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17 mins ago


The importance of germline-inherited post-translational histone modifications on priming early mammalian development is just emerging1-4. Histone H3 lysine 9 (H3K9) trimethylation is associated with heterochromatin and gene repression during cell-fate change5, whereas histone H3 lysine 4 (H3K4) trimethylation marks active gene promoters6. Mature oocytes are transcriptionally quiescent and possess remarkably broad domains of H3K4me3 (bdH3K4me3)1,2. It is unknown which factors contribute to the maintenance of the bdH3K4me3 landscape. Lysine-specific demethylase 4A (KDM4A) demethylates H3K9me3 at promoters marked by H3K4me3 in actively transcribing somatic cells7. Here, we report that KDM4A-mediated H3K9me3 demethylation at bdH3K4me3 in oocytes is crucial for normal pre-implantation development and zygotic genome activation after fertilization. The loss of KDM4A in oocytes causes aberrant H3K9me3 spreading over bdH3K4me3, resulting in insufficient transcriptional activation of genes, endogenous retroviral elements and chimeric transcripts initiated from long terminal repeats during zygotic genome activation. The catalytic activity of KDM4A is essential for normal epigenetic reprogramming and pre-implantation development. Hence, KDM4A plays a crucial role in preserving the maternal epigenome integrity required for proper zygotic genome activation and transfer of developmental control to the embryo.During mouse embryonic development, pluripotent cells rapidly divide and diversify, yet the regulatory programs that define the cell repertoire for each organ remain ill-defined. To delineate comprehensive chromatin landscapes during early organogenesis, we mapped chromatin accessibility in 19,453 single nuclei from mouse embryos at 8.25 days post-fertilization. Identification of cell-type-specific regions of open chromatin pinpointed two TAL1-bound endothelial enhancers, which we validated using transgenic mouse assays. Integrated gene expression and transcription factor motif enrichment analyses highlighted cell-type-specific transcriptional regulators. Subsequent in vivo experiments in zebrafish revealed a role for the ETS factor FEV in endothelial identity downstream of ETV2 (Etsrp in zebrafish). Concerted in vivo validation experiments in mouse and zebrafish thus illustrate how single-cell open chromatin maps, representative of a mammalian embryo, provide access to the regulatory blueprint for mammalian organogenesis.The availability of nucleotides has a direct impact on transcription. The inhibition of dihydroorotate dehydrogenase (DHODH) with leflunomide impacts nucleotide pools by reducing pyrimidine levels. Leflunomide abrogates the effective transcription elongation of genes required for neural crest development and melanoma growth in vivo1. To define the mechanism of action, we undertook an in vivo chemical suppressor screen for restoration of neural crest after leflunomide treatment. Surprisingly, we found that alterations in progesterone and progesterone receptor (Pgr) signalling strongly suppressed leflunomide-mediated neural crest effects in zebrafish. In addition, progesterone bypasses the transcriptional elongation block resulting from Paf complex deficiency, rescuing neural crest defects in ctr9 morphant and paf1(alnz24) mutant embryos. Using proteomics, we found that Pgr binds the RNA helicase protein Ddx21. ddx21-deficient zebrafish show resistance to leflunomide-induced stress. At a molecular level, nucleotide depletion reduced the chromatin occupancy of DDX21 in human A375 melanoma cells. Nucleotide supplementation reversed the gene expression signature and DDX21 occupancy changes prompted by leflunomide. Together, our results show that DDX21 acts as a sensor and mediator of transcription during nucleotide stress.In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3α/β and Mek1/2 (2i) instructs a self-renewing ground state whose endogenous inducers are unknown. Here we show that the axon guidance cue Netrin-1 promotes naive pluripotency by triggering profound signalling, transcriptomic and epigenetic changes in mESCs. Furthermore, we demonstrate that Netrin-1 can substitute for blockade of Gsk3α/β and Mek1/2 to sustain self-renewal of mESCs in combination with leukaemia inhibitory factor and regulates the formation of the mouse pluripotent blastocyst. Mechanistically, we reveal how Netrin-1 and the balance of its receptors Neo1 and Unc5B co-regulate Wnt and MAPK pathways in both mouse and human ESCs. Netrin-1 induces Fak kinase to inactivate Gsk3α/β and stabilize β-catenin while increasing the phosphatase activity of a Ppp2r2c-containing Pp2a complex to reduce Erk1/2 activity. Collectively, this work identifies Netrin-1 as a regulator of pluripotency and reveals that it mediates different effects in mESCs depending on its receptor dosage, opening perspectives for balancing self-renewal and lineage commitment.Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27-CD28-CD8+ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. https://www.selleckchem.com/products/capsazepine.html Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27-CD28-CD8+ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27-CD28-CD8+ T cells to acquire a broad-spectrum, innate-like killing activity.High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9-/- tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.

42 mins ago


Computational approaches have been proven to be complementary tools of interest for identifying potential candidates for drug repurposing. However, although the methods developed so far offer interesting opportunities and could contribute to solve issues faced by the pharmaceutical sector, they also come with their own constraints. Indeed, specific challenges ranging from data access, standardization and integration to the implementation of reliable and coherent validation methods must be addressed to allow a systematic use at a larger scale. In this mini-review, we cover computational tools recently developed for addressing some of these challenges. https://www.selleckchem.com/products/tepp-46.html This includes specific databases providing accessibility to large set of curated data with standardized annotations, web-based tools integrating flexible user interfaces to perform fast computational repurposing experiments and standardized datasets specifically annotated and balanced for validating new computational drug repurposing methods. Interestingly, these new databases combined to the increasing number of information about the outcomes of drug repurposing studies can be used to perform meta-analysis to identify key properties associated with successful drug repurposing cases. This information could further be used to design estimation methods to compute an a priori assessment of the repurposing possibilities. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.Breast cancer is the most common cancer in women worldwide. Due to the heterogeneous nature of breast cancer, the optimal treatment and expected response for each patient may not necessarily be universal. Molecular imaging techniques could play an important role in the early detection and targeted therapy evaluation of breast cancer. This review focuses on the development of peptides labeled with SPECT and PET radionuclides for breast cancer imaging. We summarized the current status of radiolabeled peptides for different receptors in breast cancer. The characteristics of radionuclides and major techniques for peptide labeling are also briefly discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.BACKGROUND Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. METHODS We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. RESULTS One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancemoting the body's immune system to fight the cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.The introduction of antibiotics to treat bacterial infections either by killing or blocking their growth has been accompanied by the studies of mechanism that allows the drugs to kill the bacteria or to stop their proliferation. In such scenario the coming of antibacterial agents active on the bacterial cell wall has been of fundamental importance in the fight against bacterial agents responsible for severe diseases. As a matter of fact cell wall, that plays many roles during lifecycle, is an essential constituent of most bacteria. This overview focus on the intracellular steps of peptidoglycan biosynthesis and the research of new antibacterial agents based on the enzymes involved in these early steps of the formation of cell membrane components. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.BACKGROUND Monoclonal antibodies (mAbs) against tumor-associated antigens have been shown to target tumors with specificity and selectivity; therefore, it was hypothesized that cancer could be treated with mAbs without side effects. In the early 1980s, clinical studies demonstrated that tumors could be visualized using radiolabeled mAbs. However, with the introduction of positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG), antibody-based imaging became less important because of its limited diagnostic accuracy. During the last two decades, a revival of imaging with radiolabeled mAbs has taken place, specifically PET with longer half-life isotopes. Development of immune checkpoints as targets for immunotherapy has opened opportunities for development of a wide variety of antibodies, such as anti-CTLA-4, anti-PD-L1, and anti-PD1. Thus, imaging with these antibodies radiolabeled with 89Zr or another long-half-life PET isotope, known as immuno-PET, has become mainstream. OBJECTIVE To review the rapid development of immuno-PET for the detection of cancer and assessment of therapeutic response combining surgery, radiation, chemotherapy, and/or immunotherapy. This review includes reports on the radiolabeling, imaging and clinical utility of 89Zr-, 64Cu-, and 124I-labeled mAbs. RESULTS More than 120 research and review articles on immuno-PET were reviewed. CONCLUSION Many mAbs have been developed and used for treatment of cancer; however, a limited number of antibodies have been radiolabeled for immuno-PET. While much progress has been made with the therapeutic applications of mAbs, immuno-PET for diagnosis and treatment assessment needs more work. Improved chelating agents and extensive imaging studies are needed to refine immuno-PET for the diagnosis of cancers and assessment of response to therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

43 mins ago


Already at 1 h of incubation, significant genotoxic effects were observed in the comet assay in concentrations as low as 1 nM. Taken together, the present study demonstrates the high Topo-poisoning and genotoxic potential of P8-D6 in human tumor cells.The toxicity of nanomaterials to microorganisms is related to their dose and environmental factors. The aim of this study was to investigate the shifts in the microbial community structure and metabolic profiles and to evaluate the environmental factors in a laboratory scale intertidal wetland system exposed to zinc oxide nanoparticles (ZnO NPs). Microbial assemblages were determined using 16S rRNA high-throughput sequencing. Community-level physiological profiles were determined using Biolog-ECO technology. Results showed Proteobacteria was the predominant (42.6%-55.8%) phylum across all the sediments, followed by Bacteroidetes (18.9%-29.0%). The genera Azoarcus, Maribacter, and Thauera were most frequently detected. At the studied concentrations (40 mg·L-1, 80 mg·L-1, 120 mg·L-1), ZnO NPs had obvious impacts on the activity of Proteobacteria. Adverse effects were particularly evident in sulfur and nitrogen cycling bacteria such as Sulfitobacter, unidentified_Nitrospiraceae, Thauera, and Azoarcus. The alpha diversity index of microbial community did not reflect stronger biological toxicity in the groups with high NP concentrations (80 mg·L-1, 120 mg·L-1) than the group with low NP concentration (40 mg·L-1). The average well color development (AWCD) values of periodically submersed groups were higher than those of long-term submersed groups. The group with NP concentration (40 mg·L-1) had the lowest AWCD value; those of the groups with high NP concentrations (80 mg·L-1, 120 mg·L-1) were slightly lower than that of the control group. The beta diversity showed that tidal activity shaped the similar microbial community among the periodically submerged groups, as well as the long-term submerged groups. The groups with high DO concentrations had higher diversity of the microbial community, better metabolic ability, and stronger resistance to ZnO NPs than the groups with a low DO concentration.The present study investigated the capability of an essential oil mix (MO 1% and 3%) in ameliorating amnesia and brain oxidative stress in a rat model of scopolamine (Sco) and tried to explore the underlying mechanism. The MO was administered by inhalation to rats once daily for 21 days, while Sco (0.7 mg/kg) treatment was delivered 30 min before behavioral tests. Donepezil (DP 5 mg/kg) was used as a positive reference drug. https://www.selleckchem.com/products/mln2480.html The cognitive-enhancing effects of the MO in the Sco rat model were assessed in the Y-maze, radial arm maze (RAM), and novel object recognition (NOR) tests. As identified by gas chromatography-mass spectrometry (GC-MS), the chemical composition of the MO is comprised by limonene (91.11%), followed by γ-terpinene (2.02%), β-myrcene (1.92%), β-pinene (1.76%), α-pinene (1.01%), sabinene (0.67%), linalool (0.55%), cymene (0.53%), and valencene (0.43%). Molecular interactions of limonene as the major compound in MO with the active site of butyrylcholinesterase (BChE) was explored via molecular docking experiments, and Van der Waals (vdW) contacts were observed between limonene and the active site residues SER198, HIS438, LEU286, VAL288, and PHE329. The brain oxidative status and acetylcholinesterase (AChE) and BChE inhibitory activities were also determined. MO reversed Sco-induced memory deficits and brain oxidative stress, along with cholinesterase inhibitory effects, which is an important mechanism in the anti-amnesia effect. Our present findings suggest that MO ameliorated memory impairment induced by Sco via restoration of the cholinergic system activity and brain antioxidant status.Somatic cell nuclear transfer (SCNT) has been an area of interest in the field of stem cell research and regenerative medicine for the past 20 years. The main biological goal of SCNT is to reverse the differentiated state of a somatic cell, for the purpose of creating blastocysts from which embryonic stem cells (ESCs) can be derived for therapeutic cloning, or for the purpose of reproductive cloning. However, the consensus is that the low efficiency in creating normal viable offspring in animals by SCNT (1-5%) and the high number of abnormalities seen in these cloned animals is due to epigenetic reprogramming failure. In this review we provide an overview of the current literature on SCNT, focusing on protocol development, which includes early SCNT protocol deficiencies and optimizations along with donor cell type and cell cycle synchrony; epigenetic reprogramming in SCNT; current protocol optimizations such as nuclear reprogramming strategies that can be applied to improve epigenetic reprogramming by SCNT; applications of SCNT; the ethical and legal implications of SCNT in humans; and specific lessons learned for establishing an optimized SCNT protocol using a mouse model.Targeting the iron requirement of Pseudomonas aeruginosa may be an effective adjunctive for conventional antibiotic treatment against biofilm-dwelling P. aeruginosa. We, therefore, assessed the anti-biofilm activity of N,N'-bis (2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED), which is a synthetic hexadentate iron chelator. The effect of HBED was studied using short-term (microtitre plate) and longer-term (flow-cell) biofilm models, under aerobic, anaerobic, and microaerobic (flow-cell) conditions and in combination with the polymyxin antibiotic colistimethate sodium (colistin). HBED was assessed against strains of P. aeruginosa from patients with cystic fibrosis and the reference strain PAO1. HBED inhibited growth and biofilm formation of all clinical strains under aerobic and anaerobic conditions, but inhibitory effects against PAO1 were predominantly exerted under anaerobic conditions. PA605, which is a clinical strain with a robust biofilm-forming phenotype, was selected for flow-cell studies. HBED significantly reduced biomass and surface coverage of PA605, and, combined with colistin, HBED significantly enhanced the microcolony killing effects of colistin to result in almost complete removal of the biofilm. HBED combined with colistin is highly effective in vitro against biofilms formed by clinical strains of P. aeruginosa.

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“Half the people kind of went, ‘Yeah, we deserve — we need this to happen. They’re trying to protect us.’

And the other half of the people recognized it, thankfully, as pathological abuse.”

Which half were you in? No judgments here. Share your story.

This topic and more in CHD’s newest book, already a #1 bestseller in “medical diagnosis” and on pre-sale now for shipping Nov. 26th! https://www.amazon.com/Medical-Pharmaceutical-Killing-Machine-Facing-Facts/dp/1648211291/ref=sr_1_1

Full episode: https://x.com/i/broadcasts/1yoKMykoaDXKQ

One of the most captivating unsolved murder cases in recent American history intertwines with a prominent assassination: the killing of President John F. Kennedy. On this episode of the Whistleblowers, host John Kiriakou explores this enigma with writer Peter Janney, author of ‘Mary’s Mosaic’. Janney delves into the murder of famed artist and JFK mistress Mary Pinchot Meyer. Janney, revealing key details, uncovers startling revelations about the death of JFK’s friend and lover.

Welcome to The Daily Wrap Up, a concise show dedicated to bringing you the most relevant independent news, as we see it, from the last 24 hours.

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“Half the people kind of went, ‘Yeah, we deserve — we need this to happen. They’re trying to protect us.’

And the other half of the people recognized it, thankfully, as pathological abuse.”

Which half were you in? No judgments here. Share your story.

This topic and more in CHD’s newest book, already a #1 bestseller in “medical diagnosis” and on pre-sale now for shipping Nov. 26th! https://www.amazon.com/Medical-Pharmaceutical-Killing-Machine-Facing-Facts/dp/1648211291/ref=sr_1_1

Full episode: https://x.com/i/broadcasts/1yoKMykoaDXKQ

One of the most captivating unsolved murder cases in recent American history intertwines with a prominent assassination: the killing of President John F. Kennedy. On this episode of the Whistleblowers, host John Kiriakou explores this enigma with writer Peter Janney, author of ‘Mary’s Mosaic’. Janney delves into the murder of famed artist and JFK mistress Mary Pinchot Meyer. Janney, revealing key details, uncovers startling revelations about the death of JFK’s friend and lover.

Welcome to The Daily Wrap Up, a concise show dedicated to bringing you the most relevant independent news, as we see it, from the last 24 hours.

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The question of “Who Killed Darren Seals?” made national headlines in 2016 after the Ferguson activist was found shot and burned to death inside his car in St. Louis. Host John Kiriakou discussed this case with filmmaker, journalist, and podcaster Ray Nowosielski and former Missouri state senator Maria Chappelle-Nadal as they investigate the life and death of Seals, who became a prominent spokesperson against police violence and racial bias following the killing of Michael Brown in Ferguson, Missouri. Why Darren Seals was under FBI scrutiny and whether his case will ever be resolved are lingering questions to be answered.

07/03/2024

Even with the arms that have been dedicated to Ukraine (many of which have not made it to the front lines), Russia has over:

-3X the manpower
-13X as many aircraft
-7X as many military ships
-and 8X as many tanks.

So what if our giving Ukraine more and more weapons is only resulting in more Ukrainian deaths?

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17 mins ago


The importance of germline-inherited post-translational histone modifications on priming early mammalian development is just emerging1-4. Histone H3 lysine 9 (H3K9) trimethylation is associated with heterochromatin and gene repression during cell-fate change5, whereas histone H3 lysine 4 (H3K4) trimethylation marks active gene promoters6. Mature oocytes are transcriptionally quiescent and possess remarkably broad domains of H3K4me3 (bdH3K4me3)1,2. It is unknown which factors contribute to the maintenance of the bdH3K4me3 landscape. Lysine-specific demethylase 4A (KDM4A) demethylates H3K9me3 at promoters marked by H3K4me3 in actively transcribing somatic cells7. Here, we report that KDM4A-mediated H3K9me3 demethylation at bdH3K4me3 in oocytes is crucial for normal pre-implantation development and zygotic genome activation after fertilization. The loss of KDM4A in oocytes causes aberrant H3K9me3 spreading over bdH3K4me3, resulting in insufficient transcriptional activation of genes, endogenous retroviral elements and chimeric transcripts initiated from long terminal repeats during zygotic genome activation. The catalytic activity of KDM4A is essential for normal epigenetic reprogramming and pre-implantation development. Hence, KDM4A plays a crucial role in preserving the maternal epigenome integrity required for proper zygotic genome activation and transfer of developmental control to the embryo.During mouse embryonic development, pluripotent cells rapidly divide and diversify, yet the regulatory programs that define the cell repertoire for each organ remain ill-defined. To delineate comprehensive chromatin landscapes during early organogenesis, we mapped chromatin accessibility in 19,453 single nuclei from mouse embryos at 8.25 days post-fertilization. Identification of cell-type-specific regions of open chromatin pinpointed two TAL1-bound endothelial enhancers, which we validated using transgenic mouse assays. Integrated gene expression and transcription factor motif enrichment analyses highlighted cell-type-specific transcriptional regulators. Subsequent in vivo experiments in zebrafish revealed a role for the ETS factor FEV in endothelial identity downstream of ETV2 (Etsrp in zebrafish). Concerted in vivo validation experiments in mouse and zebrafish thus illustrate how single-cell open chromatin maps, representative of a mammalian embryo, provide access to the regulatory blueprint for mammalian organogenesis.The availability of nucleotides has a direct impact on transcription. The inhibition of dihydroorotate dehydrogenase (DHODH) with leflunomide impacts nucleotide pools by reducing pyrimidine levels. Leflunomide abrogates the effective transcription elongation of genes required for neural crest development and melanoma growth in vivo1. To define the mechanism of action, we undertook an in vivo chemical suppressor screen for restoration of neural crest after leflunomide treatment. Surprisingly, we found that alterations in progesterone and progesterone receptor (Pgr) signalling strongly suppressed leflunomide-mediated neural crest effects in zebrafish. In addition, progesterone bypasses the transcriptional elongation block resulting from Paf complex deficiency, rescuing neural crest defects in ctr9 morphant and paf1(alnz24) mutant embryos. Using proteomics, we found that Pgr binds the RNA helicase protein Ddx21. ddx21-deficient zebrafish show resistance to leflunomide-induced stress. At a molecular level, nucleotide depletion reduced the chromatin occupancy of DDX21 in human A375 melanoma cells. Nucleotide supplementation reversed the gene expression signature and DDX21 occupancy changes prompted by leflunomide. Together, our results show that DDX21 acts as a sensor and mediator of transcription during nucleotide stress.In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3α/β and Mek1/2 (2i) instructs a self-renewing ground state whose endogenous inducers are unknown. Here we show that the axon guidance cue Netrin-1 promotes naive pluripotency by triggering profound signalling, transcriptomic and epigenetic changes in mESCs. Furthermore, we demonstrate that Netrin-1 can substitute for blockade of Gsk3α/β and Mek1/2 to sustain self-renewal of mESCs in combination with leukaemia inhibitory factor and regulates the formation of the mouse pluripotent blastocyst. Mechanistically, we reveal how Netrin-1 and the balance of its receptors Neo1 and Unc5B co-regulate Wnt and MAPK pathways in both mouse and human ESCs. Netrin-1 induces Fak kinase to inactivate Gsk3α/β and stabilize β-catenin while increasing the phosphatase activity of a Ppp2r2c-containing Pp2a complex to reduce Erk1/2 activity. Collectively, this work identifies Netrin-1 as a regulator of pluripotency and reveals that it mediates different effects in mESCs depending on its receptor dosage, opening perspectives for balancing self-renewal and lineage commitment.Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27-CD28-CD8+ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. https://www.selleckchem.com/products/capsazepine.html Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27-CD28-CD8+ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27-CD28-CD8+ T cells to acquire a broad-spectrum, innate-like killing activity.High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9-/- tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.

42 mins ago


Computational approaches have been proven to be complementary tools of interest for identifying potential candidates for drug repurposing. However, although the methods developed so far offer interesting opportunities and could contribute to solve issues faced by the pharmaceutical sector, they also come with their own constraints. Indeed, specific challenges ranging from data access, standardization and integration to the implementation of reliable and coherent validation methods must be addressed to allow a systematic use at a larger scale. In this mini-review, we cover computational tools recently developed for addressing some of these challenges. https://www.selleckchem.com/products/tepp-46.html This includes specific databases providing accessibility to large set of curated data with standardized annotations, web-based tools integrating flexible user interfaces to perform fast computational repurposing experiments and standardized datasets specifically annotated and balanced for validating new computational drug repurposing methods. Interestingly, these new databases combined to the increasing number of information about the outcomes of drug repurposing studies can be used to perform meta-analysis to identify key properties associated with successful drug repurposing cases. This information could further be used to design estimation methods to compute an a priori assessment of the repurposing possibilities. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.Breast cancer is the most common cancer in women worldwide. Due to the heterogeneous nature of breast cancer, the optimal treatment and expected response for each patient may not necessarily be universal. Molecular imaging techniques could play an important role in the early detection and targeted therapy evaluation of breast cancer. This review focuses on the development of peptides labeled with SPECT and PET radionuclides for breast cancer imaging. We summarized the current status of radiolabeled peptides for different receptors in breast cancer. The characteristics of radionuclides and major techniques for peptide labeling are also briefly discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.BACKGROUND Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. METHODS We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. RESULTS One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancemoting the body's immune system to fight the cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.The introduction of antibiotics to treat bacterial infections either by killing or blocking their growth has been accompanied by the studies of mechanism that allows the drugs to kill the bacteria or to stop their proliferation. In such scenario the coming of antibacterial agents active on the bacterial cell wall has been of fundamental importance in the fight against bacterial agents responsible for severe diseases. As a matter of fact cell wall, that plays many roles during lifecycle, is an essential constituent of most bacteria. This overview focus on the intracellular steps of peptidoglycan biosynthesis and the research of new antibacterial agents based on the enzymes involved in these early steps of the formation of cell membrane components. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.BACKGROUND Monoclonal antibodies (mAbs) against tumor-associated antigens have been shown to target tumors with specificity and selectivity; therefore, it was hypothesized that cancer could be treated with mAbs without side effects. In the early 1980s, clinical studies demonstrated that tumors could be visualized using radiolabeled mAbs. However, with the introduction of positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG), antibody-based imaging became less important because of its limited diagnostic accuracy. During the last two decades, a revival of imaging with radiolabeled mAbs has taken place, specifically PET with longer half-life isotopes. Development of immune checkpoints as targets for immunotherapy has opened opportunities for development of a wide variety of antibodies, such as anti-CTLA-4, anti-PD-L1, and anti-PD1. Thus, imaging with these antibodies radiolabeled with 89Zr or another long-half-life PET isotope, known as immuno-PET, has become mainstream. OBJECTIVE To review the rapid development of immuno-PET for the detection of cancer and assessment of therapeutic response combining surgery, radiation, chemotherapy, and/or immunotherapy. This review includes reports on the radiolabeling, imaging and clinical utility of 89Zr-, 64Cu-, and 124I-labeled mAbs. RESULTS More than 120 research and review articles on immuno-PET were reviewed. CONCLUSION Many mAbs have been developed and used for treatment of cancer; however, a limited number of antibodies have been radiolabeled for immuno-PET. While much progress has been made with the therapeutic applications of mAbs, immuno-PET for diagnosis and treatment assessment needs more work. Improved chelating agents and extensive imaging studies are needed to refine immuno-PET for the diagnosis of cancers and assessment of response to therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

43 mins ago


Already at 1 h of incubation, significant genotoxic effects were observed in the comet assay in concentrations as low as 1 nM. Taken together, the present study demonstrates the high Topo-poisoning and genotoxic potential of P8-D6 in human tumor cells.The toxicity of nanomaterials to microorganisms is related to their dose and environmental factors. The aim of this study was to investigate the shifts in the microbial community structure and metabolic profiles and to evaluate the environmental factors in a laboratory scale intertidal wetland system exposed to zinc oxide nanoparticles (ZnO NPs). Microbial assemblages were determined using 16S rRNA high-throughput sequencing. Community-level physiological profiles were determined using Biolog-ECO technology. Results showed Proteobacteria was the predominant (42.6%-55.8%) phylum across all the sediments, followed by Bacteroidetes (18.9%-29.0%). The genera Azoarcus, Maribacter, and Thauera were most frequently detected. At the studied concentrations (40 mg·L-1, 80 mg·L-1, 120 mg·L-1), ZnO NPs had obvious impacts on the activity of Proteobacteria. Adverse effects were particularly evident in sulfur and nitrogen cycling bacteria such as Sulfitobacter, unidentified_Nitrospiraceae, Thauera, and Azoarcus. The alpha diversity index of microbial community did not reflect stronger biological toxicity in the groups with high NP concentrations (80 mg·L-1, 120 mg·L-1) than the group with low NP concentration (40 mg·L-1). The average well color development (AWCD) values of periodically submersed groups were higher than those of long-term submersed groups. The group with NP concentration (40 mg·L-1) had the lowest AWCD value; those of the groups with high NP concentrations (80 mg·L-1, 120 mg·L-1) were slightly lower than that of the control group. The beta diversity showed that tidal activity shaped the similar microbial community among the periodically submerged groups, as well as the long-term submerged groups. The groups with high DO concentrations had higher diversity of the microbial community, better metabolic ability, and stronger resistance to ZnO NPs than the groups with a low DO concentration.The present study investigated the capability of an essential oil mix (MO 1% and 3%) in ameliorating amnesia and brain oxidative stress in a rat model of scopolamine (Sco) and tried to explore the underlying mechanism. The MO was administered by inhalation to rats once daily for 21 days, while Sco (0.7 mg/kg) treatment was delivered 30 min before behavioral tests. Donepezil (DP 5 mg/kg) was used as a positive reference drug. https://www.selleckchem.com/products/mln2480.html The cognitive-enhancing effects of the MO in the Sco rat model were assessed in the Y-maze, radial arm maze (RAM), and novel object recognition (NOR) tests. As identified by gas chromatography-mass spectrometry (GC-MS), the chemical composition of the MO is comprised by limonene (91.11%), followed by γ-terpinene (2.02%), β-myrcene (1.92%), β-pinene (1.76%), α-pinene (1.01%), sabinene (0.67%), linalool (0.55%), cymene (0.53%), and valencene (0.43%). Molecular interactions of limonene as the major compound in MO with the active site of butyrylcholinesterase (BChE) was explored via molecular docking experiments, and Van der Waals (vdW) contacts were observed between limonene and the active site residues SER198, HIS438, LEU286, VAL288, and PHE329. The brain oxidative status and acetylcholinesterase (AChE) and BChE inhibitory activities were also determined. MO reversed Sco-induced memory deficits and brain oxidative stress, along with cholinesterase inhibitory effects, which is an important mechanism in the anti-amnesia effect. Our present findings suggest that MO ameliorated memory impairment induced by Sco via restoration of the cholinergic system activity and brain antioxidant status.Somatic cell nuclear transfer (SCNT) has been an area of interest in the field of stem cell research and regenerative medicine for the past 20 years. The main biological goal of SCNT is to reverse the differentiated state of a somatic cell, for the purpose of creating blastocysts from which embryonic stem cells (ESCs) can be derived for therapeutic cloning, or for the purpose of reproductive cloning. However, the consensus is that the low efficiency in creating normal viable offspring in animals by SCNT (1-5%) and the high number of abnormalities seen in these cloned animals is due to epigenetic reprogramming failure. In this review we provide an overview of the current literature on SCNT, focusing on protocol development, which includes early SCNT protocol deficiencies and optimizations along with donor cell type and cell cycle synchrony; epigenetic reprogramming in SCNT; current protocol optimizations such as nuclear reprogramming strategies that can be applied to improve epigenetic reprogramming by SCNT; applications of SCNT; the ethical and legal implications of SCNT in humans; and specific lessons learned for establishing an optimized SCNT protocol using a mouse model.Targeting the iron requirement of Pseudomonas aeruginosa may be an effective adjunctive for conventional antibiotic treatment against biofilm-dwelling P. aeruginosa. We, therefore, assessed the anti-biofilm activity of N,N'-bis (2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED), which is a synthetic hexadentate iron chelator. The effect of HBED was studied using short-term (microtitre plate) and longer-term (flow-cell) biofilm models, under aerobic, anaerobic, and microaerobic (flow-cell) conditions and in combination with the polymyxin antibiotic colistimethate sodium (colistin). HBED was assessed against strains of P. aeruginosa from patients with cystic fibrosis and the reference strain PAO1. HBED inhibited growth and biofilm formation of all clinical strains under aerobic and anaerobic conditions, but inhibitory effects against PAO1 were predominantly exerted under anaerobic conditions. PA605, which is a clinical strain with a robust biofilm-forming phenotype, was selected for flow-cell studies. HBED significantly reduced biomass and surface coverage of PA605, and, combined with colistin, HBED significantly enhanced the microcolony killing effects of colistin to result in almost complete removal of the biofilm. HBED combined with colistin is highly effective in vitro against biofilms formed by clinical strains of P. aeruginosa.

47 mins ago


Exercise may reduce the risk of breast cancer through adiposity changes, but the dose-response effects of exercise volume on adiposity markers are unknown in postmenopausal women. We aimed to compare the dose-response effects of prescribed aerobic exercise volume on adiposity outcomes.

Data from the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) and Breast Cancer and Exercise Trial in Alberta (BETA) were pooled for this analysis (N = 720). These were 12-month randomized controlled trials, where participants were randomized to 225 min/week (mid-volume) of aerobic exercise versus usual inactive lifestyle (ALPHA), or 150 min/week (low-volume) versus 300 min/week (high-volume) (BETA). Fat mass and fat-free mass were measured using DXA and intra-abdominal and subcutaneous fat area were assessed with computed tomography.

After 12 months of aerobic exercise, increasing exercise volumes from no exercise/control to 300 min/week resulted in statistically significant reductions in BMI, weight, fat ect of exercise volume on adiposity markers was noted, however, the differences in adiposity markers were smaller when comparing 225 min/week to 300 min/week of exercise. Given the strong positive associations between obesity and postmenopausal breast cancer risk, this study provides evidence on the importance of exercise volume as part of the exercise prescription to reduce adiposity and, ultimately, postmenopausal breast cancer risk.The COVID-19 pandemic has emerged as a public health crisis and has placed a significant burden on healthcare systems. Patients with underlying metabolic dysfunction, such as type 2 diabetes mellitus and obesity, are at a higher risk for COVID-19 complications, including multi-organ dysfunction, secondary to a deranged immune response, and cellular energy deprivation. These patients are at a baseline state of chronic inflammation associated with increased susceptibility to the severe immune manifestations of COVID-19, which are triggered by the cellular hypoxic environment and cytokine storm. The altered metabolic profile and energy generation of immune cells affect their activation, exacerbating the imbalanced immune response. Key immunometabolic interactions may inform the development of an efficacious treatment for COVID-19. Novel therapeutic approaches with repurposed drugs, such as PPAR agonists, or newly developed molecules such as the antagomirs, which block microRNA function, have shown promising results. Those treatments, alone or in combination, target both immune and metabolic pathways and are ideal for septic COVID-19 patients with an underlying metabolic condition.This study aimed to focus on the simultaneous use of antimicrobial photodynamic therapy (aPDT) and sonodynamic antimicrobial chemotherapy (SACT), which is called photo-sonodynamic antimicrobial chemotherapy (PSACT) to attenuate the virulence of Aggregatibacter actinomycetemcomitans. Following the synthesis of Curcumin-decorated nanophytosomes (Cur-NPhs) as a novel photo-sonosensitizer, its particle size, polydispersity, ζ-potential surface morphology, physical stability, drug release, and entrapment efficiency were determined. In the Cur-NPhs-PSACT, the antimicrobial activities of Cur-NPhs against A. actinomycetemcomitans were investigated using cell viability, biofilm killing/degradation, metabolic activity, expression of quorum-sensing-associated qseB and qseC genes, and biofilm-associated rcpA gene under blue laser irradiation plus ultrasonic waves. Characterization tests showed the presence of a sphere-shaped vesicle and the self-closed structure of Cur-NPhs, resulting in a high drug-loading content and encapsulation efficiency. However, the antimicrobial effect of Cur-NPhs-PSACT was dose-dependent, PSACT using the high concentrations of Cur-NPhs (50 × 10-4 g/L) showed significant reductions (P  less then  0.05) in cell viability (13.6 log10 CFU/mL), biofilm killing/degradation (65%), metabolic activity (89.6%,), and mRNA levels of virulence determinant genes (qseB; 9.8-fold, qseC; 10.2-fold, and recA; 10.2-fold). This study concludes that the Cur-NPhs-PSACT had antimicrobial activities against A. actinomycetemcomitans by downregulating the expression of virulence genes, and may attenuate this bacterium that decreases periodontal disease severity in patients.Gallbladder cancer (GBC) is relatively rare but shows high frequency in certain geographical regions and ethnic groups, which include Northern and Eastern states of India. Previous studies in India have indicated the possible role of genetic predisposition in GBC pathogenesis. Although matrix metalloproteinase-14 (MMP14) is known modulator of tumour microenvironment and tumorigenesis and TCGA data also suggests its upregulation yet, its role in genetic predisposition for GBC is completely unknown. We explored MMP14 promoter genetic variants as risk factors and their implication in expression modulation and the pathogenesis of GBC. We genotyped all single nucleotide polymorphisms of MMP14 promoter by Sanger's sequencing in approximately 300 GBC and 300 control study subjects of Indian ethnicity and, in 26 GBC tissue samples. Protein expression of MMP14 in GBC tissue samples was checked by immunohistochemistry. In vitro luciferase reporter assay was carried out to elucidate role of promoter genetic variants on expression levels in two different cell lines. MMP14 promoter variants, rs1003349 (p value = 0.0008) and rs1004030 (p value = 0.0001) were significantly associated with GBC. https://www.selleckchem.com/products/gsk1120212-jtp-74057.html Luciferase reporter assay showed high expression for risk alleles of both the SNPs. Genotype-phenotype correlation for rs1003349 and rs1004030, in patient sample, confirmed that risk allele carriers had higher expression levels of MMP14; moreover, the correlation pattern matched with genetic association models. Overall, this study unravels the association of MMP14 promoter SNPs with GBC which contribute to pathogenesis by increasing its expression.Age-related hearing loss typically affects the hearing of high frequencies in older adults. Such hearing loss influences the processing of spoken language, including higher-level processing such as that of complex sentences. Hearing aids may alleviate some of the speech processing disadvantages associated with hearing loss. However, little is known about the relation between hearing loss, hearing aid use, and their effects on higher-level language processes. This neuroimaging (fMRI) study examined these factors by measuring the comprehension and neural processing of simple and complex spoken sentences in hard-of-hearing older adults (n = 39). Neither hearing loss severity nor hearing aid experience influenced sentence comprehension at the behavioral level. In contrast, hearing loss severity was associated with increased activity in left superior frontal areas and the left anterior insula, but only when processing specific complex sentences (i.e. object-before-subject) compared to simple sentences. Longer hearing aid experience in a sub-set of participants (n = 19) was associated with recruitment of several areas outside of the core speech processing network in the right hemisphere, including the cerebellum, the precentral gyrus, and the cingulate cortex, but only when processing complex sentences.

49 mins ago


The standard deviation of the axial strain tends to increase as the load level applied increase. The structure of the GTXnwS harms its tensile -strain behaviour, promoting axial deformation under sustained loads, at least 50% higher than GTXnwC for the same load level applied. The influence of the load level and geotextile structure in the initial axial strain is pointed out. Long-term predictions based on creep tests performed using the stepped isothermal method have proven to be conservative and they must be restricted for quality control of the investigated geotextiles.Glioblastoma (GBM) is the most common primary central nervous system tumor and one of the most lethal cancers worldwide, with morbidity of 5.26 per 100,000 population per year. These tumors are often associated with poor prognosis and terrible quality of life. Extracellular vesicles (EVs) are membrane-bound nanoparticles secreted by cells and contain lipid, protein, DNA, mRNA, miRNA and other bioactive substances. EVs perform biological functions by binding or horizontal transfer of bioactive substances to target cell receptors. In recent years, EVs have been considered as possible targets for GBM therapy. A great many types of research demonstrated that EVs played a vital role in the GBM microenvironment, development, progression, angiogenesis, invasion, and even the diagnosis of GBM. Nevertheless, the exact molecular mechanisms and roles of EVs in these processes are unclear. It can provide the basis for GBM treatment in the future that clarifying the regulatory mechanism and related signal pathways of EVs derived from GBM and their clinical value in GBM diagnosis and treatment. In this paper, the research progress and clinical application prospects of GBM-derived EVs are reviewed and discussed.Arecanut husk (AH) was selected as a material for silica replacement in the synthesis process of glass-ceramics zinc silicate and also the fact that it has no traditional use and often being dumped and results in environmental issues. The process of pyrolysis was carried out at temperature 700 °C and above based on thermogravimetric analysis to produce arecanut husk ash (AHA). The average purity of the silica content in AHA ranged from 29.17% to 45.43%. Furthermore, zinc oxide was introduced to AHA and zinc silicate started to form at sintering temperature 700 °C and showed increased diffraction intensity upon higher sintering temperature of 600 °C to 1000 °C based on X-ray diffraction (XRD) analysis. The grain sizes of the zinc silicate increased from 1011 nm to 3518 nm based on the morphological studies carried out by field emission scanning electron microscopy (FESEM). In addition, the optical band gap of the sample was measured to be in the range from 2.410 eV to 2.697 eV after sintering temperature. From the data, it is believed that a cleaner production of low-cost zinc silicate can be achieved by using arecanut husk and have the potential to be used as phosphors materials.The fungal metabolite sporidesmin is responsible for severe necrotizing inflammation of biliary tract and liver of livestock grazing on pasture containing spores of Pithomyces chartarum that synthesizes the toxin. The toxin is secreted into bile causing the erosion of the biliary epithelium accompanied by inflammation and damage to surrounding tissues. Toxicity has been suggested to be due to cycles of reduction and oxidation of sporidesmin leading to oxidative damage from the formation of reactive oxygen species. The current work is the first test of the oxidative stress hypothesis using cultured cells. Oxidative stress could not be detected in HepG2 cells incubated with sporidesmin using a dichlorodihydrofluorescein diacetate assay or by use of two-dimensional electrophoresis to search for oxidized peroxiredoxins. There was also no evidence for necrosis or apoptosis, although there was a loss of cell adhesion that was accompanied by the disruption of intracellular actin microfilaments that have known roles in cell adhesion. The results are consistent with a model in which altered contact between cells in situ leads to altered permeability and subsequent inflammation and necrosis, potentially from the leakage of toxic bile into surrounding tissues. There is now a need for the further characterization of the damage processes in vivo, including the investigation of altered permeability and mechanisms of cell death in the biliary tract and other affected organs.Human colorectal cancers are mostly microsatellite-stable with no response to anti-PD-1 blockade immunotherapy, necessitating the development of a new immunotherapy. Osteopontin (OPN) is elevated in human colorectal cancer and may function as an immune checkpoint. We aimed at elucidating the mechanism of action of OPN and determining the efficacy of OPN blockade immunotherapy in suppression of colon cancer. We report here that OPN is primarily expressed in tumor cells, myeloid cells, and innate lymphoid cells in human colorectal carcinoma. Spp1 knock out mice exhibit a high incidence and fast growth rate of carcinogen-induced tumors. Knocking out Spp1 in colon tumor cells increased tumor-specific CTL cytotoxicity in vitro and resulted in decreased tumor growth in vivo. https://www.selleckchem.com/products/icfsp1.html The OPN protein level is elevated in the peripheral blood of tumor-bearing mice. We developed four OPN neutralization monoclonal antibodies based on their efficacy in blocking OPN inhibition of T cell activation. OPN clones 100D3 and 103D6 increased the efficacy of tumor-specific CTLs in killing colon tumor cells in vitro and suppressed colon tumor growth in tumor-bearing mice in vivo. Our data indicate that OPN blockade immunotherapy with 100D3 and 103D6 has great potential to be further developed for colorectal cancer immunotherapy and for rendering a colorectal cancer response to anti-PD-1 immunotherapy.The impact of tumour associated stroma on cancer metastasis is an emerging field. However, cancer associated genes in peritumoral adipose tissue (pAT) in human colon cancer have not been explored. The aim of this study was to identify differentially expressed genes (DEGs) associated with cancer pathways in mesenteric pAT compared with adjacent adipose tissue. In total, nine patients with colon cancer pathological stage T2/T4 were employed in this study. DEGs were identified in 6 patients employing Nanostring PanCancer Pathway Panel and pathway enrichment analyses were performed. Differential expression of the 5 most up-regulated and 2 down regulated genes was validated with qRT-PCR. Results showed collagen type I alpha 1 chain (COL1A1) p = 0.007; secreted frizzled related protein (SFRP2) p = 0.057; fibroblast growth factor 7 (FGF7) not significant (ns); phospholipase A2, group IIA (PLA2G2A) ns; nerve growth factor receptor (NGFR) ns; lymphoid enhancer binding factor 1 (LEF1) p = 0.03; cadherin 1, Type 1, E-cadherin (epithelial) (CDH1) 0.