PD-L1 expression in pancreaticobiliary adenosquamous carcinoma: a single-institution case series.

Background: The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is a potent negative regulator of T-cell-mediated immune response that is upregulated in many neoplasms. Pancreaticobiliary adenosquamous carcinoma (PB-ASC) is an aggressive cancer that carries a poorer prognosis compared with pure pancreaticobiliary adenocarcinoma (PB-AC). To date, there is little published information regarding PD-L1 expression in PB-ASC. The aim of the study was to examine the relationship between PD-L1 expression and tumor-infiltrating lymphocytes in PB-ASC and PB-AC. Methods: We evaluated 15 PB-ASCs (10 pancreatic, 5 gallbladder) and 34 control PB-ACs (22 pancreatic ductal, and 12 gallbladder) for tumor expression of PD-L1 using anti-PD-L1 (E1L3N) antibody. All tumors were classified into three immune phenotypes: immune inflamed (II), immune excluded (IE), and immune desert (ID) according to the distribution of tumor-infiltrating lymphocytes in tumor tissues. Results: The frequency of PD-L1 expression was significantly higher in PB-ASC (10/15; 66.7%) than in PB-AC (3/34; 8.8%). In PB-ASC, PD-L1 expression occurred exclusively in the squamous component in six cases, exclusively in the glandular component in one case, and in both the squamous and the glandular components in three cases. PD-L1 expression in PB-ASC was irrespective of the tumor immune status, whereas its expression in PB-AC was observed only in tumors with the II or IE phenotype. The ID phenotype was relatively rare (4/15; 26.7%) in PB-ASC compared with PB-AC (22/34; 65%; P=0.02). Conclusions: PB-ASCs are notably enriched in inflammatory response and showed significantly higher PD-L1 expression than PB-AC (P<0.001), suggesting a potential therapeutic role for immune checkpoint inhibitors in managing patients with PB-ASC.

A Rare Case of Olmesartan-Associated Enteropathy Successfully Managed With Steroid Taper.

Olmesartan is a commonly used antihypertensive medication belonging to the class of angiotensin II receptor blockers. Though generally well-tolerated, olmesartan can rarely cause olmesartan-associated enteropathy (OAE) with non-bloody diarrhea, weight loss, abdominal pain, and vomiting. Patients may develop enteropathy months to years after drug initiation. In severe cases, patients may develop complications that require hospitalization. Diagnosis is often delayed due to unfamiliarity of OAE, nonspecific presenting symptoms, and normal-appearing gross endoscopic findings. Esophagogastroduodenoscopy (EGD) with biopsy is essential to the diagnosis, showing sprue-like enteropathy with intestinal villous atrophy and mucosal inflammation. This report describes a case of a 70-year-old man who presented with three months of profuse watery diarrhea and 40-pound unintentional weight loss. After an extensive workup, including EGD with duodenal biopsies, the patient was diagnosed with OAE. The biopsies showed findings consistent with acute and chronic duodenitis, mucosal desquamation and ulceration, blunting of villi, and a sprue-like pattern with neutrophils. Celiac serologies and anti-enterocyte antibodies were negative, further supporting the diagnosis of OAE. Complete resolution of symptoms was achieved by discontinuing olmesartan and administering a steroid taper. Considering the frequent use of olmesartan, the increasing occurrence of OAE, and the wide range of associated symptoms, it is crucial for providers to recognize OAE and consider early discontinuation of olmesartan. This approach can help prevent further intestinal damage, protracted symptoms, unnecessary diagnostic tests, and financial burdens on both patients and the healthcare system.

Quantifying the Impact of the COVID-19 Pandemic on Passenger Vehicle Drivers' Willingness to Pay for Travel Time Savings and Reliability.

The COVID-19 pandemic has fundamentally disrupted travel behavior and consumer preferences. To slow the spread of the virus, public health officials and state and local governments issued stay-at-home orders and, among other actions, closed nonessential businesses and educational facilities. The resulting recessionary effects have been particularly acute for U.S. toll roads, with an observed year-over-year decline in traffic and revenue of 50% to 90% in April and May 2020. These disruptions have also led to changes in the types of trip that travelers make and their frequency, their choice of travel mode, and their willingness to pay tolls for travel time savings and travel time reliability. This paper describes the results of travel behavior research conducted on behalf of the Virginia Department of Transportation before and during the COVID-19 pandemic in the National Capital Region of Washington, D.C., Maryland, and Northern Virginia. The research included a stated preference survey to estimate travelers' willingness to pay for travel time savings and travel time reliability, to support forecasts of traffic and revenue for existing and proposed toll corridors. The survey collected data between December 2019 and June 2020. A comparison of the data collected before and during the pandemic shows widespread changes in travel behavior and a reduction in willingness to pay for travel time savings and travel time reliability across all traveler types, particularly for drivers making trips to or from work. These findings have significant implications for the return of travelers to toll corridors in the region and future forecasts of traffic and revenue.

Effect of Proton Pump Inhibitor Treatment in "PPI Non-responsive" Patients with Eosinophilic Esophagitis.

BACKGROUND AND AIMS: Some eosinophilic esophagitis (EoE) patients can have a decline in eosinophil count after proton pump inhibitor (PPI) treatment without achieving histologic response, but little is known about this group. We aimed to determine the effect of PPIs on reducing esophageal eosinophilia in patients deemed non-responsive to PPI therapy. METHODS: We analyzed prospectively collected cohort data from newly diagnosed adults with EoE who were histologic non-responders (≥15 eos/hpf) to PPI-only therapy. Symptoms, endoscopic histologic features were assessed before and after PPI. Pre- and post-PPI treatment esophageal biopsies were read by pathologists to determine peak eosinophil counts and other histologic findings. RESULTS: Of 125 patients, peak eosinophil counts were 102.1 ± 69.8 and 102.9 ± 101.1 (p=0.93) before and after PPI treatment, respectively, but lamina propria fibrosis decreased from 97% to 41% (p<0.001). Heartburn frequency also decreased (19% to 11%; p=0.006), though endoscopic findings did not change. There were 75 patients (60%) who had some decrease in eosinophil counts, with 30 patients (24%) having ≥50% decrease in counts. When comparing the ≥50% and <50% decrease groups, differences in endoscopic features were identified, but the ≥50% group had improvement in eosinophil degranulation, microabscesses, spongiosis, and basal cell hyperplasia. CONCLUSION: Peak eosinophil counts did not decrease overall after PPI treatment, but symptoms of heartburn improved. Approximately a quarter had ≥50% decrease in eosinophil counts, with associated decreases in other histologic findings. Further research may consider what role PPIs have in this subset of non-responders or in combination therapies.

Long-term efficacy of proton pump inhibitors as a treatment modality for eosinophilic esophagitis.

BACKGROUND: Proton pump inhibitors (PPIs) are a first-line treatment for EoE, but data are limited concerning response durability. We aimed to determine long-term outcomes in EoE patients responsive to PPI-therapy. METHODS: We conducted a retrospective cohort study of newly diagnosed adults with EoE who had initial histologic response (<15 eosinophils per high-power-field) to PPI-only therapy. We extracted data regarding their subsequent clinical course and outcomes. We compared findings between the initial PPI-response endoscopy and the final endoscopy, and assessed factors associated with loss of PPI response. RESULTS: Of 138 EoE patients with initial histologic response to PPI, 50 had long-term endoscopic follow-up, 40 had clinical follow-up, 10 changed treatments, and 38 had no long-term follow-up. Of those with endoscopic follow-up, mean follow-up-time was 3.6 ± 2.9 years; 30 and 32 patients (60%; 64%) maintained histologic and symptom responses, respectively. However, fibrotic endoscopic findings of EoE were unchanged. Younger age (aOR 1.05, 95% CI: 1.01-1.11) and dilation prior to PPI treatment (aOR 0.21, 95% CI: 0.05-0.83) were the only factors associated with long-term loss of PPI response. CONCLUSIONS: Long-term histologic and clinical response rates for PPI therapy were 60% and 64%, respectively. Younger age and dilation at baseline were associated with histologic loss of response. These data can inform long-term EoE treatment selection.

The Automatic Classification of Pyriproxyfen-Affected Mosquito Ovaries.

Pyriproxyfen (PPF) may become an alternative insecticide for areas where pyrethroid-resistant vectors are prevalent. The efficacy of PPF can be assessed through the dissection and assessment of vector ovaries. However, this reliance on expertise is subject to limitations. We show here that these limitations can be overcome using a convolutional neural network (CNN) to automate the classification of egg development and thus fertility status. Using TensorFlow, a resnet-50 CNN was pretrained with the ImageNet dataset. This CNN architecture was then retrained using a novel dataset of 524 dissected ovary images from An. gambiae s.l. An. gambiae Akron, and An. funestus s.l., whose fertility status and PPF exposure were known. Data augmentation increased the training set to 6973 images. A test set of 157 images was used to measure accuracy. This CNN model achieved an accuracy score of 94%, and application took a mean time of 38.5 s. Such a CNN can achieve an acceptable level of precision in a quick, robust format and can be distributed in a practical, accessible, and free manner. Furthermore, this approach is useful for measuring the efficacy and durability of PPF treated bednets, and it is applicable to any PPF-treated tool or similarly acting insecticide.

Inhibition of the intestinal postprandial glucose transport by gallic acid and gallic acid derivatives.

Inhibition of glucose uptake in the intestine through sodium-dependent glucose transporter 1 (SGLT1) or glucose transporter 2 (GLUT2) may be beneficial in controlling postprandial blood glucose levels. Gallic acid and ten of its derivatives were identified in the active fractions of Terminalia chebula Retz. fructus immaturus, a popular edible plant fruit which has previously been associated with the inhibition of glucose uptake. Gallic acid derivatives (methyl gallate, ethyl gallate, pentyl gallate, 3,4,6-tri-O-galloyl-ß-d-glucose, and corilagin) showed good glucose transport inhibition with inhibitory rates of 72.1 ± 1.6%, 71.5 ± 1.4%, 79.9 ± 1.2%, 44.7 ± 1.2%, and 75.0 ± 0.7% at 5 mM d-glucose and/or 56.3 ± 2.3, 52.1 ± 3.2%, 70.2 ± 1.7%, 15.6 ± 1.6%, and 37.1 ± 0.8% at 25 mM d-glucose. However, only 3,4,6-tri-O-galloyl-ß-d-glucose and corilagin were confirmed GLUT2-specific inhibitors. Whilst some tea flavonoids demonstrated minimal glucose transport inhibition, their gallic acid derivatives strongly inhibited transport effect with GLUT2 specificity. This suggests that gallic acid structures are crucial for glucose transport inhibition. Plants, such as T. chebula, which contain high levels of gallic acid and its derivatives, show promise as natural functional ingredients for inclusion in foods and drinks designed to control postprandial glucose levels.

Generic Measures of Quality of Life Are Not Correlated with Disease Activity in Eosinophilic Esophagitis.

BACKGROUND: The relationship between histologic disease activity in eosinophilic esophagitis (EoE) and generic measures of quality of life (QoL) is unclear. AIMS: To determine differences in QoL in adults with EoE based on histologic activity and assess changes in QoL over time. METHODS: We performed an analysis of prospectively collected data from patients in the University of North Carolina EoE Registry. Patients were categorized with histologically active (≥ 15 eosinophils per high-power field [eos/hpf]) or inactive (< 15 eos/hpf) disease. Dysphagia severity was measured with a Likert scale. QoL was measured with 36-Item Short Form (SF-36), compared between active and inactive groups, and assessed longitudinally. RESULTS: Of 147 EoE cases, those with inactive disease (n = 56) reported less dysphagia severity (3.2 vs. 1.9; p = 0.003) and had lower endoscopic severity (3.8 vs. 1.0; p < 0.001) than those with active disease (n = 91). While SF-36 scores did not differ between active and inactive status, lower mental component scores (MCS) were seen in patients treated with empiric dietary elimination (44.9 vs. 50.8; p = 0.005). Dysphagia severity was negatively correlated with both physical component score (PCS) (r = -0.33; p < 0.001) and MCS (r = -0.18; p = 0.03). Despite more cases achieving histologic response over time, SF-36 scores did not improve on either raw or adjusted analyses. CONCLUSION: QoL measured by SF-36 in EoE was similar regardless of histologic disease activity and was in the range of population averages. General QoL metrics like the SF-36 do not appear to have substantial utility in EoE.

Glycocalyx sialic acids regulate Nrf2-mediated signaling by fluid shear stress in human endothelial cells.

Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is critical for vascular endothelial redox homeostasis in regions of high, unidirectional shear stress (USS), however the underlying mechanosensitive mediators are not fully understood. The endothelial glycocalyx is disrupted in arterial areas exposed to disturbed blood flow that also exhibit enhanced oxidative stress leading to atherogenesis. We investigated the contribution of glycocalyx sialic acids (SIA) to Nrf2 signaling in human endothelial cells (EC) exposed to atheroprotective USS or atherogenic low oscillatory shear stress (OSS). Cells exposed to USS exhibited a thicker glycocalyx and enhanced turnover of SIA which was reduced in cells cultured under OSS. Physiological USS, but not disturbed OSS, enhanced Nrf2-mediated expression of antioxidant enzymes, which was attenuated following SIA cleavage with exogenous neuraminidase. SIA removal disrupted kinase signaling involved in the nuclear accumulation of Nrf2 elicited by USS and promoted mitochondrial reactive oxygen species accumulation. Notably, knockdown of the endogenous sialidase NEU1 potentiated Nrf2 target gene expression, directly implicating SIA in regulation of Nrf2 signaling by USS. In the absence of SIA, deficits in Nrf2 responses to physiological flow were also associated with a pro-inflammatory EC phenotype. This study demonstrates that the glycocalyx modulates endothelial redox state in response to shear stress and provides the first evidence of an atheroprotective synergism between SIA and Nrf2 antioxidant signaling. The endothelial glycocalyx therefore represents a potential therapeutic target against EC dysfunction in cardiovascular disease and redox dyshomeostasis in ageing.

PD-L1 Expression in Extramammary Paget Disease: A Case Series.

ABSTRACT: The PD-1/PD-L1 pathway plays a critical role in the physiologic inhibition and modulation of the immune response in normal tissue. Many tumors evade immune detection and response by upregulating PD-L1 expression. Humanized monoclonal PD-1 and PD-L1 antibodies have proven as both tolerable and effective treatment in many neoplasms. Extramammary Paget disease (EMPD) is a deformative and debilitating cutaneous malignancy in which definitive treatment options are limited with high recurrence rates after surgical excision. To the best of our knowledge, there is little published information regarding EMPD and PD-L1 expression. We evaluated 18 EMPD surgical pathology cases for tumor cell and tumor-associated inflammatory (TAI) cell PD-L1 expression. We identified PD-L1 tumor cell expression in 3 (17%) of the cases: 2 of 4 invasive cases (50%) and 1 of 14 (7%) noninvasive cases. One invasive case had lymph nodal metastasis with PD-L1 tumor cell expression. The host inflammatory response intensity and PD-L1 expression were variable in cases negative for tumor cell PD-L1 expression; however, a marked inflammatory response and TAI PD-L1 expression were present in all cases positive for tumor cell PD-L1 expression. In conclusion, 1 in 14 (7%) in situ EMPD cases showed tumor cell PD-L1 expression and 2 of 4 invasive cases (50%) showed tumor cell PD-L1 expression. TAI cells were more often positive (83%) than tumor cells (17%) for PD-L1 expression.

The effect of 8 plant extracts and combinations on post-prandial blood glucose and insulin responses in healthy adults: a randomized controlled trial.

BACKGROUND: Lower post-prandial glucose (PPG) and insulin (PPI) responses to foods are associated with reduced diabetes risk and progression. Several plant extracts have been proposed to reduce PPG or PPI by inhibiting enzymes or transporters involved in carbohydrate digestion and uptake. This study evaluates a range of such extracts, consumed with a carbohydrate load, for their effects on PPG, PPI and indicators of (gastrointestinal) tolerance. METHODS: Interventions were extracts of mulberry fruit (MFE, 1.5 g), mulberry leaf (MLE, 1.0 g), white bean (WBE, 3.0 g), apple (AE, 2.0 g), elderberry (EE, 2.0 g), turmeric (TE, 0.18 g), AE + TE, and EE + TE. Each of these 8 individual extracts or combinations were added to a rice porridge containing ~ 50 g available carbohydrate (control). In a within-subject (randomised, balanced incomplete block) design, individual subjects received the control and a subset of 4 of the 8 extracts or combinations. Participants were 72 apparently healthy adults (mean [SD] age 31.2 [5.5] yr, body mass index 22.1 [2.0] kg/m2). The primary outcome was the percentage change in 2-h PPG (positive incremental area under the curve) relative to control. Secondary measures were the 2-h PPI response, 7-h breath hydrogen, measures of gastrointestinal discomfort, and urine glucose. RESULTS: In the 65 subjects who completed the control and at least one intervention treatment, additions of AE, MFE and MLE produced statistically significant reductions in PPG vs control (p < 0.05; mean effect - 24.1 to - 38.1%). All extracts and combinations except TE and WBE significantly reduced PPI (p < 0.01; mean effect - 17.3% to - 30.4%). Rises in breath hydrogen > 10 ppm were infrequent, but statistically more frequent than control only for MLE (p = 0.02). Scores for gastrointestinal discomfort were extremely low and not different from control for any treatment, and no glucosuria was observed. CONCLUSIONS: Additions of AE, MFE and MLE to rice robustly reduced PPG and PPI. EE significantly reduced only PPI, while TE and WBE showed no significant efficacy for PPG or PPI. Breath hydrogen responses to MLE suggest possible carbohydrate malabsorption at the dose used, but there were no explicit indications of intolerance to any of the extracts. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04258501. Registered 6 February 2020 - Retrospectively registered.

UVA irradiation increases ferrous iron release from human skin fibroblast and endothelial cell ferritin: Consequences for cell senescence and aging.

UVA irradiation of human dermal fibroblasts and endothelial cells induces an immediate transient increase in cytosolic Fe(II), as monitored by the fluorescence Fe(II) reporters, FeRhonox1 in cytosol and MitoFerroGreen in mitochondria. Both superoxide dismutase (SOD) inhibition by tetrathiomolybdate (ATM) and catalase inhibition by 3-amino-1, 2, 4-triazole (ATZ) increase and prolong the cytosolic Fe(II) signal after UVA irradiation. SOD inhibition with ATM also increases mitochondrial Fe(II). Thus, mitochondria do not source the UV-dependent increase in cytosolic Fe(II), but instead reflect and amplify raised cytosolic labile Fe(II) concentration. Hence control of cytosolic ferritin iron release is key to preventing UVA-induced inflammation. UVA irradiation also increases dermal endothelial cell H2O2, as monitored by the adenovirus vector Hyper-DAAO-NES(HyPer). These UVA-dependent changes in intracellular Fe(II) and H2O2 are mirrored by increases in cell superoxide, monitored with the luminescence probe L-012. UV-dependent increases in cytosolic Fe(II), H2O2 and L-012 chemiluminescence are prevented by ZnCl2 (10 µM), an effective inhibitor of Fe(II) transport via ferritin's 3-fold channels. Quercetin (10 µM), a potent membrane permeable Fe(II) chelator, abolishes the cytosolic UVA-dependent FeRhonox1, Fe(II) and HyPer, H2O2 and increase in MitoFerroGreen Fe(II) signals. The time course of the quercetin-dependent decrease in endothelial H2O2 correlates with the decrease in FeRhox1 signal and both signals are fully suppressed by preloading cells with ZnCl2. These results confirm that antioxidant enzyme activity is the key factor in controlling intracellular iron levels, and hence maintenance of cell antioxidant capacity is vitally important in prevention of skin aging and inflammation initiated by labile iron and UVA.

Mucosal Eosinophilia Is an Independent Predictor of Vedolizumab Efficacy in Inflammatory Bowel Diseases.

BACKGROUND: Peripheral and mucosal eosinophilia may be associated with more aggressive disease in inflammatory bowel disease (IBD) patients. Vedolizumab blocks T lymphocytes, eosinophil adhesion, and extravasation in the gastrointestinal tract. It is not known if mucosal eosinophilia is a predictor for the therapeutic efficacy of vedolizumab. METHODS: This was a retrospective cohort study of IBD patients with ileal or colonic biopsies who were off steroids before starting vedolizumab. Biopsies were rereviewed by pathologists, and mean eosinophil density was quantified. Patient characteristics and steroid-free clinical response 6 months after beginning vedolizumab were determined. Features were compared between nonresponders and responders, and multivariable logistic regression was performed to identify predictors of clinical response. RESULTS: Of 251 IBD patients starting vedolizumab therapy, 65 patients (48% Crohn's disease, 52% ulcerative colitis) met inclusion criteria. All IBD patients not responding to vedolizumab were more likely to have a higher baseline mean eosinophil count (340 ± 156 vs 236 ± 124; P = 0.004), be previously exposed to an anti-TNF (96% vs 56%; P = 0.001), and be male (58% vs 28%; P = 0.02). Mean eosinophil counts were significantly increased in colonic biopsies in UC nonresponders (438 ± 149 vs 299 ± 145; P = 0.01). A similar trend was seen in CD nonresponders. On multivariable analysis, colonic eosinophil density and prior anti-TNF exposure-and the combination of both-were independent predictors of response. CONCLUSION: In ulcerative colitis, colonic eosinophilia and prior anti-TNF exposure were independent predictors of 6-month clinical nonresponse to vedolizumab. Mucosal eosinophil density as a novel biomarker should be explored in larger patient cohorts.Aside from the previous anti-TNF exposure, eosinophil density in the colon of patients with UC is a negative predictor for a steroid-free long-term response to vedolizumab. The degree colonic eosinophilia may be a novel biomarker that should be further explored.

Hyperspectral imaging for non-destructive prediction of fermentation index, polyphenol content and antioxidant activity in single cocoa beans.

The aim of the current work was to use hyperspectral imaging (HSI) in the spectral range 1000-2500 nm to quantitatively predict fermentation index (FI), total polyphenols (TP) and antioxidant activity (AA) of individual dry fermented cocoa beans scanned on a single seed basis, in a non-destructive manner. Seventeen cocoa bean batches were obtained and 10 cocoa beans were used from each batch. PLS regression models were built on 170 samples. The developed HSI predictive models were able to quantify three quality-related parameters with sufficient performance for screening purposes, with external validation R2 of 0.50 (RMSEP = 0.27, RPD = 1.40), 0.70 (RMSEP = 34.1 mg ferulic acid g-1, RPD = 1.77) and 0.74 (60.0 mmol Trolog kg-1, RPD = 1.91) for FI, TP and AA, respectively. The calibrations were subsequently applied at a single bean and pixel level, so that the distribution was visualised within and between single seeds (chemical images). HSI is thus suggested as a promising approach to estimate cocoa bean composition rapidly and non-destructively, thus offering a valid tool for food inspection and quality control.

Homoisoflavonoids Are Potent Glucose Transporter 2 (GLUT2) Inhibitors: A Potential Mechanism for the Glucose-Lowering Properties of Polygonatum odoratum.

Foods of high carbohydrate content such as sucrose or starch increase postprandial blood glucose concentrations. The glucose absorption system in the intestine comprises two components: sodium-dependent glucose transporter-1 (SGLT1) and glucose transporter 2 (GLUT2). Here five sappanin-type (SAP) homoisoflavonoids were identified as novel potent GLUT2 inhibitors, with three of them isolated from the fibrous roots of Polygonatum odoratum (Mill.) Druce. SAP homoisolflavonoids had a stronger inhibitory effect on 25 mM glucose transport (41.6 ± 2.5, 50.5 ± 7.6, 47.5 ± 1.9, 42.6 ± 2.4, and 45.7 ± 4.1% for EA-1, EA-2, EA-3, MOA, and MOB) than flavonoids (19.3 ± 2.2, 11.5 ± 3.7, 16.4 ± 2.4, 5.3 ± 1.0, 3.7 ± 2.2, and 18.1 ± 2.4% for apigenin, luteolin, quercetin, naringenin, hesperetin, and genistein) and phloretin (28.1 ± 1.6%) at 15 µM. SAP homoisoflavonoids and SGLT1 inhibitors were found to synergistically inhibit the uptake of glucose using an in vitro model comprising Caco-2 cells. This observed new mechanism of the glucose-lowering action of P. odoratum suggests that SAP homoisoflavonoids and their combination with flavonoid monoglucosides show promise as naturally functional ingredients for inclusion in foods and drinks designed to control postprandial glucose levels.

Sulforaphane Delays Fibroblast Senescence by Curbing Cellular Glucose Uptake, Increased Glycolysis, and Oxidative Damage.

Increased cell senescence contributes to the pathogenesis of aging and aging-related disease. Senescence of human fibroblasts in vitro may be delayed by culture in low glucose concentration. There is also accumulating evidence of senescence delay by exposure to dietary bioactive compounds that activate transcription factor Nrf2. The mechanism of cell senescence delay and connection between these responses is unknown. We describe herein that the cruciferous vegetable-derived metabolite, sulforaphane (SFN), activates Nrf2 and delays senescence of human MRC-5 and BJ fibroblasts in vitro. Cell senescence is associated with a progressive and marked increased rate of glucose metabolism through glycolysis. This increases mitochondrial dysfunction and overwhelms defences against reactive metabolites, leading to increasing proteomic and genomic oxidative damage. Increased glucose entry into glycolysis in fibroblast senescence is mainly mediated by increased hexokinase-2. SFN delayed senescence by decreasing glucose metabolism on the approach to senescence, exhibiting a caloric restriction mimetic-like activity and thereby decreased oxidative damage to cell protein and DNA. This was associated with increased expression of thioredoxin-interacting protein, curbing entry of glucose into cells; decreased hexokinase-2, curbing entry of glucose into cellular metabolism; decreased 6-phosphofructo-2-kinase, downregulating formation of allosteric enhancer of glycolysis fructose-2,6-bisphosphate; and increased glucose-6-phosphate dehydrogenase, downregulating carbohydrate response element- (ChRE-) mediated transcriptional enhancement of glycolysis by Mondo/Mlx. SFN also enhanced clearance of proteins cross-linked by transglutaminase which otherwise increased in senescence. This suggests that screening of compounds to counter senescence-associated glycolytic overload may be an effective strategy to identify compounds with antisenescence activity and health beneficial effects of SFN in longevity may involve delay of senescence through glucose and glycolytic restriction response.

A Case of Severe Cardiac Sarcoidosis with Minimal Pulmonary Involvement: A Case Report with Literature Review.

Sarcoidosis is a granulomatous disease of unknown etiology. Although sarcoidosis is a systemic disease, there appears to be a predilection for involvement of certain organs. The pulmonary system is the most commonly affected system among all racial groups. Cardiac and respiratory complications are the leading causes of death due to sarcoidosis and in certain patient populations about half of these deaths are attributed to cardiac sarcoidosis. There are few autopsy case reports of cardiac sarcoidosis with minimal respiratory involvement making this case report relevant to the importance of the recognition and awareness of this entity. Acad Forensic Pathol. 2018 8(2): 407-415.

Bile Cast Nephropathy in Cirrhotic Patients: Effects of Chronic Hyperbilirubinemia.

OBJECTIVES: The aim of this study was to determine the prevalence of bile cast nephropathy (BCN) in autopsied cirrhotic patients and to correlate BCN with clinical and laboratory data to direct attention to this underrecognized renal complication of liver failure. METHODS: We assessed 114 autopsy cases of cirrhosis for the presence of renal intratubular bile casts using Hall stain for bile. Presence of bile casts was correlated with etiology of cirrhosis, clinical and laboratory data, and histologic findings. RESULTS: Bile casts were identified in 55% of cases. The most common etiology of cirrhosis was hepatitis C virus (HCV) infection (52%), and serum creatinine ( P = .02) and serum urea nitrogen ( P = .01) were significantly higher in the Hall-positive group. Conjugated bilirubin was below 20 mg/dL in 90%, and levels below 10 mg/dL were noted in 80% of cases. CONCLUSIONS: To our knowledge, this is the largest study of BCN in human subjects and a first report describing the association of BCN with HCV-related cirrhosis. We demonstrated that in the face of protracted chronic hyperbilirubinemia, bile casts are formed at much lower bilirubin levels than previously thought. Furthermore, we proposed an algorithm to assist in better identification of bile casts.

Isolation and characterisation of 13 pterosins and pterosides from bracken (Pteridium aquilinum (L.) Kuhn) rhizome.

Systematic phytochemical investigations of the underground rhizome of Pteridium aquilinum (L.) Kuhn (Dennstaedtiaceae) afforded thirty-five pterosins and pterosides. By detailed analysis of one- and two-dimensional nuclear magnetic resonance spectroscopy, circular dichroism (CD) and high-resolution mass spectrometric data, thirteen previously undescribed pterosins and pterosides have been identified. Interestingly, for the first time 12-O-ß-D-glucopyranoside substituted pterosins, rhedynosides C and D, and the sulfate-containing pterosin, rhedynosin H, alongside the two known compounds, histiopterosin A and (2S)-pteroside A2, were isolated from the rhizomes of subsp. aquilinum of bracken. In addition, six-membered cyclic ether pterosins and pterosides, rhedynosin A and rhedynoside A, are the first examples of this type of pterosin-sesquiterpenoid. Additionally, the three previously reported compounds (rhedynosin I, (2S)-2-hydroxymethylpterosin E and (2S)-12-hydroxypterosin A) were obtained for the first time from plants as opposed to mammalian metabolic products. Single crystal X-ray diffraction analysis was applied to the previously undescribed compounds (2R)-rhedynoside B, (2R)-pteroside B and (2S)-pteroside K, yielding the first crystal structures for pterosides, and three known pterosins, (2S)-pterosin A, trans-pterosin C and cis-pterosin C. Rhedynosin C is the only example of the cyclic lactone pterosins with a keto group at position C-14. Six selected pterosins ((2S)-pterosin A, (2R)-pterosin B and trans-pterosin C) and associated glycosides ((2S)-pteroside A, (2R)-pteroside B and pteroside Z) were assessed for their anti-diabetic activity using an intestinal glucose uptake assay; all were found to be inactive at 300 µM.

Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation.

Risk of insulin resistance, impaired glycemic control, and cardiovascular disease is excessive in overweight and obese populations. We hypothesized that increasing expression of glyoxalase 1 (Glo1)-an enzyme that catalyzes the metabolism of reactive metabolite and glycating agent methylglyoxal-may improve metabolic and vascular health. Dietary bioactive compounds were screened for Glo1 inducer activity in a functional reporter assay, hits were confirmed in cell culture, and an optimized Glo1 inducer formulation was evaluated in a randomized, placebo-controlled crossover clinical trial in 29 overweight and obese subjects. We found trans-resveratrol (tRES) and hesperetin (HESP), at concentrations achieved clinically, synergized to increase Glo1 expression. In highly overweight subjects (BMI >27.5 kg/m(2)), tRES-HESP coformulation increased expression and activity of Glo1 (27%, P < 0.05) and decreased plasma methylglyoxal (-37%, P < 0.05) and total body methylglyoxal-protein glycation (-14%, P < 0.01). It decreased fasting and postprandial plasma glucose (-5%, P < 0.01, and -8%, P < 0.03, respectively), increased oral glucose insulin sensitivity index (42 mL ⋅ min(-1) ⋅ m(-2), P < 0.02), and improved arterial dilatation Δbrachial artery flow-mediated dilatation/Δdilation response to glyceryl nitrate (95% CI 0.13-2.11). In all subjects, it decreased vascular inflammation marker soluble intercellular adhesion molecule-1 (-10%, P < 0.01). In previous clinical evaluations, tRES and HESP individually were ineffective. tRES-HESP coformulation could be a suitable treatment for improved metabolic and vascular health in overweight and obese populations.