Metformin as a Therapeutic Target in Endometrial Cancers.

Endometrial cancer is the most common gynecologic malignancy in developed countries. Its increasing incidence is thought to be related in part to the rise of metabolic syndrome, which has been shown to be a risk factor for the development of hyperestrogenic and hyperinsulinemic states. This has consequently lead to an increase in other hormone-responsive cancers as well e.g., breast and ovarian cancer. The correlation between obesity, hyperglycemia, and endometrial cancer has highlighted the important role of metabolism in cancer establishment and persistence. Tumor-mediated reprogramming of the microenvironment and macroenvironment can range from induction of cytokines and growth factors to stimulation of surrounding stromal cells to produce energy-rich catabolites, fueling the growth, and survival of cancer cells. Such mechanisms raise the prospect of the metabolic microenvironment itself as a viable target for treatment of malignancies. Metformin is a biguanide drug that is a first-line treatment for type 2 diabetes that has beneficial effects on various markers of the metabolic syndrome. Many studies suggest that metformin shows potential as an adjuvant treatment for uterine and other cancers. Here, we review the evidence for metformin as a treatment for cancers of the endometrium. We discuss the available clinical data and the molecular mechanisms by which it may exert its effects, with a focus on how it may alter the tumor microenvironment. The pleiotropic effects of metformin on cellular energy production and usage as well as intercellular and hormone-based interactions make it a promising candidate for reprogramming of the cancer ecosystem. This, along with other treatments aimed at targeting tumor metabolic pathways, may lead to novel treatment strategies for endometrial cancer

Pathologic effects of uremia in the kidney and brain

Chronic kidney disease (CKD), a reduction in kidney function, has reached pandemic proportions and imposes a major healthcare burden worldwide. A hallmark of CKD is the accumulation of several chemical compounds, called uremic toxins, which inflict systemic and renal-specific damage. Of the known uremic toxins, kynurenine (Kyn) is known to be particularly vasculotoxic and is implicated in several complications of CKD. Indoleamine 2,3-dioxygenase 1 (IDO), which catalyzes the first step in the metabolism of Tryptophan (Trp), regulates immune response to inflammatory cytokines in tissues. IDO plays a role in apoptosis and damage during acute kidney injury (AKI), a transient decrease in kidney function. During metabolism of Trp, IDO generates Kyn, a uremic solute, and therefore IDO may play a role in the brain and kidney damage due to accumulation of Kyn. The objective of the current study was to investigate the role and regulation of IDO in CKD pathology. Studies were performed to determine whether IDO is protective or pathologic and to find how IDO is regulated in the kidney during CKD. IDO in renopathology was examined using murine models of CKD. CKD was induced via a 0.2% adenine-supplemented diet (AD) model for 21 days. IDO regulation was examined using an Indoxyl Sulfate (IS)-specific solute model. Renal function in the IDO+/+ and IDO-/- AD mice was assessed through weekly measurement of blood urea nitrogen (BUN). H&E and Masson’s trichrome stains were used to assess percentages of glomerulosclerosis (GS) and immune infiltration (II), and combined interstitial fibrosis and tubular atrophy (IFTA) score in IDO+/+ and IDO-/- mice with and without CKD. IDO protein concentration in the kidneys of all mice with and without CKD and IDO+/+ IS mice was determined via immunoblotting. Patients with kidney disease suffer from neuropsychological disorders and neurocognitive decline. The effects of uremic solutes on the CNS was examined using immortalized human umbilical endothelial vein cells (HUVEC-TERT), in vitro. Cell proliferation and viability, in the presence of IS, were measured by BrdU and Alamar blue assays, respectively. In both IDO+/+ and IDO-/-, 21 days of AD results in significant deterioration of renal function. The average IFTA score and percentage of II in IDO-/- mice increased with AD compared to ND (p<0.05, p<0.001). IDO expression was seen sporadically in the glomeruli and walls of major vessels in the kidneys of 4d AD IDO+/+ mice, and in the tubules and vessel walls in the kidneys of 14d AD IDO+/+ mice. In IDO+/+ ND mice, endogenous IDO protein expression was undetectable at a signal intensity of 119.86 ± 268.01, whereas IDO+/+ AD mice showed a 370-fold higher level of IDO protein expression compared to IDO+/+ ND (p<0.001). IDO-/- AD IDO protein expression was 9.5-fold higher than in IDO-/- AD (p<0.05). IDO expression was found to be 58-fold higher in IDO+/+ mice with IS treatment (p<0.05). In the IS mice, non-significant trends toward decrease in cellular proliferation and viability with time were also observed (p=ns). IDO is upregulated at the protein level both in a CKD model and directly by the uremic solute, IS. IDO appears to be protective in the kidney during CKD, given the trend toward increased percentage of GS and II in IDO-/- compared to IDO+/+ mice with CKD, though there is little difference seen in total kidney IFTA. IDO upregulation is linked to increased apoptosis. Blocking uremic solute production would therefore prevent IDO protein upregulation and reduce apoptosis, alleviating renal damage during CKD

Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia

Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%; P = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined. This trial was registered at www.clinicaltrials.gov as #NCT01976416

Common and Unique Representations in pFC for Place Attractiveness

Although previous neuroimaging research has identified overlapping correlates of subjective value across different reward types in the ventromedial pFC (vmPFC), it is not clear whether this “common currency” evaluative signal extends to the aesthetic domain. To examine this issue, we scanned human participants with fMRI while they made attractiveness judgments of faces and places—two stimulus categories that are associated with different underlying rewards, have very different visual properties, and are rarely compared with each other. We found overlapping signals for face and place attractiveness in the vmPFC, consistent with the idea that this region codes a signal for value that applies across disparate reward types and across both economic and aesthetic judgments. However, we also identified a subregion of vmPFC within which activity patterns for face and place attractiveness were distinguishable, suggesting that some category-specific attractiveness information is retained in this region. Finally, we observed two separate functional regions in lateral OFC: one region that exhibited a category-unique response to face attractiveness and another region that responded strongly to faces but was insensitive to their value. Our results suggest that vmPFC supports a common mechanism for reward evaluation while also retaining a degree of category-specific information, whereas lateral OFC may be involved in basic reward processing that is specific to only some stimulus categories

The effects of PPO activity on the proteome of ingested red clover and implications for improving the nutrition of grazing cattle

AbstractIncreasing the rumen-stable protein content of feed would lead to improved nitrogen utilisation in cattle, and less nitrogenous waste. Red clover (Trifolium pratense L.) is a high protein ruminant feed containing high polyphenol oxidase (PPO) activity. PPO mediated protein-quinone binding has been linked to protecting plant proteins from proteolysis. To explore the mechanism underlying the effect of PPO on protein protection in fresh forage feeds, proteomic components of feed down-boli produced from wild-type red clover and a low PPO mutant, at point of ingestion and after 4h in vitro incubation with rumen inoculum were analysed. Significant differences in proteomic profiles between wild-type and mutant red clover were determined after 4h incubation, with over 50% less spots in mutant than wild-type proteomes, indicating decreased proteolysis in the latter. Protein identifications revealed preferentially retained proteins localised within the chloroplast, suggesting that PPO mediated protection in the wild-type operates due to the proximity of target proteins to the enzyme and substrates, either diffusing into this compartment from the vacuole or are present in the chloroplast. This increased understanding of protein targets of PPO indicates that wider exploitation of the trait could contribute to increased protein use efficiency in grazing cattle.Biological significanceOne of the main challenges for sustainable livestock farming is improving capture of dietary nitrogen by ruminants. Typically up to 70% of ingested protein-N is excreted representing a loss of productivity potential and a serious environmental problem in terms of nitrogenous pollution of lands and water. Identification of key characteristics of rumen-protected protein will deliver target traits for selection in forage breeding programmes. The chloroplastic enzyme PPO catalyzes the oxidation of phenols to quinones, which react with protein. Little is currently known about the intracellular protein targets of the products of PPO activity or the mechanism underlying protein complexing, including whether there is any specificity to the reaction. Here we have determined significant differences in the proteomes of freshly ingested down boli corresponding to the presence or absence of active PPO. These results show that in the presence of PPO the forage protein is less amenable to proteolysis and provide the novel information that the protected proteins are putatively chloroplastically located. These data also contribute to a growing evidence base that a chloroplastic PPO substrate exists in red clover in addition to the currently known vacuolar substrates

Practice analysis of certified public accountants: technical report

https://egrove.olemiss.edu/aicpa_assoc/1354/thumbnail.jp

IDENTIFICATION AND DESCRIPTION OF BUCEPHALUS MINIMUS (DIGENEA: BUCEPHALIDAE) LIFE CYCLE IN PORTUGAL: MORPHOLOGICAL, HISTOPATHOLOGICAL, AND MOLECULAR DATA

The cercaria of Bucephalus minimus infects the digestive gland and gonads of its first intermediate host, the edible cockle. Cerastoderma edule. Light microscopy (LM) and scanning electron microscopy (SEM) of the cercaria showed a tail formed by a central stem, with 2 long contractile arms presenting distinct morphological surfaces. The encysted metacercaria naturally infected the flathead grey mullet, Mugil cephalus. The cysts found in the heart, liver, and spleen were shown to be identical by the internal transcribed spacer (ITS1) sequence and morphological features and were associated with encapsulation, recruitment of cell infiltrates, and presence of melanomacrophages and adipose tissue. To establish the life cycle. we compared the ITS1 sequence in an adult from the known definitive host, Dicentrarchus labrax: encysted metacercariac from the liver, heart, and spleen of M. cephalus; and a cercaria from C. edule. With this comparison, we determined that they had a 100% similarity. Therefore, the ITS1 sequence data clearly indicate that these 3 parasitic stages belong to the same species, i.e., B. minimus