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The HMGA2 architectural protein functions in a variety of cellular processes, such as cell growth, transcription regulation, neoplastic transformation, and progression. Up-regulation of HMGA2 protein is observed in many tumors and is associated with advanced cancers with poor prognoses. Although the expression and biochemical properties of HMGA2 protein are regulated by microRNA and phosphorylation, it is unknown whether HMGA2 activity can also be regulated by SUMOylation, and that is what is investigated in this report. We identified HMGA2 as a SUMOylation target and showed that the expression of wild-type HMGA2, but not SUMOylation-defective HMGA2(2K/R), selectively lowered the steady-state level of PML protein. Consequently, the HMGA2-elicited PML down-regulation rendered a reduction in the average number of PML nuclear bodies per cell and the volume of PML assembled per PML nuclear body. Using small interfering RNA to suppress endogenous ubiquitin expression and proteasome inhibitor to repress ubiquitin-mediated protein degradation, we showed that HMGA2 confers PML down-regulation through ubiquitin-proteasome–dependent protein degradation. Importantly, arsenic trioxide treatment stimulated HMGA2 SUMOylation, leading to the formation of HMGA2 nuclear foci surrounding PML nuclear bodies and the stimulation of PML degradation. Collectively, our results unveil a previously unrecognized effect by HMGA2 on the modulation of PML protein level, providing a novel mechanism underlying HMGA2 function and underscoring the molecular basis for oncogenic progression by HMGA2. [Mol Cancer Ther 2008;7(4):923–34]

Supplementary Figure 1 from SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome

Purpose: This study aims to address the hypothesis that the high-mobility group A2 (HMGA2), an oncofetal protein, relates to survivability and serves as a prognostic biomarker for colorectal cancer (CRC).Experimental Design: This is a retroprospective multiple center study. The HMGA2 expression level was determined by performing immunohistochemistry on surgical tissue samples of 89 CRCs from a training set and 191 CRCs from a validation set. The Kaplan–Meier analysis and COX proportional hazard model were employed to analyze the survivability.Results: Multivariate logistic analysis indicated that the expression of HMGA2 significantly correlates with distant metastasis in training set (odds ratio, OR = 3.53, 95% CI: 1.37–9.70) and validation set (OR = 6.38, 95% CI: 1.47–43.95). Survival analysis revealed that the overexpression of HMGA2 is significantly associated with poor survival of CRC patients (P < 0.05). The adjusted HRs for overall survival were 2.38 (95% CI: 1.30–4.34) and 2.14 (95% CI: 1.21–3.79) in training and validation sets, respectively. Further investigation revealed that HMGA2 delays the clearance of γ-H2AX in HCT-116 and SW480 cells post γ-irradiation, which supports our finding that CRC patients with HMAG2-positive staining in primary tumors had augmented the efficacy of adjuvant radiotherapy (HR = 0.18, 95% CI: 0.04–0.63).Conclusion: Overexpression of HMGA2 is associated with metastasis and unequivocally occurred in parallel with reduced survival rates of patients with CRC. Therefore, HMGA2 may potentially serve as a biomarker for predicting aggressive CRC with poor survivability and as an indicator for better response of radiotherapy. Clin Cancer Res; 17(8); 2570–80. ©2011 AACR.

Supplementary Figure 1 from Suppression of Nonhomologous End Joining Repair by Overexpression of HMGA2

Supplementary Figure 2 from Suppression of Nonhomologous End Joining Repair by Overexpression of HMGA2

Supplementary Figure 4 from Suppression of Nonhomologous End Joining Repair by Overexpression of HMGA2

Supplementary Figure 5 from Suppression of Nonhomologous End Joining Repair by Overexpression of HMGA2

Supplementary Figure 3 from Suppression of Nonhomologous End Joining Repair by Overexpression of HMGA2

Microplastic pollution has become a worldwide concern in aquatic and terrestrial environments. Microplastics could also enter the food chain, causing potential harm to human health. To facilitate the risk assessment of microplastics to humans, it is critically important to have a reliable analytical technique to detect, quantify, and identify microplastics of various materials, sizes, and shapes from environmental, agricultural, and food matrices. Spectroscopic techniques, mainly vibrational spectroscopy (Raman and infrared), are commonly used techniques for microplastic analysis. This review focuses on recent advances of these spectroscopic techniques for the analysis of microplastics in food. The fundamental, recent technical advances of the spectroscopic techniques and their advantages and limitations were summarized. The food sample pretreatment methods and recent applications for detecting and quantifying microplastics in different types of food were reviewed. In addition, the current technical challenges and future research directions were discussed. It is anticipated that the advances in instrument development and methodology innovation will enable spectroscopic techniques to solve critical analytical challenges in microplastic analysis in food, which will facilitate the reliable risk assessment.

Aims To determine the efficacy of dietary interventions in Heart Failure with preserved Ejection Fraction (HFpEF). Method and results Keyword searches were performed in five bibliographic databases to identify randomized or controlled studies of dietary interventions conducted in HFpEF or mixed heart failure (HF) samples published in the English language. Studies were appraised for bias and synthesized into seven categories based on the similarity of the intervention or targeted population. The quality of the body of evidence was assessed via the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework. Twenty-five unique interventions were identified; 17 were considered for meta-analysis. Most studies were judged to be at high risk of bias. There was moderate-quality evidence that caloric restriction led to clinically meaningful improvements in blood pressure and body weight. There was moderate-quality evidence that carbohydrate restriction resulted in meaningful reductions in blood pressure. There was very low-quality evidence that protein supplementation improved blood pressure and body weight and moderate-quality evidence for clinically meaningful improvements in function. Conclusions While some types of dietary interventions appeared to deliver clinically meaningful change in critical outcomes; the study heterogeneity and overall quality of the evidence make it difficult to make firm recommendations. Greater transparency when reporting the nutritional composition of interventions would enhance the ability to pool studies. Registration PROSPERO CRD42019145388.

BackgroundProne positioning has a beneficial role in coronavirus disease 2019 (COVID-19) patients receiving ventilation but lacks evidence in awake non-ventilated patients, with most studies being retrospective, lacking control populations and information on subjective tolerability.MethodsWe conducted a prospective, single-centre study of prone positioning in awake non-ventilated patients with COVID-19 and non-COVID-19 pneumonia. The primary outcome was change in peripheral oxygenation in prone versus supine position. Secondary outcomes assessed effects on end-tidal CO2, respiratory rate, heart rate and subjective symptoms. We also recruited healthy volunteers to undergo proning during hypoxic challenge.Results238 hospitalised patients with pneumonia were screened; 55 were eligible with 25 COVID-19 patients and three non-COVID-19 patients agreeing to undergo proning – the latter insufficient for further analysis. 10 healthy control volunteers underwent hypoxic challenge. Patients with COVID-19 had a median age of 64 years (interquartile range 53–75). Proning led to an increase in oxygen saturation measured by pulse oximetry (SpO2) compared to supine position (difference +1.62%; p=0.003) and occurred within 10 min of proning. There were no effects on end-tidal CO2, respiratory rate or heart rate. There was an increase in subjective discomfort (p=0.003), with no difference in breathlessness. Among healthy controls undergoing hypoxic challenge, proning did not lead to a change in SpO2 or subjective symptom scores.ConclusionIdentification of suitable patients with COVID-19 requiring oxygen supplementation from general ward environments for awake proning is challenging. Prone positioning leads to a small increase in SpO2 within 10 min of proning though is associated with increased discomfort.

To determine the efficacy of dietary interventions in Heart Failure with preserved Ejection Fraction (HFpEF).Key word searches were performed in five bibliographic databases to identify randomised or controlled studies of dietary interventions conducted in HFpEF or mixed heart failure (HF) samples published in the English language. Studies were appraised for bias and synthesised into seven categories based on similarity of the intervention or targeted population. The quality of the body of evidence was assessed via the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework.Twenty-five unique interventions were identified; seventeen were considered for meta-analysis. Most studies were judged to be at high risk of bias. There was moderate quality evidence that caloric restriction led to clinically meaningful improvements in blood pressure and body weight. There was moderate quality evidence carbohydrate restriction resulted in meaningful reductions in blood pressure. There was very low quality evidence protein supplementation improved blood pressure and body weight and moderate quality evidence for clinically meaningful improvements in function.Whilst some types of dietary interventions appeared to deliver clinically meaningful change in critical outcomes; the study heterogeneity and overall quality of the evidence makes it difficult to make firm recommendations. Greater transparency when reporting nutritional composition of interventions would enhance ability to pool studies.

RationaleImmunosuppression in the tumor microenvironment (TME) is key to the pathogenesis of solid tumors. Tumor cell-intrinsic autophagy is critical for sustaining both tumor cell metabolism and survival. However, the role of autophagy in the host immune system that allows cancer cells to escape immune destruction remains poorly understood. Here, we determined if attenuated host autophagy is sufficient to induce tumor rejection through reinforced adaptive immunity. Furthermore, we determined whether dietary glutamine supplementation, mimicking attenuated host autophagy, is capable of promoting antitumor immunity.MethodsA syngeneic orthotopic tumor model in Atg5+/+ and Atg5flox/flox mice was established to determine the impact of host autophagy on the antitumor effects against mouse malignant salivary gland tumors (MSTs). Multiple cohorts of immunocompetent mice were used for oncoimmunology studies, including inflammatory cytokine levels, macrophage, CD4+, and CD8+ cells tumor infiltration at 14 days and 28 days after MST inoculation. In vitro differentiation and in vivo dietary glutamine supplementation were used to assess the effects of glutamine on Treg differentiation and tumor expansion.ResultsWe showed that mice deficient in the essential autophagy gene, Atg5, rejected orthotopic allografts of isogenic MST cells. An enhanced antitumor immune response evidenced by reduction of both M1 and M2 macrophages, increased infiltration of CD8+ T cells, elevated IFN-γ production, as well as decreased inhibitory Tregs within TME and spleens of tumor-bearing Atg5flox/flox mice. Mechanistically, ATG5 deficiency increased glutamine level in tumors. We further demonstrated that dietary glutamine supplementation partially increased glutamine levels and restored potent antitumor responses in Atg5+/+ mice.ConclusionsDietary glutamine supplementation exposes a previously undefined difference in plasticity between cancer cells, cytotoxic CD8+ T cells and Tregs.

Common genetic variants interact with environmental factors to impact risk of heritable diseases. A notable example of this is a single-nucleotide variant in the Solute Carrier Family 39 Member 8 (SLC39A8) gene encoding the missense variant A391T, which is associated with a variety of traits ranging from Parkinson's disease and neuropsychiatric disease to cardiovascular and metabolic diseases and Crohn's disease. The remarkable extent of pleiotropy exhibited by SLC39A8 A391T raises key questions regarding how a single coding variant can contribute to this diversity of clinical outcomes and what is the mechanistic basis for this pleiotropy. Here, we generate a murine model for the Slc39a8 A391T allele and demonstrate that these mice exhibit Mn deficiency in the colon associated with impaired intestinal barrier function and epithelial glycocalyx disruption. Consequently, Slc39a8 A391T mice exhibit increased sensitivity to epithelial injury and pathological inflammation in the colon. Taken together, our results link a genetic variant with a dietary trace element to shed light on a tissue-specific mechanism of disease risk based on impaired intestinal barrier integrity.

Background Crenezumab, a fully humanized anti-beta-amyloid (Aβ) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of Aβ. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) of crenezumab and its interaction with monomeric Aβ(1–40) and Aβ(1–42) peptides in serum/plasma and cerebrospinal fluid (CSF) samples from the phase II ABBY and BLAZE studies and the phase Ib GN29632 study. Methods In ABBY, BLAZE, and GN29632 studies, patients with mild-to-moderate AD were treated with either placebo or crenezumab (300 mg subcutaneously every 2 weeks [q2w], or 15 mg/kg, 30 mg/kg, 45 mg/kg, 60 mg/kg, or 120 mg/kg intravenously q4w). Serum/plasma PK/PD analyses included samples from 131 patients who received crenezumab in all three studies. CSF PK/PD analyses included samples from 76 patients who received crenezumab in ABBY or BLAZE. The impact of baseline patient factors on Aβ profiles was also evaluated. Results The serum concentration of crenezumab increased in a dose-proportional manner between 15 and 120 mg/kg q4w. Total monomeric plasma Aβ(1–40) and Aβ(1–42) levels significantly increased after crenezumab administration. The mean crenezumab CSF to serum ratio was ~ 0.3% and was similar across dosing cohorts/routes of administration. No clear correlation was observed between crenezumab concentration and Aβ(1–42) increase in CSF at week 69. The target-mediated drug disposition (TMDD) model described the observed plasma concentration–time profiles of crenezumab and Aβ well. Elimination clearance (CLel) and central volume of distribution (Vcent) of crenezumab were estimated at 0.159 L/day and 2.89 L, respectively, corresponding to a half-life of ~ 20 days. Subcutaneous bioavailability was estimated at 66.2%. Conclusions Crenezumab PK was dose proportional up to 120 mg/kg, with a half-life consistent with IgG monoclonal antibodies. Our findings provide evidence for peripheral target engagement in patients with mild-to-moderate AD. The study also showed that a model-based approach is useful in making inference on PK/PD relationship with unmeasured species such as free plasma Aβ levels. Trial registrations ABBY: ClinicalTrials.gov, NCT01343966. Registered April 28, 2011. BLAZE: ClinicalTrials.gov, NCT01397578. Registered July 19, 2011. GN29632: ClinicalTrials.gov, NCT02353598. Registered February 3, 2015.

Recently, we presented a strategy for packaging peptides as side-chains in high-density brush polymers. For this globular protein-like polymer (PLP) formulation, therapeutic peptides were shown to resist proteolytic degradation, enter cells efficiently and maintain biological function. In this paper, we establish the role charge plays in dictating the cellular uptake of these peptide formulations, finding that peptides with a net positive charge will enter cells when polymerized, while those formed from anionic or neutral peptides remain outside of cells. Given these findings, we explored whether cellular uptake could be selectively induced by a stimulus. In our design, a cationic peptide is appended to a sequence of charge-neutralizing anionic amino acids through stimuli-responsive cleavable linkers. As a proof-of-concept study, we tested this strategy with two different classes of stimuli, exogenous UV light and an enzyme (a matrix metalloproteinase) associated with the inflammatory response. The key finding is that these materials enter cells only when acted upon by the stimulus. This approach makes it possible to achieve delivery of the polymers, therapeutic peptides or an appended cargo into cells in response to an appropriate stimulus.

Previous studies have shown that the pH-driven method can be used to load curcumin into a variety of colloidal particles, including micelles, liposomes, lipid droplets, and oil bodies. This method is based on the increase in hydrophobicity and a corresponding decrease in water-solubility of curcumin when the pH changes from highly alkaline to acidic. In this study, we examined the physical and chemical stability of curcumin-loaded soybean oil bodies prepared using the pH-driven method. First, the impact of pH (from 6.5 to 8) on the stability of curcumin-loaded soymilk during storage was investigated at 4 °C for 36 days. At this low storage temperature, more than 85% of the alkaline-sensitive curcumin was retained at all three pH values, without any evidence of color fading. The impact of holding temperature (4, 20, 37, and 55 °C) on the physicochemical stability of the curcumin-loaded soymilks was then measured during storage at pH 7 for 14 days. At 4 and 20 °C, the emulsions remained physically stable, most of the curcumin (>90%) was retained, and there was no evidence of color fading. At the higher temperatures, however, the rate of curcumin degradation increased. For instance, around 30% and 70% of curcumin was lost when the soymilks were stored at 37 and 55 °C, respectively. On the other hand, the soymilks remained physically stable throughout this period. This study provides valuable information about the loading of curcumin into pre-existing plant-based milks and creamers, which may be useful for developing a new category of functional foods and beverages.

Prejudice and workplace discrimination have been paid attention to by people from different culture backgrounds, and one possible explanation for some of the defect in hiring that we come up with is that previous employees are more or less a benchmark when companies look for new employees to replace them. In this report, we design and carry out rigorous statistics-based analysis to investigate the possible hiring bias based on status quo. Through providing definitions of the key factors of status quo and describing the proposed steps for our studies, we identify that the personality of the previous employees has the greatest influence on hiring new employees, followed by appearance, gender, region and educational background.

Aims This study aimed to measure physical activity (PA) in participants with suspected heart failure with preserved ejection fraction (HFpEF) and assess associations between PA and participant characteristics. Methods and results Adults with presumed HFpEF were recruited and received diagnostic evaluation and clinical assessment. Physical activity was objectively measured using accelerometers over 7 days. To examine predictors of PA, a best subset analysis was used, with the optimal model defined as that with the lowest Bayesian information criterion. One hundred and twenty-four participants with presumed HFpEF who had valid accelerometer data were included in this study. Seventy-six were confirmed by a cardiologist as meeting the European Society of Cardiology diagnosis criteria for HFpEF. The median age of all participants was 80.1 years, and 47.4% were female. Patients spent most of each 24-h period at low-intensity PA and few or no durations at high-intensity PA, with lower activity for those with HFpEF. Gait speed was the best univariate correlate of activity levels (adjusted R2 0.29). The optimal model using best subsets regression included six variables and improved adjusted R2 to 0.47. In the model, lower levels of PA were associated with slower gait speed, lower levels of anxiety, higher levels of depression, past smoking history, a confirmed HFpEF diagnosis, and higher body mass index. Conclusion Participants demonstrated very low PA levels. The study has identified important patient characteristics associated with PA, which may help to identify those most in need of interventions. Notably, participants with confirmed HFpEF were more inactive than participants with other heart failure phenotypes.

Significance SLC39A8 A391T exhibits remarkable pleiotropic effects on multiple conditions, including cardiovascular diseases, Parkinson’s disease, and Crohn’s disease. However, how this single coding variant impacts such a wide range of pathologies has not been investigated. We generated Slc39a8 A391T knockin mice and show that they exhibit severe Mn deficiency in the colon, and impaired intestinal barrier integrity due to glycoprotein barrier structure defects, leading to indolent inflammation that can prime further inflammation driven by epithelial injury. Thus, we highlight the importance of Mn in gut homeostasis, and mechanistically unravel how A391T impacts intestinal barrier integrity., Common genetic variants interact with environmental factors to impact risk of heritable diseases. A notable example of this is a single-nucleotide variant in the Solute Carrier Family 39 Member 8 (SLC39A8)geneencoding the missense variant A391T, which is associated with a variety of traits ranging from Parkinson’s disease and neuropsychiatric disease to cardiovascular and metabolic diseases and Crohn’s disease. The remarkable extent of pleiotropy exhibited by SLC39A8 A391T raises key questions regarding how a single coding variant can contribute to this diversity of clinical outcomes and what is the mechanistic basis for this pleiotropy. Here, we generate a murine model for the Slc39a8 A391T allele and demonstrate that these mice exhibit Mn deficiency in the colon associated with impaired intestinal barrier function and epithelial glycocalyx disruption. Consequently, Slc39a8 A391T mice exhibit increased sensitivity to epithelial injury and pathological inflammation in the colon. Taken together, our results link a genetic variant with a dietary trace element to shed light on a tissue-specific mechanism of disease risk based on impaired intestinal barrier integrity.

Campylobacter jejuni is a leading cause of food-borne gastrointestinal disease in humans and uropathogenic Escherichia coli is a leading cause of urinary tract infections. Both human pathogens harbour a homologous iron uptake system (termed cjFetM-P19 in C. jejuni and ecFetM-FetP in E. coli). Although these systems are important for growth under iron limitation, the mechanisms by which these systems function during iron transport remain undefined. The copper ions bound to P19 and FetP, the homologous periplasmic proteins, are coordinated in an uncommon penta-dentate manner involving a Met-Glu-His3 motif and exhibit positional plasticity. Here we demonstrate the function of the Met and Glu residues in modulating copper binding and controlling copper positioning through site-directed variants, binding assays, and crystal structures. Growth of C. jejuni strains with these p19 variants is impaired under iron limited conditions as compared to the wild-type strain. Additionally, an acidic residue-rich secondary site is required for binding iron and function in vivo. Finally, western blot analyses demonstrate direct and specific interactions between periplasmic P19 and FetP with the large periplasmic domain of their respective inner membrane transporters cjFetM and ecFetM.

Background Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. Objective This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. Methods In this multicenter, double-blind study, participants (aged 50-90 years) with mild-to-moderate Alzheimer's disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n = 21), 60 mg/kg (Cohort 2, n = 21), or 120 mg/kg (Cohort 3, n = 19) or corresponding placebo (n = 14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. Results Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose-proportional and maintained for each dose level. Conclusion Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials.

Defective arginine synthesis, due to the silencing of argininosuccinate synthase 1 (ASS1), is a common metabolic vulnerability in cancer, known as arginine auxotrophy. Understanding how arginine depletion kills arginine-auxotrophic cancer cells will facilitate the development of anti-cancer therapeutic strategies. Here we show that depletion of extracellular arginine in arginine-auxotrophic cancer cells causes mitochondrial distress and transcriptional reprogramming. Mechanistically, arginine starvation induces asparagine synthetase (ASNS), depleting these cancer cells of aspartate, and disrupting their malate-aspartate shuttle. Supplementation of aspartate, depletion of mitochondria, and knockdown of ASNS all protect the arginine-starved cells, establishing the causal effects of aspartate depletion and mitochondrial dysfunction on the arginine starvation-induced cell death. Furthermore, dietary arginine restriction reduced tumor growth in a xenograft model of ASS1-deficient breast cancer. Our data challenge the view that ASNS promotes homeostasis, arguing instead that ASNS-induced aspartate depletion promotes cytotoxicity, which can be exploited for anti-cancer therapies., Chun-Ting Cheng et al. demonstrate that arginine starvation kills arginine-auxotrophic cancer cells by depleting them of aspartate through asparagine synthetase (ASNS) and disrupting their mitochondrial metabolism. This study presents ASNS-induced aspartate depletion as an anti-cancer therapeutic strategy.

Defects in basal autophagy limit the nutrient supply from recycling of intracellular constituents. Despite our understanding of the pro-survival role of macroautophagy/autophagy, how nutrient deprivation, caused by compromised autophagy, affects oncogenic KRAS-driven tumor progression is poorly understood. Here, we demonstrate that conditional impairment of the autophagy gene Atg5 (atg5-KO) extends the survival of KRASG12V-driven tumor-bearing mice by 38%. atg5-KO tumors spread more slowly during late tumorigenesis, despite a faster onset. atg5-KO tumor cells displayed reduced mitochondrial function and increased mitochondrial fragmentation. Metabolite profiles indicated a deficiency in the nonessential amino acid asparagine despite a compensatory overexpression of ASNS (asparagine synthetase), key enzyme for de novo asparagine synthesis. Inhibition of either autophagy or ASNS reduced KRASG12V-driven tumor cell proliferation, migration, and invasion, which was rescued by asparagine supplementation or knockdown of MFF (mitochondrial fission factor). Finally, these observations were reflected in human cancer-derived data, linking ASNS overexpression with poor clinical outcome in multiple cancers. Together, our data document a widespread yet specific asparagine homeostasis control by autophagy and ASNS, highlighting the previously unrecognized role of autophagy in suppressing the metabolic barriers of low asparagine and excessive mitochondrial fragmentation to permit malignant KRAS-driven tumor progression.

Salivary gland cancers (SGCs), categorized as head and neck cancers (HNCs), constitute about 6% of head and neck cancer diagnoses based on estimate by American Head and Neck Society. Salivary gland tumors originate from different glandular cell types and are thus morphologically diverse. These tumors arise from any of the three major and various minor salivary glands. The incidence of SGCs has slowly increased during the last four decades. The etiology of SGCs is mostly unknown; however, specific gene mutations are associated with certain types of salivary tumors. Treatment options include surgical resection, radiation therapy (RT), chemotherapy, and multimodality therapy. HNC patients treated with RT often develop xerostomia and salivary hypofunction due to damaged salivary glands. In this review, we discuss etiology of SGCs, present findings on the role of autophagy in salivary tumorigenesis, review adverse effects of radiation treatment, and examine remedies for restoration of salivary function.

Aim The aim of this study was to evaluate undergraduate nursing students' perceptions of using telehealth-based simulations for practicing their breastfeeding education skills. Background Telehealth can help bridge the gap between the high need for healthcare services and the limited access to these services, such as breastfeeding mothers in rural settings. However current literature suggests that there is lack of telehealth education among healthcare providers, as well as, a shortage of adequately trained nurses on breastfeeding, making it difficult to provide new mothers with the support they need to successfully breastfeed. Telehealth simulation has shown to be acceptable and helpful in teaching clinical reasoning, increasing exposure to telehealth experiences, and preparing nursing students for real interaction experiences with patients. Design For this cross-sectional descriptive study, two breastfeeding telehealth simulation scenarios were developed and delivered through Zoom for Bachelor of Science in Nursing students in a high-level institution in Florida. Selected students interacted over Zoom as healthcare providers with a female simulated patient who played as a mother with a breastfeeding concern. Students in their role of healthcare providers assessed the breastfeeding needs of the mother and conducted breastfeeding education as appropriate. After debriefing, students received feedback from faculty and students who observed the simulation and completed an optional evaluation about their telehealth simulated experience. Results A total of 205 students completed the evaluation. Most students (n = 136, 66.3%) were not familiar with telehealth prior to the simulation. Most students (n = 199, 97.1%) also found the simulation helpful for supporting breastfeeding mothers and wanted more telehealth simulations in the future (n = 162, 79%). Feedback for improving the simulations included: improving the technical setup (n = 17, 8.3%), increasing the time that students interacted with the mother (n = 16, 7.8%), and observing the correct performance of the simulation after debriefing (n = 16, 7.8%). Conclusion Telehealth simulation is a promising modality for clinical competency assessment, thus it is essential to integrate telehealth education into nursing curriculum. It is evident that telehealth-based breastfeeding simulations can be used to address the exposure/knowledge gap among nursing students who are missing or have limited exposure to breastfeeding content and telehealth use in their nursing curriculum.

Summary A predictive but tunable model for the liquid viscosity of characterized crude oils was developed by use of the generalized Walther correlation (Walther 1931; Yarranton et al. 2013). The crude oils are each characterized into maltene pseudocomponents and a single C5-asphaltene component. The viscosity model requires two pseudocomponent parameters (A and B), two whole-oil parameters (δ1 and δ2), and binary-interaction parameters. The asphaltene parameters were determined experimentally and fixed for all cases. Correlations were developed for the maltene-pseudocomponent parameters and the binary-interaction parameters. The required data are the absolute temperature, pressure, the C5-asphaltene content, the specific gravity (SG) and molecular weight (MW) of the oil, and the boiling-point distribution of the maltenes. The SG and MW distributions of the maltenes are also required, but are generated from existing correlations. The proposed model predicted the viscosity of five western Canadian and two Colombian bitumens; three American, one Mexican, one Venezuelan, and one European heavy oil; and also a conventional oil from the Middle East with an overall average deviation of 57%. Tuning to a single viscosity data point with a single tuning parameter reduced the overall deviation to 8%, close to the 4% deviation obtained when the model was fitted to the data.

The pH-shift method is a simple approach for incorporating certain kinds of polyphenol-based nutraceuticals into already existing colloidal systems. The polyphenols can be loaded into hydrophobic particles due to the fact that their water-solubility is relatively high under alkaline conditions but low under acid or neutral conditions. In this study, it was demonstrated that bovine milk could be enriched with curcumin using this approach, without adversely affecting milk fat globule stability. The storage stability of the curcumin-enriched bovine milk was assessed when samples were incubated for 60 days at different pH values and temperatures. The pH-stability was determined by storing curcumin-enriched milk at 4 °C for 60 days at pH 6.5, 7.0, and/or 8.0. At this low storage temperature, all milk samples were stable to fat globule aggregation, creaming, curcumin degradation ( 37 °C (21%) > 20 °C (10%) > 4 °C (5%). Interestingly, the color of the curcumin-enriched milks incubated at 4, 20, and 37 °C remained similar to that of the initial samples, but the sample stored at 55 °C showed significant color fading. Curcumin bioaccessibility determined using an in vitro gastrointestinal tract was around 40%, which was attributed to some chemical degradation and binding of the curcumin reducing its stability and solubilization. This study shows that a hydrophobic nutraceutical (curcumin) can be loaded into dairy milk products using a simple method, which could facilitate the creation of novel functional foods and beverages.

Inorganic arsenic (iAs) in foods has raised significant concerns because it is carcinogenic to human beings. Herein, we integrated the Gutzeit method with X-ray fluorescence (XRF) spectroscopy to measure iAs in selected beverages within 45 min. Briefly, iAs was firstly reduced to arsine under acidic conditions. Transformed arsine was then trapped on mercury bromide test discs and subsequently measured by XRF. Interference from dimethylarsinate on the test discs was minimized by an acetone rinsing step to a great extent. A standard curve with a linear range from 0 to 133.3 μg/L was established, and the limit of detection and quantification were 1.9 and 5.7 μg/L, respectively. This method was further evaluated with commercial beverages, and the results were compared with those from a commercial arsenic test kit and by inductively coupled plasma mass spectroscopy. We demonstrated that this method is sensitive, reliable, fast, and comparatively cost-effective for use in iAs screening in the food industry.

Hydraulic conductivity (K) is crucial for groundwater studies and is conventionally obtained through pumping tests, which are costly due to well installation, resulting in a limited amount of data. Recent studies have addressed this limitation by estimating K through the integration of a pumping-test K and electrical resistivity measurements. While this approach is suitable for local areas, it cannot readily be applied to determine K fields for the composite fan delta. This study proposes and demonstrates an advanced method to estimate the K&rsquo, s spatial distribution of a composite fan delta. The proposed method included data classification, linear regression, and kriging interpolation. Data classification was conducted using a physical-based zonation method. The K and formation factor (F) data pairs were classified into several groups. Linear regression was used to develop K-F mapping for each group. The regression results showed a good correlation between K and F in each group. These K-F mappings were verified by additional pumping tests. These results indicate that estimation errors were between 7 m/day and 58 m/day, and the correlation coefficient of each data group was greater than 0.8. Based on these regression equations and ordinary kriging method, the detailed K spatial distribution of the study area was derived. According to these results, the proposed method is efficient and economical to delineate K&rsquo, s spatial features for regional groundwater systems and can benefit groundwater-related studies.