Patient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully ...recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches.
Toll-like receptor 4 (TLR4) plays an essential role in mediating organ injury in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Herein, we assess whether inhibiting TLR4 ...signaling can ameliorate liver failure and serve as a potential treatment.
Circulating TLR4 ligands and hepatic TLR4 expression were measured in plasma samples and liver biopsies from patients with cirrhosis. TAK-242 (TLR4 inhibitor) was tested in vivo (10 mg/kg intraperitoneally) in rodent models of ACLF (bile duct ligation + lipopolysaccharide LPS; carbon tetrachloride + LPS) and ALF (galactosamine + LPS) and in vitro on immortalized human monocytes (THP-1) and hepatocytes (HHL5). The in vivo therapeutic effect was assessed by coma-free survival, organ injury and cytokine release and in vitro by measuring IL-6, IL-1β or cell injury (TUNEL), respectively.
In patients with cirrhosis, hepatic TLR4 expression was upregulated and circulating TLR4 ligands were increased (p <0.001). ACLF in rodents was associated with a switch from apoptotic cell death in ALF to non-apoptotic forms of cell death. TAK-242 reduced LPS-induced cytokine secretion and cell death (p = 0.002) in hepatocytes and monocytes in vitro. In rodent models of ACLF, TAK-242 administration improved coma-free survival, reduced the degree of hepatocyte cell death in the liver (p <0.001) and kidneys (p = 0.048) and reduced circulating cytokine levels (IL-1β, p <0.001). In a rodent model of ALF, TAK-242 prevented organ injury (p <0.001) and systemic inflammation (IL-1β, p <0.001).
This study shows that TLR4 signaling is a key factor in the development of both ACLF and ALF; its inhibition reduces the severity of organ injury and improves outcome. TAK-242 may be of therapeutic relevance in patients with liver failure.
Toll-like receptor 4 (or TLR4) mediates endotoxin-induced tissue injury in liver failure and cirrhosis. This receptor sensitizes cells to endotoxins, which are produced by gram-negative bacteria. Thus, inhibiting TLR4 signaling with an inhibitor (TAK-242) ameliorates organ injury and systemic inflammation in rodent models of acute and acute-on-chronic liver failure.
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•Cirrhosis is associated with TLR4-related sensitization to endotoxins and a switch from apoptotic to necroptotic cell death.•Inhibition of TLR4 signaling by TAK-242 reduces immune cell responses and hepatocyte injury in response to LPS in vitro.•In models of acute and acute-on-chronic liver failure, TAK-242 mitigated LPS-driven systemic inflammation and organ injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Melatonin (N-acetyl-5-hydroxy tryptamine), a multipotent biomolecule is well known for its ability to confer tolerance to several abiotic and biotic stresses. The regulation of melatonin-mediated ...drought tolerance in drought-distinguished varieties can be different due to discriminating redox levels. The present study was focused on assessing the effects of melatonin priming against polyethylene glycol (PEG)-induced stress with respect to the antioxidant system, photosynthetic parameters, lipoxygenase expression, JA and ABA levels in drought-sensitive (Kadiri-7) and drought-tolerant (Kadiri-9) varieties. Exogenous melatonin alleviated the drought stress effects in sensitive variety (Kadiri-7) by increasing the endogenous melatonin content with an improved antioxidant system and photosynthetic attributes. The primed stressed plants of the sensitive variety exhibited reduced expression and activity of the chlorophyll degrading enzymes (Chl-deg PRX, pheophytinase and chlorophyllase) with a concomitant increase in chlorophyll content in comparison to unprimed controls. Interestingly, melatonin priming stimulated higher expression and activity of lipoxygenase (LOX) as well as enhanced the expression of genes involved in the synthesis of jasmonic acid (JA) including its content in drought stressed plants of the sensitive variety. The expression of
(involved in ABA-biosynthesis) was upregulated while
(ABA-degradation) was downregulated which corresponded with higher ABA levels. Contrastingly, priming caused a decrease in endogenous melatonin content under drought stress in tolerant variety (Kadiri-9) which might be due to feedback inhibition of its synthesis to maintain intracellular redox balance and regulate better plant metabolism. Furthermore, the higher endogenous melatonin content along with improved antioxidant system, photosynthetic efficiency and LOX expression associated with the increased levels of JA and ABA in unprimed stressed plants of the tolerant variety (Kadiri-9) is pointing towards the effectiveness of melatonin in mediating drought stress tolerance. Overall, exogenous melatonin alleviated the adverse effects of drought stress in sensitive variety while having no add-on effect on drought stress responses of tolerant variety which is inherently equipped to withstand the given duration of drought stress treatment.
In tumor engineering, 3D approaches are used to model components of the tumor microenvironment and to test new treatments. Pancreatic cancers are a cancer of substantial unmet need and survival rates ...are lower compared to any other cancer. Bioengineering techniques are increasingly applied to understand the unique biology of pancreatic tumors and to design patient-specific models. Here we summarize how extracellular and cellular elements of the pancreatic tumor microenvironment and their interactions have been studied in 3D cell cultures. We review selected clinical trials, assess the benefits of therapies interfering with the tumor microenvironment and address their limitations and future perspectives.
Soy protein isolate has received much attention in recent decades due to its abundance, eco-friendliness, low cost, film-forming capacity, and processability. In this study, novel soy protein isolate ...(SPI)-based bionanocomposite films were prepared by integrating Mg–Allayered double hydroxide (LDH) at different loadings (0%, 2%, 5%, and 9% w/w) using a simple solution casting process. The Mg–Al LDH was synthesized in a 2:1 molar ratio via a co-precipitation method. Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), field-emission scanning electron microscopy, and thermogravimetric analysis (TGA) revealed intercalation/exfoliation of Mg–Al LDH sheets in the SPI matrix of bionanocomposite films. Agglomeration of Mg–Al LDH was distinctly noticed as its concentration increased from 0 to 9% (w/w). The bionanocomposite films showed considerable thermal stability. Mechanical and biodegradation qualities were also investigated. The tensile strength values of the prepared films with 0%, 2%, 5%, and 9% w/w LDH loadings were found to be 2.12 ± 0.25, 1.60 ± 0.15, 1.64 ± 0.08 and 1.58 ± 0.06 KNm/g, respectively. The SPI-Mg/Al LDH 5% film showed a substantial increase in tensile strength and efficiently degraded in non-sterile soil.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Isolation of metastatic circulating tumor cells (CTCs) from cancer patients is of high value for disease monitoring and molecular characterization. Despite the development of many new CTC isolation ...platforms in the last decade, their isolation and detection has remained a challenge due to the lack of specific and sensitive markers. In this feasibility study, we present a method for CTC isolation based on the specific binding of the malaria rVAR2 protein to oncofetal chondroitin sulfate (ofCS). We show that rVAR2 efficiently captures CTCs from hepatic, lung, pancreatic, and prostate carcinoma patients with minimal contamination of peripheral blood mononuclear cells. Expression of ofCS is present on epithelial and mesenchymal cancer cells and is equally preserved during epithelial-mesenchymal transition of cancer cells. In 25 stage I-IV prostate cancer patient samples, CTC enumeration significantly correlates with disease stage. Lastly, rVAR2 targets a larger and more diverse population of CTCs compared to anti-EpCAM strategies.
The global proliferation of plastic waste is a dire concern as fumble wastes in the environment degrade plastics into smaller fragments that pose a prodigious menace to biota. Plastics are persistent ...due to their inherent properties which have found omnipresent applications in automotive, electronics, energy, adhesives, household components, paints, coatings, and the myriad of medical fields, etc. Nevertheless, plastics have a caliginous side. However, plausible methods and cogent techniques to deal with emerging plastic wastes have not been established which results in the amalgamation of waste creating havoc. The cognizance of fostering and sharing of actual management of plastic wastes involving harmonization of specific standards and practices could assist inappropriate management of plastic wastes. Moreover, the conversion of plastic waste into a gamut of applications such as energy recovery, components of building construction, production of nanomaterials, evolve novel monomers, etc could be a propitious endeavor for mankind. Nevertheless, the diminution of ubiquitous concern should headway from the end-of-pipe approach to pre-emptive strategies by utilizing the plastic wastes into intrinsic applications or by eradicating the single-use plastics. This exploration will proffer a vision in the conversion of waste into gimmick applications useful for mankind and to contemplate whether recycling is the only magic bullet or we could utilize it head-on.
Predicted global mismanaged plastic projected in 2025 and representation of the great pacific garbage patch. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The present work demonstrates the development of hydroxyapatite (HA)/gold (Au) nanocomposites to increase the adsorption of methylene blue (MB) dye from the wastewater. HA nanopowder was prepared via ...a wet chemical precipitation method by means of Ca(OH)2 and H3PO4 as starting materials. The biosynthesis of gold nanoparticles (AuNPs) has been reported for the first time by using the plant extract of Acrocarpus fraxinifolius. Finally, the as-prepared HA nanopowder was mixed with an optimized AuNPs solution to produce HA/Au nanocomposite. The prepared HA/Au nanocomposite was studied by using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis (EDX) analysis. Adsorption studies were executed by batch experiments on the synthesized composite. The effect of the amount of adsorbent, pH, dye concentration and temperature was studied. Pseudo-first-order and pseudo-second-order models were used to fit the kinetic data and the kinetic modeling results reflected that the experimental data is perfectly matched with the pseudo-first-order kinetic model. The dye adsorbed waste materials have also been investigated against Pseudomonas aeruginosa, Micrococcus luteus, and Staphylococcus aureus bacteria by the agar well diffusion method. The inhibition zones of dye adsorbed samples are more or less the same as compared to as-prepared samples. The results so obtained indicates the suitability of the synthesized sample to be exploited as an adsorbent for effective treatment of MB dye from wastewater and dye adsorbed waste as an effective antibacterial agent from an economic point of view.
•Loss of p53 confers aggressive mesenchymal phenotypes upon EMT induction in CRCs.•SATB1 shows agonistic relationship with EMT TFs SNAI1, SNAI2 and VIM with loss of p53.•Lysine Demethylase KDM6B ...epigenetically regulates EMT via SNAI1.•SATB1 expression in CRC patients correlates with enhanced levels of ZEB1 and KDM6A.
Epithelial to Mesenchymal transition (EMT) drives cancer metastasis and is governed by genetic and epigenetic alterations at multiple levels of regulation. It is well established that loss/mutation of p53 confers oncogenic function to cancer cells and promotes metastasis. Though transcription factors like ZEB1, SLUG, SNAIL and TWIST have been implied in EMT signalling, p53 mediated alterations in the epigenetic machinery accompanying EMT are not clearly understood. This work attempts to explore epigenetic signalling during EMT in colorectal cancer (CRC) cells with varying status of p53. Towards this, we have induced EMT using TGFβ on CRC cell lines with wild type, null and mutant p53 and have assayed epigenetic alterations after EMT induction. Transcriptomic profiling of the four CRC cell lines revealed that the loss of p53 confers more mesenchymal phenotype with EMT induction than its mutant counterparts. This was also accompanied by upregulation of epigenetic writer and eraser machinery suggesting an epigenetic signalling cascade triggered by TGFβ signalling in CRC. Significant agonist and antagonistic relationships observed between EMT factor SNAI1 and SNAI2 with epigenetic enzymes KDM6A/6B and the chromatin organiser SATB1 in p53 null CRC cells suggest a crosstalk between epigenetic and EMT factors. The observed epigenetic regulation of EMT factor SNAI1 correlates with poor clinical outcomes in 270 colorectal cancer patients taken from TCGA-COAD. This unique p53 dependent interplay between epigenetic enzymes and EMT factors in CRC cells may be exploited for development of synergistic therapies for CRC patients presenting to the clinic with loss of p53.
Wild type p53 binding sites are associated with promoters of SATB1 and with the loss of p53, these promoters are occupied by repressive histone marks H3K27me3 correlating with decreased expression of SATB1 (unpublished work from the lab). Expression of SATB1 antagonistically relates with EZH2 which correlates with our findings. Upon EMT induction with TGF-β treatment, the expression of SATB1 increases in p53 null CRC cells. The higher expression of SATB1 also correlates with increased level of SNAI1, SNAI2 and VIM suggesting that chromatin regulation plays a vital role in regulating EMT. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which ...descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately innervate the skeletal muscle. Perturbation of these neural circuits and consequent loss of both UMNs and LMNs, leading to muscle wastage and impaired movement, is the key pathophysiology observed. Despite decades of research, we are still lacking in ALS disease-modifying treatments. In this review, we document the current research from patient studies, rodent models, and human stem cell models in understanding the mechanisms of corticomotor circuit dysfunction and its implication in ALS. We summarize the current knowledge about cortical UMN dysfunction and degeneration, altered excitability in LMNs, neuromuscular junction degeneration, and the non-cell autonomous role of glial cells in motor circuit dysfunction in relation to ALS. We further highlight the advances in human stem cell technology to model the complex neural circuitry and how these can aid in future studies to better understand the mechanisms of neural circuit dysfunction underpinning ALS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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