TP53 mutations and CDKN2A mutations/deletions are highly recurrent molecular alterations in the malignant progression of sinonasal papillomas

xloma.fota.13 shared this article with you from Inoreader Message: Abstract Sinonasal papillomas are benign epithelial tumors of the sinonasal tract that are associated with a synchronous or metachronous sinonasal carcinoma in a subset of cases. Our group recently identified mutually exclusive EGFR mutations and human papillomavirus (HPV) infection in inverted sinonasal papillomas and frequent KRAS mutations in oncocytic sinonasal papillomas. We also demonstrated concordant mutational and HPV infection status in sinonasal papilloma-associated sinonasal carcinomas, confirming a clonal relationship between these tumors. Despite our emerging understanding of the oncogenic mechanisms driving formation of sinonasal papillomas, little is currently known about the molecular mechanisms of malignant progression to sinonasal carcinoma. In the present study, we utilized targeted next-generation DNA sequencing to characterize the molecular landscape of a large cohort of sinonasal papilloma-associated sinonasal carcinomas. As expected, EGFR or KRAS mutations were present in the vast majority of tumors. In addition, highly recurrent TP53 mutations, CDKN2A mutations, and/or CDKN2A copy-number losses were detected; overall, nearly all tumors (n = 28/29; 96.6%) harbored at least one TP53 or CDKN2A alteration. TERT copy-number gains also occurred frequently (27.6%); however, no TERT promoter mutations were identified. Other recurrent molecular alterations included NFE2L2 and PIK3CA mutations and SOX2, CCND1, MYC, FGFR1, and EGFR copy-number gains. Importantly, TP53 mutations and CDKN2A alterations were not detected in matched sinonasal papillomas, suggesting that these molecular events are associated with malignant transformation. Compared to aerodigestive tract squamous cell carcinomas from The Cancer Genome Atlas (TCGA) project, sinonasal papilloma-associated sinonasal carcinomas have a distinct molecular phenotype, including more frequent EGFR, KRAS, and CDKN2A mutations, TERT copy-number gains, and low-risk human papillomavirus (HPV) infection. These findings shed light on the molecular mechanisms of malignant progression of sinonasal papillomas and may have important diagnostic and therapeutic implications for patients with advanced sinonasal cancer. <i>TP53</i> mutations and <i>CDKN2A</i> mutations/deletions are highly recurrent molecular alterations in the malignant progression of sinonasal papillomas Via Modern Pathology - AOP - nature.com science feeds Modern Pathology, Published online: 17 November 2020; doi:10.1038/s41379-020-00716-3 TP53 mutations and CDKN2A mutations/deletions are highly recurrent molecular alterations in the malignant progression of sinonasal papillomas View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

TFEB rearranged renal cell carcinoma. A clinicopathologic and molecular study of 13 cases. Tumors harboring MALAT1-TFEB, ACTB-TFEB, and the novel NEAT1-TFEB translocations constantly express PDL1

xloma.fota.13 shared this article with you from Inoreader Message: Abstract Renal cell carcinomas with t(6;11) chromosome translocation has been classically characterized by the rearrangement of the TFEB gene, located on chromosome 6, and MALAT1 gene, located on chromosome 11. Recently, a few other genes have been described as fusion partners in TFEB rearranged renal cell carcinomas. Although most of TFEB rearranged renal cell carcinomas have an indolent behavior, in the rare cases of advanced metastatic disease targeted therapy and predictive markers remain lacking. In the present study, we collected 13 TFEB rearranged renal cell carcinomas, confirmed by FISH, analyzing their morphology and exploring the novel gene partners. Looking for predictive markers, we have also performed PDL1 immunohistochemical analysis by using four different assays (E1L3N, 22C3, SP142, and SP263). MALAT1 gene rearrangement has been found in ten tumors, five cases showing classical biphasic morphology with "rosettes", five cases without "rosettes" mimicking other renal cel l carcinomas or epithelioid angiomyolipoma/pure epithelioid PEComa. We identified two different partner genes, ACTB and NEAT1, the latter previously unreported and occurring in a tumor with an unusual solid and cystic appearance. In both cases, the "rosettes" were absent. In one case no gene partner was identified. Overall, in 12 of 13 TFEB-rearranged renal cell carcinomas staining for PDL1 SP263 was observed, whereas the other antibodies were less reliable or more difficult to interpret. In conclusion, we described the third case of ACTB-TFEB rearranged renal cell carcinoma and a novel NEAT1-TFEB rearranged renal cell carcinoma, both without the distinctive biphasic morphology typical of t(6;11) renal cell carcinoma. Finally, PDL1 SP263 was constantly expressed in TFEB rearranged renal cell carcinoma with possible clinical benefit which requires further investigations. <i>TFEB</i> rearranged renal cell carcinoma. A clinicopathologic and molecular study of 13 cases. Tumors harboring <i>MALAT1-TFEB, ACTB-TFEB,</i> and the novel <i>NEAT1-TFEB</i> translocations constantly express PDL1 Via Modern Pathology - AOP - nature.com science feeds Modern Pathology, Published online: 18 November 2020; doi:10.1038/s41379-020-00713-6 TFEB rearranged renal cell carcinoma. A clinicopathologic and molecular study of 13 cases. Tumors harboring MALAT1-TFEB, ACTB-TFEB, and the novel NEAT1-TFEB translocations constantly express PDL1 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Clinico-pathologic predictors of patterns of residual disease following neoadjuvant chemotherapy for breast cancer

xloma.fota.13 shared this article with you from Inoreader Message: Abstract Among breast cancer patients treated with neoadjuvant chemotherapy (NAC) who do not experience a pathologic complete response (pCR), the pattern of residual disease in the breast varies. Pre-treatment clinico-pathologic features that predict the pattern of residual tumor are not well established. To investigate this issue, we performed a detailed review of histologic sections of the post-treatment surgical specimens for 665 patients with stage I-III breast cancer treated with NAC followed by surgery from 2004 to 2014 and for whom slides of the post-NAC surgical specimen were available for review. This included 242 (36.4%) patients with hormone receptor (HR)+/HER2− cancers, 216 (32.5%) with HER2+ tumors, and 207 (31.1%) with triple negative breast cancer (TNBC). Slide review was blinded to pre-treatment clinico-pathologic features. pCR was achieved in 7.9%, 37.0%, and 37.7%, of HR+/HER2− cancers, HER2+ cancers, and TNBC respectively (p < 0.001). Among 389 patients with residua l invasive cancer in whom the pattern of residual disease could be assessed, 287 (73.8%) had a scattered pattern and 102 (26.2%) had a circumscribed pattern. In both univariate and multivariate analyses, there was a significant association between tumor subtype and pattern of response. Among patients with HR+/HER2− tumors, 89.4% had a scattered pattern and only 10.6% had a circumscribed pattern. In contrast, among those with TNBC 52.8% had a circumscribed pattern and 47.2% had a scattered pattern (p < 0.001). In addition to subtype, histologic grade and tumor size at presentation were also significantly related to the pattern of residual disease in multivariate analysis, with lower grade and larger size each associated with a scattered response pattern (p = 0.002 and p = 0.01, respectively). A better understanding of the relationship between pre-treatment clinico-pathologic features of the tumor and pattern of residual disease may be of value for helping to guide post- chemotherapy surgical management. Clinico-pathologic predictors of patterns of residual disease following neoadjuvant chemotherapy for breast cancer Via Modern Pathology - AOP - nature.com science feeds Modern Pathology, Published online: 20 November 2020; doi:10.1038/s41379-020-00714-5 Clinico-pathologic predictors of patterns of residual disease following neoadjuvant chemotherapy for breast cancer View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Comparing programmed death ligand 1 scores for predicting pembrolizumab efficacy in head and neck cancer

xloma.fota.13 shared this article with you from Inoreader Message: Abstract Tumor proportion score (TPS) and combined positive score ([CPS] includes immune cells), 2 methods for scoring programmed death ligand 1 (PD-L1) expression, have been used in clinical trials investigating the immune checkpoint inhibitor pembrolizumab in head and neck squamous cell carcinoma (HNSCC). These trials resulted in regulatory approval for pembrolizumab in the first- and second-line setting outside the United States. We performed a post hoc analysis of the KEYNOTE-040 study (NCT02252042) to determine whether CPS is a practical and suitable alternative scoring method to TPS. In KEYNOTE-040, patients with metastatic HNSCC received pembrolizumab or investigator choice of standard of care (SOC). The relative utility and equivalence of CPS ≥ 50 and TPS ≥ 50% for defining PD-L1 expression status in patients with HNSCC and comparability of scoring methods by tandem receiver operating characteristic (ROC) analysis were analyzed. The cutoff for each method was also evaluate d. CPS ≥ 50 appeared equivalent to TPS ≥ 50% for predicting objective response rate (ORR), overall survival, and progression-free survival. ORR for pembrolizumab versus SOC was 26.2 versus 8.5% for TPS ≥ 50%, 28.1 versus 7.7% for CPS ≥ 50, 10.6 versus 11.6% for TPS < 50%, and 10.0 versus 12.0% for CPS < 50. Tandem ROC analysis showed that TPS 50% and CPS 50 maximized delta Youden index and suggested that CPS is more sensitive than TPS at lower cutoffs (i.e., CPS ≥ 1). In conclusion, CPS 50 can be used interchangeably with TPS 50% to determine PD-L1 status in patients with HNSCC. CPS may be more sensitive than TPS at lower cutoffs. Comparing programmed death ligand 1 scores for predicting pembrolizumab efficacy in head and neck cancer Via Modern Pathology - AOP - nature.com science feeds Modern Pathology, Published online: 25 November 2020; doi:10.1038/s41379-020-00710-9 Comparing programmed death ligand 1 scores for predicting pembrolizumab efficacy in head and neck cancer View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Quantification of DNA through the NanoDrop Spectrophotometer: Methodological Validation Using Standard Reference Material and Sprague Dawley Rat and Human DNA

alkiviadis.1961 shared this article with you from Inoreader Quantification of DNA through the NanoDrop Spectrophotometer: Methodological Validation Using Standard Reference Material and Sprague Dawley Rat and Human DNA Via Hindawi Publishing Corporation This study aimed to validate an analytical method to determine DNA concentration using standard reference material (NIST SRM 2372) and Sprague Dawley rat and human DNA. Microvolumes were used to analyse DNA samples. Linearity showed correlation coefficients higher than R ≥ 0.9950, and the precision value was ≤2% CV. Trueness based on bias and the percentage of recovery showed bias values lower than Z-test with a 95% confidence level and a recovery percentage within the range (% Rec = 100% ± 5%), and the stability of the samples was 60 days (2–4°C). View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Biochemical Constituents of Phaleria macrocarpa (Leaf) Methanolic Extract Inhibit ROS Production in SH-SY5Y Cells Model

alkiviadis.1961 shared this article with you from Inoreader Biochemical Constituents of Phaleria macrocarpa (Leaf) Methanolic Extract Inhibit ROS Production in SH-SY5Y Cells Model Via Hindawi Publishing Corporation Background. Reactive oxygen species generation in mammalian cells profoundly affects several critical cellular functions, and the lack of efficient cellular detoxification mechanisms which remove these radicals may lead to several human diseases. Several studies show that ROS is incriminated as destructive agents in the context of the nervous system especially with advance in age leading to neurodegeneration. Current treatments of this disease are not effective and result in several side effects. Thus, the search for alternative medicines is in high demand. Therefore, the aim of this study is to evaluate the reactive oxygen inhibitory effect of Phaleria macrocarpa 80% (leaf) extract. Methods. The leaf was extracted with 80% methanol. Cytotoxicity studies were carried out using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and ROS inhibitory activities were evaluated using dichlorofluorescein diacetate (DCF-DA) assay in the SH-SY5Y cells model. Results. The result revealed ROS inhibitory activities of the crude extract with highly significant differences at between the group that were treated with crude extract only, the group treated with crude extract and exposed to H2O2, and the group exposed to H2O2 only as well as the group that were maintained in complete media. Bioactive compounds show the presence of vitexin and isovitexin following the HPLC method. Conclusion. High antioxidant activities and low toxicity effect of this crude revealed its high benefit to be used as natural medicine/supplements. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The Rise of Transradial Artery Access for Percutaneous Coronary Intervention in Patients with Acute Coronary Syndromes in Australia

alkiviadis.1961 shared this article with you from Inoreader The Rise of Transradial Artery Access for Percutaneous Coronary Intervention in Patients with Acute Coronary Syndromes in Australia Via Hindawi Publishing Corporation Objectives. The aim of this study was to evaluate the outcomes of acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) via transradial artery access (TRA) or transfemoral artery access (TFA). Background. Over the last decade, evidence for the benefit of TRA for PCI has grown, leading to a steady uptake of TRA around the world. Despite this, the topic remains controversial with contrary evidence to suggest no significant benefit over TFA. Methods. A retrospective study of consecutive ACS patients from 2011 to 2017 who underwent PCI via TRA or TFA. The primary outcome was Major Adverse Cardiovascular Events (MACE), a composite of death, myocardial infarction (MI), target lesion revascularisation (TLR), or coronary artery bypass graft surgery (CABG) at 12 months. Secondar y outcomes included Bleeding Academic Research Consortium (BARC) bleeding events scored 2 or higher, haematoma formation, and stent thrombosis, in addition to all individual components of MACE. Results. We treated 3624 patients (77% male), with PCI via TFA (n = 2391) or TRA (n = 1233). Transradial artery access was associated with a reduction in mortality (3% vs 6.3%; ), MI (1.8% vs 3.9%; ), CABG (0.6% vs 1.5%; ), TLR (1% vs 2.9%; ), large haematoma (0.4% vs 1.8%; ), BARC 2 (0.2% vs 1.1%; ), and BARC 3 events (0.4% vs 1.0%; ). On multivariate Cox regression analysis, TFA, age ≥ 75, prior PCI, use of bare metal stents, cardiogenic shock, cardiac arrest, and multivessel coronary artery disease were associated with an increased risk of MACE. Conclusion. Despite the limitations secondary to the observational nature of our study and multiple confounders, our results are in line with results of major trials and, as such, we feel that our results support the use of TRA as the preferred access site in patients undergoing PCI for ACS to improve patient outcomes. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Increased Frequencies of Switched Memory B Cells and Plasmablasts in Peripheral Blood from Patients with ANCA-Associated Vasculitis

alkiviadis.1961 shared this article with you from Inoreader Increased Frequencies of Switched Memory B Cells and Plasmablasts in Peripheral Blood from Patients with ANCA-Associated Vasculitis Via Hindawi Publishing Corporation B cells are thought to play a central role in the pathogenesis of antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV). ANCAs have been proposed to cause vasculitis by activating primed neutrophils to damage small blood vessels. We studied a cohort of AAV patients of which a majority were in remission and diagnosed with granulomatosis with polyangiitis (GPA). Using flow cytometry, the frequencies of CD19+ B cells and subsets in peripheral blood from 106 patients with AAV and 134 healthy controls were assessed. B cells were divided into naive, preswitch memory, switched memory, and exhausted memory cells. Naive and switched memory cells were further subdivided into transitional cells and plasmablasts, respectively. In addition, serum concentrations of immunoglobulin A, G, and M were measure d and clinical data were retrieved. AAV patients displayed, in relation to healthy controls, a decreased frequency of B cells of lymphocytes (5.1% vs. 8.3%) and total B cell number. For the subsets, a decrease in percentage of transitional B cells (0.7% vs. 4.4%) and expansions of switched memory B cells (22.3% vs. 16.5%) and plasmablasts (0.9% vs. 0.3%) were seen. A higher proportion of B cells was activated (CD95+) in patients (20.6% vs. 10.3%), and immunoglobulin levels were largely unaltered. No differences in B cell frequencies between patients in active disease and remission were observed. Patients in remission with a tendency to relapse had, compared to nonrelapsing patients, decreased frequencies of B cells (3.5% vs. 6.5%) and transitional B cells (0.1% vs. 1.1%) and an increased frequency of activated exhausted memory B cells (30.8% vs. 22.3%). AAV patients exhibit specific changes in frequencies of CD19+ B cells and their subsets in peripheral blood. These alterations coul d contribute to the autoantibody-driven inflammatory process in AAV. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The Importance of the Deep Deltoid Ligament Repair in Treating Supination-External Rotation Stage IV Ankle Fracture: A Comparative Retrospective Cohort Study

alkiviadis.1961 shared this article with you from Inoreader The Importance of the Deep Deltoid Ligament Repair in Treating Supination-External Rotation Stage IV Ankle Fracture: A Comparative Retrospective Cohort Study Via Hindawi Publishing Corporation Background. The necessity of the deep deltoid ligament repair in the treatment of supination-external rotation (SER) ankle stage IV fracture with deltoid ligament rupture is highly debated. We conducted this retrospective research aimed at exploring the curative effect of the deep deltoid ligament repair in treating SER fracture. Methods. Sixty-three patients with closed SER stage IV fractures received open reduction and internal fixation (ORIF), using either deep deltoid ligament repair (the DDLR group, 31 patients) or nondeep deltoid ligament repair (the NDDLR group, 32 patients). The radiographic parameters examined include the talocrural angle (TA), fibular length (FL), tibiomedial malleolar angle (TMMA), medial clear space (MCS), and tibiofibular clear space (TFCS). The functional performance paramete rs examined in the study were visual analog scale (VAS) pain score, American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot scales, and range of motion of bilateral ankles (RMBA). Complications, including bone nonunion, infection, and fragment displacement, were also recorded and compared. Results. Similar basic characteristics were found in both cohorts. All patients completed follow-up ranging from 12 to 22 months (mean time: months). The DDLR group had significantly reduced VAS score (), with markedly increased RMBA () compared to the NDDLR group. The two cohorts showed similar follow-up performance at 3 months (), 6 months (), and 12 months (), in terms of parameters including TA, FL, TMMA, MCS, TCS, and AOFAS ankle-hindfoot scales. Conclusion. Although similar radiographic performances were achieved in both cohorts, the DDLR group displayed enhanced functional outcome postsurgery, indicating that DDLR may be a better potential for the treatment of SER stage IV fra cture with deltoid ligament rupture. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Matcha Improves Metabolic Imbalance-Induced Cognitive Dysfunction

alkiviadis.1961 shared this article with you from Inoreader Matcha Improves Metabolic Imbalance-Induced Cognitive Dysfunction Via Hindawi Publishing Corporation This study was conducted to assess the protective effect of extract of match (EM) on high-fat diet- (HFD-) induced cognitive deficits in male C57BL/6 mice. It was found that EM improved glucose tolerance status by measuring OGTT and IPGTT with HFD-induced mice. EM protected behavioral and memory dysfunction in Y-maze, passive avoidance, and Morris water maze tests. Consumption of EM reduced fat mass, dyslipidemia, and inflammation in adipose tissue. Also, EM ameliorated hepatic and cerebral antioxidant systems. EM improved the cerebral cholinergic system by regulating ACh contents and expression of AChE and ChAT. Also, EM restored mitochondrial function in liver and brain tissue. EM attenuated hepatic inflammatory effect, lipid synthesis, and cholesterol metabolism by regulating the protein expression of T NF-α, TNFR1, p-IRS-1, p-JNK, IL-1β, iNOS, COX-2, HMGCR, PPARγ, and FAS. Finally, EM regulated cognitive function and neuroinflammation in the whole brain, hippocampus, and cerebral cortex by regulating the protein expression of p-JNK, p-Akt, p-tau, Aβ, BDNF, IDE, COX-2, and IL-1β. These findings suggest that EM might be a potential source of functional food to improve metabolic disorder-associated cognitive dysfunction. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Prophylaxis of Pain and Fractures within Feet in the Course of Osteoporosis: The Issue of Diagnosing

alkiviadis.1961 shared this article with you from Inoreader Prophylaxis of Pain and Fractures within Feet in the Course of Osteoporosis: The Issue of Diagnosing Via Hindawi Publishing Corporation Background. Considering the enormous risk of fractures in the course of osteoporosis in the area of the feet, an important aspect of prophylaxis is periodic and, in special cases, ongoing monitoring of defects and deformations as well as pressure distribution. The purpose of this article is to indicate the role of the examination of posture and pressure distribution during standing, postural balance, and gait, in the prevention of fatigue fractures in the course of osteoporosis, based on the literature review and examples of patients. Methods. The manuscript consists of two parts; it has a review-analytical character. The first part reviews the literature. The data were obtained using the MEDLINE (PubMed), as well as Cochrane and Embase databases. The database review was carried out focusing mainly on English -language publications, while taking into account the topicality of scientific and research works in the area of osteoporosis. The problem of multiaspects in the area of bone density was pointed out. Considering the above, in the second part, the authors analyzed 11 exemplary patients with osteoporosis, referring to the assessment of foot and lower limb defects using traditional posturological methods and including pedobarography to diagnostic procedures that are used in the assessment of pressure distribution, standing and moving, and an attempt to balance. Results. Analysis of the research and scientific literature proved the lack of unambiguous diagnostic procedures of the locomotor system recommended for the prevention of fatigue fractures in the course of osteoporosis. The main diagnostic recommendations are imaging tests (most often X-ray), which are recommended in the case of specific clinical symptoms. The analysis of exemplary patients with osteoporosis showed numerous diso rders in the distribution of pressure in the plantar part of the feet, which are related, among other things, with their individual defects and lower limbs. Conclusions. Detailed posture diagnostics and gait estimation, along with the analysis of pressure distribution within the feet are a very important aspect of the prevention of structural degradation and fatigue fractures within the feet. An important postulate for further research and scientific work is the elaboration of the procedures that will serve the preventive diagnostics of the locomotor system, aimed at early detection of threats of fatigue fractures. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.