Targeting tumor-associated MUC1 overcomes anoikis-resistance in pancreatic cancer.

The third leading cause of cancer-related deaths in the United States is pancreatic cancer, more than 95% of which is pancreatic ductal adenocarcinoma (PDA). The incidence rate of PDA nearly matches its mortality rate and the best treatment till date is surgical resection for which only 25% are eligible. Tumor recurrence and metastasis are the main causes of cancer-related mortality. MUC1 is a transmembrane glycoprotein expressed on most epithelial cells. It is overexpressed and aberrantly glycosylated in cancer and is known as tumor-associated MUC1 (tMUC1). More than 80% of PDAs express tMUC1. A monoclonal antibody called TAB004 has been developed specifically against human tMUC1 extracellular domain. We report that treatment with TAB004 significantly reduced the colony forming potential of multiple PDA cell lines while sparing normal pancreatic epithelial cell line. Binding of TAB004 to tMUC1 compromised desmosomal integrity, induced ER stress and anoikis in PDA cells. The mechanisms underlying TAB004's antitumor effects were found to be reduced activation of the EGFR-PI3K signaling pathway, and degradation of tMUC1, thereby reducing expression of its transcriptional targets, c-Src and c-Myc. This reduction in oncogenic signaling triggered anoikis as indicated by reduced expression of antiapoptotic proteins, PTRH2 and BCL2. TAB004 treatment slowed the growth of PDA xenograft compared to IgG control and enhanced survival of mice when combined with 5-FU. Since TAB004 significantly reduced colony forming potential and triggered anoikis in the PDA cells, we suggest that it could be used as a potential prophylactic agent to curb tumor relapse after surgery, prevent metastasis and help increase the efficacy of chemotherapeutic agents.

Cooking affects pork proteins in vitro rate of digestion due to different structural and chemical modifications.

The effect of thermal processing on the in vitro digestibility of pork proteins was studied. Raw samples were considered the control group, while the thermal treatments included 58, 80, 98 and 160 °C for 72 min, 118 °C for 8 min and 58 °C for 17 h, resembling a range of different cooking procedures. Samples were subsequently subjected to pepsin digestion at pH 3.00 in the gastric phase followed by trypsin and α-chymotrypsin at pH 8.00 in the intestinal phase. Pork cooked at 58 °C for 72 min had a significantly higher pepsin digestibility rate than meat cooked at 80 °C or 160 °C. The trend was similar in the intestinal phase, with samples cooked at 58 °C for 72 min having enhanced digestion rate over other treatments after 120 min of digestion. A PLS model pointed out to an inverse relationship between in vitro proteolysis rate and variables like Maillard reaction compounds or protein structural changes.

Beyond carbon flux partitioning: Carbon allocation and nonstructural carbon dynamics inferred from continuous fluxes.

Carbon (C) allocation and nonstructural carbon (NSC) dynamics play essential roles in plant growth and survival under stress and disturbance. However, quantitative understanding of these processes remains limited. Here we propose a framework where we connect commonly measured carbon cycle components (eddy covariance fluxes of canopy CO2 exchange, soil CO2 efflux, and allometry-based biomass and net primary production) by a simple mass balance model to derive ecosystem-level NSC dynamics (NSCi ), C translocation (dCi ), and the biomass production efficiency (BPEi ) in above- and belowground plant (i = agp and bgp) compartments. We applied this framework to two long-term monitored loblolly pine (Pinus taeda) plantations of different ages in North Carolina and characterized the variations of NSC and allocation in years under normal and drought conditions. The results indicated that the young stand did not have net NSC flux at the annual scale, whereas the mature stand stored a near-constant proportion of new assimilates as NSC every year under normal conditions, which was comparable in magnitude to new structural growth. Roots consumed NSC in drought and stored a significant amount of NSC post drought. The above- and belowground dCi and BPEi varied more from year to year in the young stand and approached a relatively stable pattern in the mature stand. The belowground BPEbgp differed the most between the young and mature stands and was most responsive to drought. With the internal C dynamics quantified, this framework may also improve biomass production estimation, which reveals the variations resulting from droughts. Overall, these quantified ecosystem-scale dynamics were consistent with existing evidence from tree-based manipulative experiments and measurements and demonstrated that combining the continuous fluxes as proposed here can provide additional information about plant internal C dynamics. Given that it is based on broadly available flux data, the proposed framework is promising to improve the allocation algorithms in ecosystem C cycle models and offers new insights into observed variability in soil-plant-climate interactions.

Acute monocyte pro inflammatory response predicts higher positive to negative acute phase reactants ratio and severe hemostatic derangement in dengue fever.

PURPOSE: The present study was intended to investigate whether monocyte immune activation shapes plasma positive to negative acute phase reactants (APRs) ratio and predicts disease severity in dengue infection. METHODS: Serum level of ferritin, ceruloplasmin and transferrin was measured by means of electrochemiluminescence and immunoturbidimetry, respectively. Gene expression and plasma level for TNF-α, IL-6 and IL1-ß was measured by means of RT-qPCR and ELISA. RESULTS: A significant increased serum ferritin to transferrin [6.6 (3-11.7) vs 3.4 (1.9-6.1)] and ceruloplasmin to transferrin ratio [0.48 (0.21-0.87) vs 0.22 (0.13-0.43)] has been detected among the subjects with secondary dengue infection (SDENI) compared to primarily infected (PDENI) subjects (P < 0.001). Significant increased expression for CD14+ monocyte TNF-α, IL-6 and IL-1ß has been detected in SDENI patients (vs PDENI and control, P < 0.001). Plasma ferritin to transferrin ratio was found in a significant association with high level of plasma TNF-α [ρ = 0.6522, 95% CI (0.4714-0.7805)], IL-6 [ρ = 0.6181, 95% CI (0.4257-0.7571)] and IL- 1ß [ρ = 0.4119, 95% CI (0.1689-0.6077)] level among SDENI patients at 5th day time point after progression of the disease, with significantly low platelet [P < 0.001] and prolonging prothrombin time [P < 0.001] compared to control and PDENI subjects, respectively. CONCLUSION: Acute proinflammatory cytokine response is significantly associated with increased positive to negative APRs ratio in SDENI patients, which predicts intense immune activation, and renders SDENI patients extremely susceptible to hemostatic derangement.

Substantial hysteresis in emergent temperature sensitivity of global wetland CH4 emissions.

Wetland methane (CH4) emissions ([Formula: see text]) are important in global carbon budgets and climate change assessments. Currently, [Formula: see text] projections rely on prescribed static temperature sensitivity that varies among biogeochemical models. Meta-analyses have proposed a consistent [Formula: see text] temperature dependence across spatial scales for use in models; however, site-level studies demonstrate that [Formula: see text] are often controlled by factors beyond temperature. Here, we evaluate the relationship between [Formula: see text] and temperature using observations from the FLUXNET-CH4 database. Measurements collected across the globe show substantial seasonal hysteresis between [Formula: see text] and temperature, suggesting larger [Formula: see text] sensitivity to temperature later in the frost-free season (about 77% of site-years). Results derived from a machine-learning model and several regression models highlight the importance of representing the large spatial and temporal variability within site-years and ecosystem types. Mechanistic advancements in biogeochemical model parameterization and detailed measurements in factors modulating CH4 production are thus needed to improve global CH4 budget assessments.

Reply to the letter from Dr. Pirjo Pärnänen et al.

Nutraceuticals could be used to increase immunity against viral infections and therefore more research should be done on them to better manage COVID-19 and future pandemics.

Mucin signature as a potential tool to predict susceptibility to COVID-19.

The Corona Virus Infectious Disease-19 (COVID-19) pandemic has played havoc on both the global health and economy. It is necessary to find a molecular signature that differentiates between low-risk and high-risk individuals. Pathogens, including viruses of the upper respiratory tract, utilize mucin proteins to enter into host cells. Mucins are critical components of innate immunity and also play important roles in infectious disease progression. Their expression is regulated by different cytokines during infection and inflammation. A comparison of mucin signatures between an asymptomatic versus symptomatic and between patients with mild versus severe symptoms could help identify other important proteins involved in the pathology of this new virus. Recent studies on the pathogenicity of the SARS-CoV-2 have found receptors that help its entry into the cells. In this review, we present an overview of how mucins are connected to the pathogenicity of the virus and propose that studying the glycome and mucin signature may lead to the development of a biomarker in predicting the susceptibility, progression, and response to therapy in COVID-19 patients.

Automatic identification of clinically relevant regions from oral tissue histological images for oral squamous cell carcinoma diagnosis.

Identification of various constituent layers such as epithelial, subepithelial, and keratin of oral mucosa and characterization of keratin pearls within keratin region as well, are the important and mandatory tasks for clinicians during the diagnosis of different stages in oral cancer (such as precancerous and cancerous). The architectural variations of epithelial layers and the presence of keratin pearls, which can be observed in microscopic images, are the key visual features in oral cancer diagnosis. The computer aided tool doing the same identification task would certainly provide crucial aid to clinicians for evaluation of histological images during diagnosis. In this paper, a two-stage approach is proposed for computing oral histology images, where 12-layered (7 × 7×3 channel patches) deep convolution neural network (CNN) are used for segmentation of constituent layers in the first stage and in the second stage the keratin pearls are detected from the segmented keratin regions using texture-based feature (Gabor filter) trained random forests. The performance of the proposed computing algorithm is tested in our developed oral cancer microscopic image database. The proposed texture-based random forest classifier has achieved 96.88% detection accuracy for detection of keratin pearls.

Advanced glycation end products, protein crosslinks and post translational modifications in pork subjected to different heat treatments.

The aim of the study was to characterize Maillard reactions in meat under different cooking treatments. Considered temperature-time combinations included raw samples (control), 58, 80, 98 and 160 °C for 72 min, 118 °C for 8 min and 58 °C for 17 h. Furosine, a marker for heat treatment, was detected in all groups with roasting having a 4-fold increase over the control. Sous-vide treatment at 80 °C, boiling and autoclaving also contribute to a significant increase in furosine. Nɛ-carboxymethyllysine, an indicator for advanced glycation end products, showed negligible amount in control, but increased with cooking temperature, with oven samples showing the highest values. A similar increasing trend was observed in lanthionine, covalently bonded protein crosslinks, which arises due to severe thermal regimes. Simultaneously, glycation and deamidation formation were tracked in meat proteins through peptidomics to highlight residue level changes that might affect nutrient value in processed muscle based foods.

Dairy Fats and Cardiovascular Disease: Do We Really Need to be Concerned?

Cardiovascular diseases (CVD) remain a major cause of death and morbidity globally and diet plays a crucial role in the disease prevention and pathology. The negative perception of dairy fats stems from the effort to reduce dietary saturated fatty acid (SFA) intake due to their association with increased cholesterol levels upon consumption and the increased risk of CVD development. Institutions that set dietary guidelines have approached dairy products with negative bias and used poor scientific data in the past. As a result, the consumption of dairy products was considered detrimental to our cardiovascular health. In western societies, dietary trends indicate that generally there is a reduction of full-fat dairy product consumption and increased low-fat dairy consumption. However, recent research and meta-analyses have demonstrated the benefits of full-fat dairy consumption, based on higher bioavailability of high-value nutrients and anti-inflammatory properties. In this review, the relationship between dairy consumption, cardiometabolic risk factors and the incidence of cardiovascular diseases are discussed. Functional dairy foods and the health implications of dairy alternatives are also considered. In general, evidence suggests that milk has a neutral effect on cardiovascular outcomes but fermented dairy products, such as yoghurt, kefir and cheese may have a positive or neutral effect. Particular focus is placed on the effects of the lipid content on cardiovascular health.

Pork proteins oxidative modifications under the influence of varied time-temperature thermal treatments: A chemical and redox proteomics assessment.

The impact of thermal processing on meat proteins oxidation was investigated. Cooking treatments included 58 °C for either 72 min or 17 h (mimicking low temperature-long time sous vide cooking), 80, 98 and 160 °C for 72 min (mimicking common cooked meat products, stewing and roasting, respectively) and 118 °C for 8 min (autoclaving). Tryptophan degradation, fluorescent oxidation products, free thiol content and α-aminoadipic and γ-glutamic semialdehydes were tracked. For all of them, there was a consistent trend to increased levels of oxidative damage with higher cooking temperatures and longer cooking times, although the extent varied from one indicator to another. Through proteomics, peptide oxidative modifications like carbonylation, malonaldehyde adducts and hydroxykynurenin (tryptophan oxidation products) were also detected at residue level. Our findings indicate that protein oxidation is dependent upon the heat treatment, which point out to a different effect on the nutritional quality of proteins in meat products.

Tracking hydrophobicity state, aggregation behaviour and structural modifications of pork proteins under the influence of assorted heat treatments.

Structural modifications of pork proteins under an assortment of industrial heat treatments were studied. With raw as control, assorted heat treatments involved were 58, 80, 98 and 160°C for 72min, 118°C for 8min and 58°C for 17h, resembling most common processing procedures. Protein denaturation, surface protein hydrophobicity state and protein aggregation behaviour were investigated. Modifications and molecular chemistry in protein structures were tracked by Fourier Transform Infrared Spectroscopy in order to extract relative proportions of ß-sheet, α-helix and residual conformations. In comparison to uncooked samples, cooked ones showed more than two-fold increase in hydrophobicity and larger particles. Thermograms from differential scanning calorimetry showed endothermic transitions (positive enthalpy) indicating a different pattern of protein denaturation as a result of varied cooking temperatures and cooking times. Deconvolution and curve fitting procedures (R2=0.99) provided information on rise of the ß-sheet to α-helix ratio that further confirmed aggregation with thermal rise and longer cooking time.

The Satiating Properties of Pork are not Affected by Cooking Methods, Sousvide Holding Time or Mincing in Healthy Men-A Randomized Cross-Over Meal Test Study.

Low temperature long time (LTLT) sous-vide cooking may modify meat proteins in a way that could promote satiety. We investigated the effects of (1) cooking method (LTLT 58 °C vs. oven 160 °C), (2) LTLT holding time (17 h vs. 72 min), and (3) pork structure, LTLT 58 °C for 17 h (minced vs. roast) on appetite regulation and in vitro protein digestibility. In a cross-over study, 37 healthy men consumed four meals containing pork: LTLT-cooked roast, 58 °C, 72 min; LTLT-cooked roast, 58 °C, 17 h; and, oven-cooked roast, 160 °C to a core temperature of 58 °C and LTLT-cooked minced patties, 58 °C, 17 h. Ad libitum energy intake (EI) after three hours was the primary endpoint. Moreover, subjective appetite sensations were assessed. Protein digestibility was determined in an in vitro simulated digestion model. Ad libitum EI did not differ between the meals. Furthermore, appetite ratings were not clearly affected. LTLT cooking for 72 min increased the proteolytic rate in the early gastric phase during digestion as compared to LTLT cooking for 17 h or oven cooking. In conclusion, LTLT cooking, LTLT holding time, and pork structure did not affect ad libitum EI. However, LTLT cooking at 58 °C for 72 min seemed to enhance in vitro protein digestibility.

Hyperlipidemia-Mediated Increased Advanced Lipoxidation End Products Formation, an Important Factor Associated with Decreased Erythrocyte Glucose-6-Phosphate Dehydrogenase Activity in Mild Nonproliferative Diabetic Retinopathy.

OBJECTIVES: The present study aimed to evaluate the role of hyperlipidemia in increased formation of advanced lipoxidation end products (ALEs) and to evaluate whether there is any relationship between ALEs generation and erythrocyte glucose-6-phosphate dehydrogenase (G6PD) activity in cases of mild nonproliferative diabetic retinopathy (MNPDR). METHODS: In this study, we enrolled 100 patients with type 2 diabetes and MNPDR, 100 subjects with type 2 diabetes but without retinopathy (DNR) and 90 normal individuals without diabetes as healthy controls (HCs). Erythrocyte nicotinamide dinucleotide phosphate (NADPH), G6PD activity, serum total cholesterol, low- and high-density lipoprotein (LDL, HDL) and triglyceride levels were determined by photometric assay. Serum malondialdehyde (MDA) protein adduct and hexanoyl-lysine (HEL) were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: A robust linear relationship was observed between MDA protein adduct and LDL or cholesterol or triglyceride levels, and HEL and LDL or cholesterol or triglyceride levels in subjects with MNPDR (p=0.0001). A significant inverse association was observed between erythrocyte G6PD activity and serum MDA protein adductor HEL levels in subjects with MNPDR (p=0.0001). CONCLUSIONS: Hyperlipidemia is an important factor that is associated with increased ALEs formation in persons with MNPDR. Increased ALEs generation was associated with decreased G6PD activity and low NADPH levels in cases of MNPDR, suggesting their detrimental role in the occurrence of early NPDR.

Adenomyoepithelial Adenosis of Breast: A Rare Case Report.

Myoepithelial cells of the breast and their hyperplasia is found in many benign conditions resulting in a spectrum of lesions of myoepitheliosis to myoepithelial carcinoma. We present a rare case of adenomyoepithelial adenosis in a 17-year-old female who presented with a palpable right breast lump. Although considered benign, adenomyoepithelial lesions have a high chance of recurrence due to inadequate excision. Recurrence and even metastasis are therefore important issues in the follow-up of adenomyoepithelial lesions.

Predicting full thickness skin sensitization using a support vector machine.

To assess the public's propensity for allergic contact dermatitis (ACD), many alternatives to in vivo chemical screening have been developed which generally incorporate a small panel of cell surface and secreted dendritic cell biomarkers. However, given the underlying complexity of ACD, one cell type and limited cellular metrics may be insufficient to predict contact sensitizers accurately. To identify a molecular signature that can further characterize sensitization, we developed a novel system using RealSkin, a full thickness skin equivalent, in co-culture with MUTZ-3 derived Langerhan's cells. This system was used to distinguish a model moderate pro-hapten isoeugenol (IE) and a model strong pre-hapten p-phenylenediamine (PPD) from irritant, salicylic acid (SA). Commonly evaluated metrics such as CD86, CD54, and IL-8 secretion were assessed, in concert with a 27-cytokine multi-plex screen and a functional chemotaxis assay. Data were analyzed with feature selection methods using ANOVA, hierarchical cluster analysis, and a support vector machine to identify the best molecular signature for sensitization. A panel consisting of IL-12, IL-9, VEGF, and IFN-γ predicted sensitization with over 90% accuracy using this co-culture system analysis. Thus, a multi-metric approach that has the potential to identify a molecular signature may be more predictive of contact sensitization.

Oxidative stress-associated neuroretinal dysfunction and nitrosative stress in diabetic retinopathy.

OBJECTIVE: The present study was intended to investigate whether oxidative stress is the key regulator to alter neuroretinal biochemical homeostasis and in turn aggravate the process of diabetic retinopathy by inducing nitrosative stress in the retinal neurovascular unit. METHODS: Peripheral blood mononuclear cell reactive oxygen species level was measured by flow cytometry along with spectrophotometric detection of malondialdehyde (MDA) and glutamate from serum or plasma and a vitreous sample of study groups (i.e. subjects with proliferative diabetic retinopathy [PDR], type 2 diabetes without retinopathy [DNR] and healthy controls [HCs]). Further, nitrosative stress assessment was performed by spectrophotometric and enzyme-linked immunosorbent assay-based detection of serum and vitreous nitrite and nitrotyrosine concentrations, respectively. RESULTS: The plasma glutamate level remains insignificant between subjects with PDR and DNR (p=0.505) or in HC (p=0.1344) individuals. However, serum MDA (p=0.0004), nitrite (p=0.0147) and nitrotyrosine (p=0.0129) were found to be strikingly higher among PDR subjects compared with the DNR group. Significantly increased levels of peripheral blood mononuclear cell reactive oxygen species (p<0.0001), vitreous glutamate (p=0.0009, p<0.0001), MDA (p=0.0058, p=0.0003), nitrite (p=0.0014, p<0.0001) and nitrotyrosine (p=0.0008, p<0.0001) were found in PDR subjects compared with DNR and HC subjects, respectively. CONCLUSIONS: Our observation suggests that oxidative stress is associated with impairment in neuroretinal biochemical homeostasis among PDR subjects, which further augments retinal nitrosative stress and thus worsens the pathogenic process of retinopathy among PDR subjects.

Ovarian haemangioma: A rare case report.

INTRODUCTION: Haemangioma of ovary is a rare tumour. PRESENTATION OF CASE: We report an ovarian haemangioma which presented as an acute abdomen due to an adnexal mass. DISCUSSION: We report an ovarian haemangioma which presented as an acute abdomen due to an adnexal mass. Haemangiomas have been reported in other organs but ovarian haemangioma is a rare tumor, usually asymptomatic and presenting as an incidental finding. Large lesions tend to present clinically with pain. A few cases have been described in the literature. CONCLUSION: Considering their rare occurrence such tumors are a diagnostic challenge.

Association of hyperglycemia mediated increased advanced glycation and erythrocyte antioxidant enzyme activity in different stages of diabetic retinopathy.

AIM: This study aimed to evaluate whether hyperglycemia mediated increased formation of advanced glycation end products (AGEs) was associated with erythrocyte antioxidant enzyme activity in subjects with different stages of diabetic retinopathy (DR). METHODS: Serum level of AGEs was determined by enzyme linked immunosorbent assay. Erythrocyte superoxide dismutase (SOD), glutathione reductase (GR) and catalase activity were estimated by enzymatic reaction based spectrophotometric assay in patients with type 2 diabetes with proliferative diabetic retinopathy (PDR), non-proliferative diabetic retinopathy (NPDR) and no retinopathy (DNR) and also in healthy non-diabetic controls (HC). RESULT: Erythrocyte SOD and GR activity was significantly lower among NPDR (p=0.024, 0.0017, respectively) and PDR (p=0.0003, 0.0001, respectively) subjects compared with DNR individuals. A significant inverse correlation was observed between serum AGEs and erythrocyte SOD or GR activity in DNR (p=0.0019; r=-0.3033, p=0.0021; r=-0.3015, respectively), NPDR (p=0.0001; r=-0.4602, p=0.0003; r=-0.4161, respectively), and PDR (p<0.0001; r=-0.6753, p<0.0001; r=-0.5854, respectively) individuals. CONCLUSION: Poor glycemia may be the key factor enhancing AGE formation, which may be associated with lower erythrocyte SOD and GR activity along with increased catalase activity in DR.

Role of N-ε- carboxy methyl lysine, advanced glycation end products and reactive oxygen species for the development of nonproliferative and proliferative retinopathy in type 2 diabetes mellitus.

PURPOSE: The aim of the present study was to evaluate the collective role of N-epsilon-carboxy methyl lysine (N(ε)-CML), advanced glycation end-products (AGEs), and reactive oxygen species (ROS) for the development of retinopathy among type 2 diabetic subjects. METHODS: Seventy type 2 diabetic subjects with nonproliferative diabetic retinopathy (NPDR), 105 subjects with proliferative diabetic retinopathy (PDR), and 102 patients with diabetes but without retinopathy (DNR) were enrolled in this study. In addition, 95 normal individuals without diabetes were enrolled as healthy controls in this study. Serum and vitreous N(ε)-CML and AGEs were measured by enzyme-linked immunosorbent assay. The peripheral blood mononuclear cell (PBMC) ROS level was measured by flow cytometric analysis. Serum and PBMC total thiols were measured by spectrophotometry. RESULTS: Serum AGEs and N(ε)-CML levels were significantly elevated in subjects with PDR (p<0.0001) and NPDR (p=0.0297 and p<0.0001, respectively) compared to DNR subjects. Further vitreous AGEs and N(ε)-CML levels were found to be significantly high among PDR subjects compared to the control group (p<0.0001). PBMC ROS production was found to be strikingly high among NPDR (p<0.0001) and PDR (p<0.0001) subjects as compared to the DNR group. Serum and PBMC total thiol levels were remarkably decreased in NPDR (p<0.0001 and p=0.0043, respectively) and PDR (p=0.0108 and p=0.0332 respectively) subjects than those were considered as DNR. CONCLUSIONS: Our findings suggest that N(ε)-CML and ROS are the key modulators for the development of nonproliferative retinopathy among poorly controlled type 2 diabetic subjects. Furthermore, AGEs under persistent oxidative stress and the deprived antioxidant state might instigate the pathogenic process of retinopathy from the nonproliferative to the proliferative state.