Notes

Mix Methods for HPV16+ Cancer.
The human epidermal growth factor receptor 2 (HER2) is a well-known negative prognostic factor in breast cancer and a target of the monoclonal antibody trastuzumab as well as of other anti-HER2 compounds. Pioneering works on HER2-positive breast cancer in the 90s' launched a new era in clinical research and oncology practice that has reshaped the natural history of this disease. In diagnostic pathology the HER2 status is routinely assessed by using a combination of immunohistochemistry (IHC, to evaluate HER2 protein expression levels) and in situ hybridization (ISH, to assess HER2 gene status). For this purpose, international recommendations have been developed by a consensus of experts in the field, which have changed over the years according to new experimental and clinical data. In this review article we will document the changes that have contributed to a better evaluation of the HER2 status in clinical practice, furthermore we will discuss HER2 heterogeneity defined by IHC and ISH as well as by transcriptomic analysis and we will critically describe the complexity of HER2 equivocal results. Finally, we will introduce the clinical impact of HER2 mutations and we will define the upcoming category of HER2-low breast cancer with respect to emerging clinical data on the efficacy of specific anti-HER2 agents in subgroups of breast carcinomas lacking the classical oncogene addition dictated by HER2 amplification. BACKGROUND Liver fibrosis, in which hepatocyte damage and inflammatory response play critical roles, is a physiological response to chronic or iterative liver injury and can progress to cirrhosis over time. Nuclear factor E2-related factor 2 (Nrf2) is a master transcription factor that regulates oxidative and xenobiotic stress responses as well as inflammation. METHOD To ascertain the cell-specific roles of Nrf2 in hepatocytes and myeloid lineage cells in the progression of liver fibrosis, mice lacking Nrf2 specifically in hepatocytes [Nrf2(L)-KO] and myeloid lineage cells [Nrf2(M)-KO] were generated to evaluate carbon tetrachloride (CCl4)-induced liver injury, subsequent inflammation and fibrosis. In addition, mouse primary hepatocytes were used to investigate the underlying mechanisms. RESULTS Nrf2-mediated antioxidant response in the liver is responsive to acute CCl4 exposure in mice. With repeated CCl4 administration, Nrf2(L)-KO, but not Nrf2(M)-KO, mice showed more severe liver fibrosis than Nrf2-LoxP control mice. In addition, in response to acute CCl4 exposure, Nrf2(L)-KO mice displayed aggravated liver injury, elevated lipid peroxidation and inflammatory response compared to control mice. In mouse primary hepatocytes, deficiency of Nrf2 resulted in more severe CCl4-induced lipid oxidation and inflammatory response. CONCLUSION Deficiency of Nrf2 in hepatocytes sensitizes the cells to CCl4-induced oxidative damage and inflammatory response, which are initiator and enhancer of subsequent hepatic inflammation and fibrosis. Thus, Nrf2 is a critical determinant of liver injury and fibrosis in response to CCl4, suggesting that Nrf2 might be a valuable target for the intervention. Organochlorine pesticides (OCPs) are persistent environmental contaminants that act as endocrine disruptors and organ system toxicants. These pesticides (e.g. dichlorodiphenyltrichloroethane (DDT), dieldrin, toxaphene, among others) are ranked as some of the most concerning chemicals for human health. These pesticides (1) act as teratogens, (2) are neuroendocrine disruptors, (3) suppress the immune and reproductive systems, and (4) dysregulate lipids and metabolism. Using a computational approach, we revealed enriched endocrine-related pathways in the Comparative Toxicogenomics Database sensitive to this chemical class, and these included reproduction (gonadotropins, estradiol, androgen, steroid biosynthesis, oxytocin), thyroid hormone, and insulin. Insight from the Tox21 and ToxCast programs confirm that these agrochemicals activate estrogen receptors, androgen receptors, and retinoic acid receptors with relatively high affinity, although differences exist in their potency. We propose an adverse outcome pathway for OCPs toxicity in the fish testis as a novel contribution to further understanding of OCP-induced toxicity. Organochlorine pesticides, due to their persistence and high toxicity to aquatic and terrestrial wildlife as well as humans, remain significant agrochemicals of concern. PURPOSE Nephrogenic system fibrosis (NSF) is a rare complication detected in patients with renal insufficiency exposed to gadolinium-based contrast agents (GBCAs). The aim of our study is to evaluate the prevalence of NSF in a cohort of patients on renal replacement treatment who underwent GBCA-enhanced magnetic resonance imaging (MRI). METHOD We retrospectively reviewed all the charts of kidney transplant (KT) recipients, patients on hemodialysis (HD) and peritoneal dialysis (PD) who received a uniform protocol for contrast material enhanced-MRI with gadoteric acid at our center from January 2004 to December 2017. RESULTS Three-hundred forty-four patients (44.1% on HD, 11.3% on PD and 44.4% KT recipients) underwent 551 gadoteric acid-enhanced MRI. The median age of the patients was 58 years (IQR, 45-70 years) and 65.1% were men. Sixty-three patients (18.3%) had skin punch biopsy after integumentary assessment performed by a dermatologist. No cases of NSF were detected after a median follow-up of 4.5 years (IQR, 1.9-8.2 years). During this period of observation, 116 (33.7%) patients died and 11 (3.1%) were lost at follow-up. CONCLUSIONS None of the patients exposed to gadoteric acid developed NSF. Our results, in line with more recent studies, suggest that the use of gadoteric acid, a macrocyclic GBCA, appears safe even in chronic kidney disease (CKD) patients receiving dialysis. Helicobacter pylori is a microorganism that in the last years has been associated with extragastric disorders such as respiratory diseases, however, its impact on lung is partially understood. The aim of this work was to study infection impact of H. pylori on the inflammatory markers expression at the pulmonary level using an animal model. Infection was performed by BALB/c wild type (WT) mice orotracheal instillation with 20 μl of 1 × 108H. pylori reference strain suspension once per day throughout 3 days. Inflammatory response was evaluated at 3, 7, 14, 21 and 30 days post infection. Lung was aseptically removed and pulmonary edema index values showed a significant change at 30 days of infection. Hematoxylin-Eosin (H-E) stain allowed to visualizing H. pylori presence in lung samples at 3 days of infection near the phagocytic cells or in the alveoli lumen. Bronchoalveolar lavage (BAL) was used for inflammatory response evaluation. Lactate dehydrogenase values showed a gradual increase in infected animals along infection time. Protein concentrations in mg/ml from BAL increased significantly at 7 days in infected animals. Macrophages viability obtained from BAL, decreased at the first moment of infection, maintaining constant values along contamination time. Results obtained demonstrate an inflammatory response in lung after orotracheal H. pylori infection and suggest that the pathogenic mechanism is strongly evidenced by tissue damage, endothelial dysfunction inflammatory mediators and markers expression at the pulmonary level. Murine norovirus (MNV), is a prevalent pathogen of laboratory mice closely related to human norovirus (HuNoV), a contagious pathogen known to cause gastroenteritis worldwide; however, the mechanism of norovirus replication remains poorly understood. Both heat shock protein 90 (Hsp90) and heat shock protein 70 (Hsp70) play an important role in viral genome replication and viral gene expression. In this study, we first found that heat stress exerted a positive effect on the replication of MNV in the murine macrophage RAW264.7 cell line. Inhibition of Hsp70 and Hsp90 by the specific inhibitors, KNK437 and 17-AGG, respectively showed that Hsp70 and Hsp90 enhanced MNV genome replication and virion production. In addition, we found that KNK437 and 17-AGG could decrease the level of IL-1β, IL-10, and TNF-α mRNA expression in MNV-infected cells. These data suggested that heat stress can positively regulate MNV replication, which advances our understanding of the molecular mechanism of MNV infection. This study investigated if in vitro maturation (IVM) before or after vitrification would be more successful for prepubertal oocytes. To mimic prepubertal conditions in an experimental setup, oocytes were collected from healthy 14, 21 and 28day old Swiss albino mice. The germinal vesicle (GV) stage oocytes and in vitro matured MII oocytes were subjected to vitrification-warming. Both structural (meiotic spindle morphology, mitochondrial integrity, cortical granules) and functional (sperm zona binding, fertilization) characteristics were assessed in oocytes after warming. 4-Methylumbelliferone compound library inhibitor This study demonstrated that IVM was more detrimental to prepubertal oocytes than to young adults. Further, vitrification of the IVM oocytes resulted in an increase in the number of abnormal meiotic spindles, a change in the cortical distribution pattern, a reduction in sperm zona binding and the fertilization rate. Importantly, oocyte integrity was better when prepubertal oocytes were vitrified before, rather than after, IVM. The above observations support GV stage vitrification for prepubertal oocytes requiring fertility preservation. Understanding the mechanisms behind the differing outcomes for oocytes from immature females will help in refining current protocol, thereby retaining the oocytes' maximum structural and functional integrity Further investigation is necessary to determine whether human prepubertal oocytes also behave in a similar way. It is to be noted here, with great emphasis, that a major limitation of this study is that the oocytes' abilities were tested only until fertilisation, as a consequence of which the study cannot reveal the developmental potentials of the embryos beyond fertilisation. During the last decades, many techniques have been developed to reduce sample volume and improve cooling and warming rates during embryo vitrification. The vast majority are based on the "minimum drop size" concept, in which the vitrification solution around embryos is reduced by aspiration, leaving a tiny part of volume surrounding embryos. However, novel cryodevices were aimed to remove the entire vitrification solution. This study was designed to compare the "minimum drop size" technique using Cryotop® with the nylon mesh as cryodevice on rabbit morula embryos. The outcomes assessed were the in vitro development rates (experiment 1) and the offspring rates at birth (experiment 2). Embryos were vitrified in a two-step procedure; equilibrium (10% EG + 10% Me2SO) for 2 min and vitrification (20% EG + 20% Me2SO) for 1 min. In experiment 1, embryos (n = 323) were warmed and subsequently in vitro cultured for 48 h to assess the embryo developmental capability to reach the hatching-hatched blastocyst stage. In experiment 2, embryos were transferred using the laparoscopic technique (n = 369) to assess the offspring rate at birth. In this context, rates of in vitro embryo development were similar between vitrified groups (0.73 ± 0.042% and 0.66 ± 0.047% for Cryotop® and nylon mesh device, respectively), but lower than in the fresh group (0.97 ± 0.016%, p  less then  0.05). In experiment 2, there were no significant differences in survival rates (offspring born/total embryos transferred) among the Cryotop® device group and fresh group (0.41 ± 0.049% and 0.49 ± 0.050%, respectively). But significantly lower value was obtained in the nylon mesh device group (0.18 ± 0.030%). These results indicate that nylon mesh is not suitable as cryodevice for rabbit morula vitrification, remaining those using the "minimum drop size" methodology as the best option.
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