Granthamaldridge0135
The CDKN1B gene, encoding for the CDK inhibitor p27kip1 , is mutated in defined human cancer subtypes, including breast, prostate carcinomas and small intestine neuroendocrine tumors. Lessons learned from small intestine neuroendocrine tumors suggest that CDKN1B mutations could be subclonal, raising the question of whether a deeper sequencing approach could lead to the identification of higher numbers of patients with mutations. Here, we addressed this question and analyzed human cancer biopsies from breast (n = 396), ovarian (n = 110) and head and neck squamous carcinoma (n = 202) patients, using an ultra-deep sequencing approach. Notwithstanding this effort, the mutation rate of CDKN1B remained substantially aligned with values from the literature, showing that essentially only hormone receptor-positive breast cancer displayed CDKN1B mutations in a relevant number of cases (3%). However, the analysis of copy number variation showed that another fraction of luminal breast cancer displayed loss (8%) or gain ( 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.Preliminary results and emerging data have shown that lipid droplet high (LDhi ) immunosuppressive cells accumulate in tumour tissues. By tracking and phenotypic profiling of LDhi cells, we find that LDhi CD19+ , LDhi CD11b+ , and LDhi Ly6G+ immune cell populations appear in the spleen, thymus, and tumour tissues in a syngeneic tumour model. Using a contact-dependent reporter system, we discover a LDhi CCR7hi immunosuppressive cell population that migrates from tumour tissues to the spleen and thymus. Hence, we engineered a family of chimeric antigen receptor-modified macrophages (CAR-Ms) that direct macrophages to CCR7-positive cells and show that the cytosolic domain from Mer receptor tyrosine kinase (MerTK) triggers tumour cell cytotoxicity by the CAR-Ms. In vivo, CCR7-targeted CAR-Ms suppressed tumour growth and prolonged survival by preventing metastasis and by inducing systemic anti-tumour immunity through retarding the migration of LDhi CCR7hi immunosuppressive cells from tumour tissues to distal immune organs, indicating an important role for CCR7 in tumour cell-induced immune tolerance. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Psoriasis is a chronic immune-mediated inflammatory skin disease that easily recurs and is difficult to cure. DGT is a novel synthetic heterocyclic diterpenoid, whose structure has not been previously reported. We have investigated the action of DGT against psoriasis, specifically the hyperproliferation of epidermal keratinocytes, angiogenesis and pathogenic inflammatory responses.
We investigated its pharmacokinetics in skin after topical administration. We characterized its pharmacological actions in vitro and in vivo using cell proliferation assay, cell apoptosis assay, diethylstilbestrol-induced mouse vaginal epithelial cell mitosis model, tube formation assay, cell migration assay, chick embryonic chorioallantoic membrane (CAM) assay, histological, flow cytometric analysis and imiquimod (IMQ)-induced psoriasis-like model.
DGT was found to be mainly distributed in the epidermis and dermis, which indicated that DGT was suitable as a topical treatment. DGT inhibited cell proliferation and induced apoptotic cell death of keratinocytes in vitro and in vivo. Moreover, DGT inhibited endothelial cell proliferation, tube formation and migration of in vitro angiogenesis, as well as in vivo CAM angiogenesis. In an IMQ-induced psoriasis-like skin inflammation murine model, topical application of DGT ameliorated keratinocyte proliferation and inflammatory response, especially in IL-17-related psoriasiform dermatitis. check details Furthermore, our results demonstrated that DGT prevented these pathological processes of psoriasis through suppression of STAT3 phosphorylation.
DGT has great potential as a novel therapeutic agent for the treatment of psoriatic skin disease.
DGT has great potential as a novel therapeutic agent for the treatment of psoriatic skin disease.
Surgical management of large sinonasal tumors, spreading to the pterygopalatine, and infratemporal fossae have always been a challenge for the ENT surgeon and the multidisciplinary team.
Endoscopic Denker's approach allows complete exposure of the anterior, inferior, and lateral recesses of the maxillary sinus, without necessitating a gingivobuccal or a transseptal incision. Moreover, endoscopic Denker's approach facilitates direct, straight entry to the pterygopalatine and infratemporal fossae.
Twenty-two patients with extensive sinonasal pathology underwent resection via an endoscopic Denker's approach at our institution, with the majority of them being diagnosed with JNA and inverted papilloma. Denker's procedure facilitated wide exposure of the surgical field and total tumor resection, without significant perioperative complications and good disease-free results in follow up.
Our experience is in accordance with the literature, where this approach seems to be superior to alternative options for accessing the pterygopalatine and infratemporal fossae. We believe that adequate expertise in endoscopic sinonasal surgery is necessary prior to embarking on this technique, but in general, it represents a valuable tool in the surgeon's armamentarium.
4 Laryngoscope, 2020.
4 Laryngoscope, 2020.
The tactile sensation of hair is an important consumer-perceivable attribute. There are limited instrumental options to measure the haptic properties of hair. In this study, we introduce a novel technique using the acoustic emissions produced when skin comes in contact with dry hair in a stroking motion.
Using a free-field microphone with a frequency response of 8-12,500Hz, we recorded acoustic emission data of the interaction of skin with hair. Data were captured with Electroacoustics Toolbox software and analysed with Matlab. Acoustic emission profiles were generated allowing us to monitor the acoustic response at distinct frequencies.
Various experiments were conducted to develop this novel technique as a suitable measure to monitor the surface properties of hair. Increasing the normal force and velocity of the interaction led to an increase in acoustic emissions. We also examined the acoustic profile of hair that underwent chemical treatment. For example, bleached hair produced a much higher magnitutioning of the fibre.The aim of the study was to understand the hydraulic response to salt stress of the root system of the comparatively salt-tolerant crop barley (Hordeum vulgare L.). We focused on the transcellular path of water movement across the root cylinder that involves the crossing of membranes. This path allows for selective water uptake, while excluding salt ions. Hydroponically grown plants were exposed to 100 mM NaCl for 5-7 days and analysed when 15-17 days old. A range of complementary and novel approaches was used to determine hydraulic conductivity (Lp). This included analyses at cell, root and plant level and modelling of water flow. Apoplastic barrier formation and gene expression level of aquaporins (AQPs) was analysed. Salt stress reduced the Lp of root system through reducing water flow along the transcellular path. This involved changes in the activity and gene expression level of AQPs. Modelling of root-Lp showed that the reduction in root-Lp did not require added hydraulic resistances through apoplastic barriers at the endodermis. The bulk of data points to a near-perfect semi-permeability of roots of control plants (solute reflection coefficient σ ~1.0). Roots of salt-stressed plants are almost as semi-permeable (σ > 0.8).Vascular invasion is a critical risk factor for hepatocellular carcinoma (HCC) recurrence and poor survival. The molecular drivers of vascular invasion in HCC are largely unknown. Deciphering the molecular landscape of invasive HCC will help identify novel therapeutic targets and noninvasive biomarkers. To this end, we undertook this study to evaluate the genomic, transcriptomic, and proteomic profile of tumors with vascular invasion using the multi-platform cancer genome atlas (TCGA) data (n=373). In the TCGA liver hepatocellular carcinoma (LIHC) cohort, macrovascular invasion was present in 5% (n=17) of tumors and microvascular invasion in 25% (n=94) of tumors. Functional pathway analysis revealed that the MYC oncogene was a common upstream regulator of the mRNA, miRNA and proteomic changes in vascular invasion. We performed comparative proteomic analyses of invasive human HCC and MYC driven murine HCC and identified fibronectin to be proteomic biomarker of invasive HCC (mouse Fn1 p= 1.7 X 10-11 ; human FN1 p=1.5 X 10-4 ) conserved across the two species. Mechanistically, we show that FN1 promotes the migratory and invasive phenotype of HCC cancer cells. We demonstrate tissue overexpression of fibronectin in human HCC using a large independent cohort of human HCC tissue microarray (n=153; p less then 0.001). Lastly, we showed that plasma fibronectin levels were significantly elevated in patients with HCC (n=35, mean=307.7 μg/ml, SEM=35.9) when compared to cirrhosis (n=10, mean=41.8 μg/ml, SEM=13.3; p less then 0.0001). CONCLUSION Our study evaluates the molecular landscape of tumors with vascular invasion, identifying distinct transcriptional, epigenetic and proteomic changes driven by the MYC oncogene. We show that MYC upregulates fibronectin expression which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising non-invasive proteomic biomarker of vascular invasion in HCC.In the last 20 years, the global regulatory frameworks for drug assessment have been managing the challenges posed by using cellular products as new therapeutic tools. Currently, they are defined as "Advanced Therapy Medicinal Products", comprising a large group of cellular types that either alone or in combination with gene and tissue engineering technology. They have the potential to change the natural course of still lethal or highly debilitating diseases, including cancers, opportunistic infections and chronic inflammatory conditions. Globally, more than 50 cell-based products have obtained market authorization. This overview describes the advantages and unsolved challenges on developing cells as innovative therapeutic vehicles. The main cell therapy players and the legal framework are discussed, starting from chimeric antigen receptor T-cells for leukaemia and solid tumours, dealing then with lymphocytes as potent anti-microbiological tools and then focusing on mesenchymal stem/stromal cells whose role covers regenerative medicine, immunology and anti-tumour therapy.Within artificial intelligence and machine learning, a generative model is a powerful tool for learning any kind of data distribution. With the advent of deep learning and its success in image recognition, the field of deep generative models has clearly emerged as one of the promising fields for medical imaging. In a recent issue of The Journal of Pathology, Levine, Peng et al demonstrate the ability of generative models to synthesize high-quality pathology images. They suggested that generative models can serve as an unlimited source of images either for educating freshman pathologists or training machine learning models for diverse image analysis tasks, especially in scarce cases, while resolving patients' privacy and confidentiality concerns. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
