inherent drug toxicity, ineffectiveness, and resistance due to impediments against intracellular drug delivery. From a therapeutic delivery standpoint, novel delivery vehicles are required that are both biocompatible and non-immunogenic for a patient in order to maximize the chances of cure. This is possible by utilizing an autologous biological material, which can be applied as a personalized medicine to match the individual circumstances and molecular profile of the patient. One such approach has been optimized in our lab, which utilizes exosomes from the matched tumor adjacent normal (NAT) area following surgical resection. Using exosomes as a scaffold, our objective is to deliver therapeutics safely and effectively to the patient tumor site. Results: NAT derived exosomes showed effective size and zeta potential (size: 44.12 ± 0.89; Zeta potential: -14.9 mV), which is ideal for drug delivery purposes. The purification of exosomes was confirmed using proteins isolated from exosomes through Western blotting for expression of exosomal markers, such as CD63 expression. Immunofluorescence for CD63 expression confirmed the efficient delivery of exosomes in PanCa cells. Our results indicated high drug loading capacity of NAT derived exosomes as demonstrated using drug, Ormeloxifene (ORM) though UPLC. Exo-ORM treatment efficiently delivered ORM into the cancer cells and inhibited the cancer cell characteristics, such as, proliferation compared with ORM alone. Additionally, NAT derived exosomes showed enhanced expression of tumor suppressor microRNA, miR-145, suggestive of their therapeutic importance. We observed restoration of lost miR-145 levels in PanCa cells on incubation with NAT derived exosomes for 48hrs. This further indicates their relevance for their utilization in the development of an anti-cancer therapy. Conclusion: Our observations offer importance of the utilization of NAT derived exosomes for personalized medicine as a therapeutic delivery vehicle in PanCa

Metagenomic analysis unveils the microbial landscape of pancreatic tumors

The composition of resident microbes in the human body is linked to various diseases and their treatment outcomes. Although studies have identified pancreatic ductal adenocarcinoma (PDAC)-associated bacterial communities in the oral and gut samples, herein, we hypothesize that the prevalence of microbiota in pancreatic tumor tissues is different as compared with their matched adjacent, histologically normal appearing tissues, and these microbial molecular signatures can be highly useful for PDAC diagnosis/prognosis. In this study, we performed comparative profiling of bacterial populations in pancreatic tumors and their respective adjacent normal tissues using 16S rRNA-based metagenomics analysis. This study revealed a higher abundance of Proteobacteria and Actinomycetota in tumor tissues compared with adjacent normal tissues. Interestingly, the linear discriminant analysis (LDA) scores unambiguously revealed an enrichment of Delftia in tumor tissues, whereas Sphingomonas, Streptococcus, and Citrobacter exhibited a depletion in tumor tissues. Furthermore, we analyzed the microbial composition between different groups of patients with different tumor differentiation stages. The bacterial genera, Delftia and Staphylococcus, were very high at the G1 stages (well differentiated) compared with G2 (well to moderate/moderately differentiated) and G3/G4 (poorly differentiated) stages. However, the abundance of Actinobacter and Cloacibacterium was found to be very high in G2 and G3, respectively. Additionally, we evaluated the correlation of programmed death-ligand (PDL1) expression with the abundance of bacterial genera in tumor lesions. Our results indicated that three genera such as Streptomyces, Cutibacterium, and Delftia have a positive correlation with PD-L1 expression. Collectively, these findings demonstrate that PDAC lesions harbor relatively different microbiota compared with their normal tumor adjacent tissues, and this information may be helpful for the diagnosis and prognosis of PADC patients

Clinical Significance of MUC13 in Pancreatic Ductal Adenocarcinoma

Background—Poor prognosis of pancreatic cancer (PanCa) is associated with lack of an effective early diagnostic biomarker. This study elucidates significance of MUC13, as a diagnostic/prognostic marker of PanCa. Methods—MUC13 was assessed in tissues using our in-house generated anti-MUC13 mouse monoclonal antibody and analyzed for clinical correlation by immunohistochemistry, immunoblotting, RT-PCR, computational and submicron scale mass-density fluctuation analyses, ROC and Kaplan Meir curve analyses. Results—MUC13 expression was detected in 100% pancreatic intraepithelial neoplasia (PanIN) lesions (Mean composite score: MCS=5.8; AUC \u3e0.8, P\u3c0.0001), 94.6% of pancreatic ductal adenocarcinoma (PDAC) samples (MCS=9.7, P\u3c0.0001) as compared to low expression in tumor adjacent tissues (MCS=4, P\u3c0.001) along with faint or no expression in normal pancreatic tissues (MCS=0.8; AUC \u3e0.8; P\u3c0.0001). Nuclear MUC13 expression positively correlated with nodal metastasis (P\u3c0.05), invasion of cancer to peripheral tissues (P\u3c0.5) and poor patient survival (P\u3c0.05; prognostic AUC=0.9). Submicron scale mass density and artificial intelligence based algorithm analyses also elucidated association of MUC13 with greater morphological disorder (P\u3c0.001) and nuclear MUC13 as strong predictor for cancer aggressiveness and poor patient survival. Conclusion—This study provides significant information regarding MUC13 expression/ subcellular localization in PanCa samples and supporting the use anti-MUC13 MAb for the development of PanCa diagnostic/prognostic test

MicroRNA-145 replacement as a therapeutic tool to Improve TRAIL therapy

Pancreatic cancer (PanCa) is a third leading cause of cancer related deaths in US. Unlike other cancers, PanCa is highly resistant to TNF-related apoptosis-inducing ligand (TRAIL) that emerges as one of the most-promising therapy in clinical trials. Our group has previously identified microRNA-145 (miR-145) is downregulated in PanCa, the restoration of which inhibits tumor growth and enhances gemcitabine sensitivity. In this study, we have observed that miR-145 restoration in PanCa cells renders them sensitive to TRAIL treatment. Therefore, we have engineered unique superparamagnetic nanoparticles (SPs) for co-delivering miR-145 and TRAIL in PanCa for improving their therapeutic response to TRAIL. The results in this study demonstrate that acquired resistance to TRAIL in PanCa cells can overcome with the replacement of lost levels of miR-145 expression. Our SP nanoparticles were engineered to co-deliver miR-145 and TRAIL to PanCa cells, which resulted in simultaneous restoration of miR-145 and inhibition of acquired resistance to TRAIL. Combined actions of miR-145 and TRAIL markedly improve TRAIL-induced apoptotic effects in PanCa cells through the activation of an extrinsic apoptosis pathway pathway as indicated by activation of DR5, FLIP, FADD and enhanced expression of caspase-8/3. The co-delivery of miR-145 and TRAIL using SP nanoparticles inhibited tumorigenic characteristics of PanCa cells, which include proliferation, invasion, migration and clonogenicity. The results were reciprocated and got further confirmed with the inhibition of tumorsphere formation and in vivo tumorigencity in xenograft mice. Immunohistochemical staining of excised tumor tissues demonstrate an activation of death receptor pathway and subsequent expression of apoptotic markers. The study provides novel insights on two facades- how resistance of cancer cells to TRAIL-based pro-apoptotic therapies can be tackled, and how efficient intracellular delivery of TRAIL can be achieved. Our results suggest that acquired resistance to TRAIL can be overcome by co-delivery of miR-145 and pEGFP-TRAIL using SP nanoparticles