Mcdowellholman8240

Particulate matter (PM) is the principal component of air pollution. PM includes a range of particle sizes, such as coarse, fine, and ultrafine particles. Particles that are less then 100 nm in diameter are defined as ultrafine particles (UFPs). UFPs are found to a large extent in urban air as both singlet and aggregated particles. UFPs are classified into two major categories based on their source. Typically, UFPs are incidentally generated in the environment, often as byproducts of fossil fuel combustion, condensation of semivolatile substances or industrial emissions, whereas nanoparticles are manufactured through controlled engineering processes. The primary exposure mechanism of PM is inhalation. Inhalation of PM exacerbates respiratory symptoms in patients with chronic airway diseases, but the mechanisms underlying this response remain unclear. This review offers insights into the mechanisms by which particles, including UFPs, influence airway inflammation and discusses several mechanisms that may explain the relationship between particulate air pollutants and human health, particularly respiratory health. Understanding the mechanisms of PM-mediated lung injury will enhance efforts to protect at-risk individuals from the harmful health effects of air pollutants.Skeletal muscle is a major organ for glucose disposal and thermogenesis. While hepatic fructose-1,6-bisphosphatase is well known as a key enzyme for gluconeogenesis, the role of muscle fructose-1,6-bisphosphatase 2 (Fbp2) in glucose disposal and thermogenesis is unknown. Here, using Fbp2 knockout (KO) mice, we assessed the physiological role of Fbp2 in energy and glucose metabolism and thermogenesis. In vivo assessments of energy metabolism, glucose metabolism, and thermogenesis were performed by indirect calorimetry, hyperinsulinemic-euglycemic clamp, and cold challenge studies, respectively. Under both feeding and fasting conditions, Fbp2 KO mice showed similar phenotypes regarding energy and glucose metabolism compared to wild-type (WT) mice. However, Fbp2 KO mice were severely intolerant to cold challenge under fasting conditions. Mechanistically, the cold-induced intramuscular conversion of lactate to glycogen (glyconeogenesis) is completely abolished in the KO muscle, which leads to a lack of glycogen source for thermogenesis in Fbp2 KO mice. The cold-intolerant phenotype of KO mice disappeared after feeding, and the KO mice were equally as cold tolerant as the WT mice and survived during the cold challenge for three weeks. Taken together, these data demonstrate that Fbp2 is essential for muscle thermogenesis by replenishing the intramuscular glycogen pool through glyconeogenesis when the exogenous glucose source is limited. These data imply the physiological importance of Fbp2 in thermal homeostasis and suggest a potential novel therapy targeted to increase glycogen replenishment upon cold stress.Aging, which is associated with age-related changes in physiological processes, is the most significant risk factor for the development and progression of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Accumulating evidence has indicated that sphingolipids are significant regulators that are associated with pathogenesis in aging and several age-related neurodegenerative diseases. In particular, abnormal levels of acid sphingomyelinase (ASM), one of the significant sphingolipid-metabolizing enzymes, have been found in the blood and some tissues under various neuropathological conditions. Moreover, recent studies have reported the importance of ASM as a critical mediator that contributes to pathologies in aging and age-related neurodegenerative diseases. In this review, we describe the pathophysiological processes that are regulated by ASM, focusing on the age-related neurodegenerative environment. Furthermore, we discuss novel insights into how new therapeutics targeting ASM may potentially lead to effective strategies to combat aging and age-related neurodegenerative diseases.The recent literature has shown that vulvar squamous cell carcinoma (VSCC) can be stratified into two prognostically relevant groups based on human papillomavirus (HPV) status. The prognostic value of p53 for further sub-stratification, particularly in the HPV-independent group, has not been agreed upon. This disagreement is likely due to tremendous variations in p53 immunohistochemical (IHC) interpretation. To address this problem, we sought to compare p53 IHC patterns with TP53 mutation status. We studied 61 VSCC (48 conventional VSCC, 2 VSCC with sarcomatoid features, and 11 verrucous carcinomas) and 42 in situ lesions (30 differentiated vulvar intraepithelial neoplasia [dVIN], 9 differentiated exophytic vulvar intraepithelial lesions [deVIL], and 3 high-grade squamous intraepithelial lesions or usual vulvar intraepithelial neoplasia [HSIL/uVIN]). IHC for p16 and p53, and sequencing of TP53 exons 4-9 were performed. HPV in situ hybridization (ISH) was performed in selected cases. We identified six major p53 IHC patterns, two wild-type patterns (1) scattered, (2) mid-epithelial expression (with basal sparing), and four mutant patterns (3) basal overexpression, (4) parabasal/diffuse overexpression, (5) absent, and (6) cytoplasmic expression. These IHC patterns were consistent with TP53 mutation status in 58/61 (95%) VSCC and 39/42 (93%) in situ lesions. Cases that exhibited strong scattered staining and those with a weak basal overexpression pattern could be easily confused. The mid-epithelial pattern was exclusively observed in p16-positive lesions; the basal and parabasal layers that had absent p53 staining, appeared to correlate with the cells that were positive for HPV-ISH. This study describes a pattern-based p53 IHC interpretation framework, which can be utilized as a surrogate marker for TP53 mutational status in both VSCC and vulvar in situ lesions.Telomeres are nucleoprotein complexes located at the termini of eukaryotic chromosomes that prevent exonucleolytic degradation and end-to-end chromosomal fusions. Cancers often have critically shortened, dysfunctional telomeres contributing to genomic instability. Telomere shortening has been reported in a wide range of precancerous lesions and invasive carcinomas. However, the role of telomere alterations, including the presence of alternative lengthening of telomeres (ALT), has not been studied in pituitary adenomas. Telomere length and the presence of ALT were assessed directly at the single cell level using a telomere-specific fluorescence in situ hybridization assay in tissue microarrays. Tumors were characterized as either ALT-positive or having short, normal, or long telomere lengths and then these categories were compared with clinicopathological characteristics. ATRX and DAXX expression was studied through immunohistochemistry. We characterized a discovery set of 106 pituitary adenomas including both functional and nonfunctional subsets (88 primary, 18 recurrent). Telomere lengths were estimated and we observed 64 (59.4%) cases with short, 39 (36.8%) cases with normal, and 0 (0%) cases with long telomeres. AS1517499 in vitro We did not observe significant differences in the clinicopathological characteristics of the group with abnormally shortened telomeres compared to the group with normal telomeres. However, three pituitary adenomas were identified as ALT-positive of which two were recurrent tumors. Two of these three ALT-positive cases had alterations in either of the chromatin remodeling proteins, ATRX and DAXX, which are routinely altered in other ALT-positive tumor subtypes. In a second cohort of 32 recurrent pituitary adenomas from 22 patients, we found that the tumors from 36% of patients (n = 8) were ALT-positive. This study demonstrates that short telomere lengths are prevalent in pituitary adenomas and that ALT-positive pituitary adenomas are enriched in recurrent disease.Magee Equations™ are multivariable models that can estimate oncotype DX® Recurrence Score, and Magee Equation 3 has been shown to have chemopredictive value in the neoadjuvant setting as a standalone test. The current study tests the accuracy of Magee Decision Algorithm™ using a large in-house database. According to the algorithm, if all Magee Equation scores are 25) appears to have an excellent outcome on endocrine therapy alone.The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) have recently issued updated guidelines on human epidermal growth factor receptor 2 (HER2) testing by fluorescence in situ hybridization (FISH) in invasive breast cancers. Cases with a HER2/chromosome enumeration probe 17 (CEP17) ratio of ≥2.0 but an average HER2 copy number of less then 4.0 signals per cell (ISH group 2) are no longer automatically classified as ISH positive. Herein, 30 cases in ISH group 2 were collected. Another 100 patients with a HER2/CEP17 ratio less then 2.0 and less then 4.0 HER2 signals per cell (ISH group 5) and 100 patients with a HER2/CEP17 ratio of ≥2.0 and an average HER2 copy number of ≥4.0 signals per cell (ISH group 1) were also recruited for comparison. According to the 2018 ASCO/CAP guidelines, all the cases in ISH group 2 were categorized as HER2 negative. The clinicopathological characteristics of the patients in ISH group 2 were intermediate between ISH group 1 and group 5. Survival analyses revealed that there was no significant disease-free survival (DFS) and overall survival (OS) difference between patients with or without targeted therapy in ISH group 2, as well as between patients with targeted therapy in ISH group 1 and patients in ISH group 2. Patients without targeted therapy in ISH group 2 had a significantly worse OS than patients with targeted therapy in ISH group 1 and patients in ISH group 5. In conclusion, patients in ISH group 2 represent a biologically heterogeneous subset, which are different from those in ISH group 1 and 5. A larger cohort of patients in ISH group 2 should be included for future researches to define the efficacy of HER2-targeted therapy.Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n = 7), primary aGCTs that subsequently recurred (n = 9) and their matched recurrences (n = 9), and aGCT recurrences without matched primary tumors (n = 10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.