bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dietary tocotrienols improve glucose homeostasis and bone turnover biomarkers in high‐fat‐diet‐ induced obese male mice
Authors: Shen Chwan‐Li (Leslie) , Kaur Gurvinder , Ramalingam Latha , Tomison Michael D , Chung Eunhee , Moustaid‐Moussa Naima , Guo Chun , Web Cynthia Reinoso , Mo Huanbiao , Dufour Jannette D 
Published: November 2023

Diabetes is a risk factor for osteoporosis. It is critical to emphasize the importance of glycemic control during osteoporosis treatment in patients with type 2 diabetes (T2D). However, diabetic therapies have potentially adverse effects on bone metabolism. In this study, we evaluated the effects of dietary tocotrienols (TT) on glucose homeostasis and bone turnover biomarkers in high‐fat‐diet‐induced obese male mice. Fifty‐eight male C57BL/6J mice were divided into 5 groups: low‐fat diet (LFD), high‐fat diet (HFD), HFD+400 mg TT/kg (lowTT), HFD+1600 mg TT/kg (highTT), and HFD+200 mg metformin/kg (Met, used as a T2D positive control treatment) for 14 weeks. Compared to the LFD group, the HFD group had greater body weight, hyperglycemia, insulin resistance, lower serum procollagen I intact N‐terminal propeptide (P1NP, bone formation marker), and higher serum collagen type 1 cross‐linked C‐telopeptide (CTX, bone resorption marker). Relative to the HFD group, TT supplementation (1) improved glucose homeostasis by lowering 2‐hour fasting blood glucose levels from both glucose tolerance test (369.3±22.6, 285.1±20.5, 228.8±18.9 mg/dL for HFD, low TT, and high TT, respectively) and insulin tolerance test (relative to time zero: HFD: 53.1%, low TT: 47.6%, high TT: 42.9%) in a dose‐dependent manner, (2) increased P1NP concentrations, and (3) decreased CTX levels. There were no significant differences in glucose homeostasis and bone markers between the HFD and the Met groups. This study demonstrates that the protective effect of tocotrienols on bone turnover biomarkers that may be mediated in part through improved glucose homeostasis in T2D animals.Support or Funding InformationFunded by American River Nutrition, Inc.
Acute Effects on Satiety from White Button and Shiitake Mushroom Powder Supplementation in a High Fat Meal
Authors: Robak Theodore J , Talal Lillian A , Morris Matthew J , Williams Brian T , Browne Richard W , Horvath Peter J 
Published: November 2023

BackgroundThe current trend of rising obesity leads to an increase in cardiovascular disease and dyslipidemia. One of the factors involved with this trend are diets high in fat. Supplementing high‐fat meals with bioactive compounds may be an effective way to limit the negative consequences of such a diet. Mushrooms contain high levels of fungosterols and β‐glucans which are thought to be involved in the primary mechanism for improved postprandial lipemia. Mushroom supplementation may have effects on acute satiety which could dictate eating habits.PurposeTo examine the acute effects on satiety by adding shiitake and white button mushroom powder to a high‐fat meal.MethodsThree high‐fat meals were administered to 13 healthy subjects (6 males and 7 females, 24 ± 2yr, 20±6 % body fat, 57.1±11.5 kg fat free mass) in a double blinded, randomized design. Each meal (Control, White Button (WB), Shiitake (SH)) consisted of an 8oz cooked beef patty and a bun (819 kcal, 47g fat) with no mushroom powder or 14g of WB or 14 g of SH dried mushroom powder. Dietary intake on the day before testing was similar among subjects (2079 ± 791 kcal). Subjects were fasted and avoided vigorous exercise on the day prior to testing. Satiety was measured using a Likert visual analog scale every 2 hours for 6 hours following each meal. Blood from an indwelling catheter was also taken every 2 hours to measure plasma glucose and lipids. The effects of each meal were determined by measuring differences between meals.ResultsA more gradual decline in satiation from hour 2 to 6 was observed for treatments with mushrooms as compared to the control treatment. With the control burger there was a significant decline in satiety between hour 4 and 6 (P = 0.01) that was not seen with either mushroom powder. Plasma glucose was positively correlated with satiety values in all groups (P = 0.02). However, there was no relationship between plasma triglycerides and satiety.ConclusionAdding mushroom supplements to a high‐fat meal does not appear to change subjective satiety from 0 to 4 hours after consumption. However, between hours 4 and 6 after consumption, subjects were likely to have a longer feeling of fullness with mushrooms than without mushrooms. Plasma triglycerides levels did not predict satiety levels while plasma glucose was shown to be a better predictor of satiety. Using mushroom supplementation may limit the rise in felt hunger following a meal and could lead to less food consumption overall.Support or Funding InformationSupported by a grant from the University at Buffalo Honors College.
Effects of Raspberry Dietary Supplementation on Risk Biomarkers of Diabetes Related Complications and Heart Disease in Diabetic Mice
Authors: Noratto Giuliana , Chew Boon , Mencia Alejandra 
Published: November 2023

We investigated the effects of raspberry consumption on diabetes‐related complications and heart disease in obese diabetic mice. Mice (4–5 wk old) were fed either AIN‐93G (control) or AIN‐93G supplemented with freeze‐dried raspberries (9.75%) (isocaloric) for 8 wk. At the end of the study, blood and heart tissues were collected and analyzed using standard analytical protocols.Raspberry intake, at dose equivalent to 208 g freeze dried raspberry/day for a 60‐kg human adult; protected against appetite loss, weight loss and cachexia observed in the control group. However, levels of lipid peroxidation, pro‐atherogenic molecules, and endotoxins in plasma were similar between groups. Plasma adipokine resistin, a hormone signaling molecule correlated with hyperinsulinemia/hyperglycemia, was higher in raspberry group (1777 vs 1165 ρg/mL, p < 0.05). Controversially, no differences were found in plasma insulin concentrations; whereas fasting glucose tended (p = 0.08) to be lower in the raspberry group (688 vs 759 mg/dL). This suggests that higher concentrations of plasma resistin in the raspberry group is correlated with higher body weight and is consistent with its delayed cachexia. Heart tissue disease biomarkers leptin, resistin, total cholesterol, triglycerides, and oxidized lipids were similar between experimental groups. However; plasminogen activator inhibitor‐1 (PAI‐1) tended to be lower in the raspberry compared to the control group (1124 vs 1234 ρg/mg protein) (p > 0.05). PAI‐1 has been linked to decreased oxidative stress and interleukin‐6 in blood.These findings demonstrate that raspberry consumption helps to decrease cachexia and may decrease cardiac fibrosis in diabetes at an advanced age. Future studies are needed to prove the clinical relevance of raspberry consumption.Support or Funding InformationNational Processed Raspberry Council, Grant # 3057‐6667
Blueberry supplementation impacts gut microbiota, inflammatory profiles, and insulin sensitivity in high‐fat fed rats
Authors: Lee Sunhye , Kirkland Rebecca , Fischer Joan G. , de La Serre Claire 
Published: November 2023

Obesity and insulin resistance are associated with chronic inflammation, which is believed to originate from the gastrointestinal (GI) tract. Changes in microbiota composition and an increase in circulating pro‐inflammatory endotoxin are notably associated with impaired glucose tolerance. Our objective was to determine whether blueberry supplementation could impact microbiota composition and systemic inflammation as well as glucose tolerance in high‐fat fed rats.Wistar rats (n=8/group) were fed low‐fat (LF, 10% fat), high‐fat (HF, 45% fat) or high‐fat with 10% blueberry (HF_BB) diets for 8 weeks. HF and HF_BB diets were isocolaric and animals were pair‐fed. All diets were matched for sugar and fiber contents.Compared to the LF diet, HF feeding resulted in increased adiposity and liver fat deposition in both HF and HF_BB rats. Blueberry supplementation altered the microbiota composition, with decreases in Firmicutes and Bacteroidetes and increases in Proteobacteria and Fusobacteria. Gammaproteobacteria were the most noticeable change in the HF_BB group. Along with these changes, GI barrier integrity was improved in HF_BB animals, characterized by a decrease in circulating lipopolysaccharide‐binding protein and increases in protective gene expression levels in the ileum (defensin β2 and mucin 2). Moreover, blueberry treatment significantly decreased systemic inflammation, characterized by a decrease in tumor necrosis factor α (TNFα) and interleukin‐6 protein levels in the liver and reduced TNFα and cluster of differentiation 11d (a macrophage infiltration marker) gene expression in visceral fat. Inflammation has been shown to affect insulin signaling and HF_BB rats showed improvements in glucose tolerance and insulin sensitivity. Glucose and insulin levels during an oral glucose tolerance test were significantly decreased in HF_BB rats. Additionally, blueberry treatment increased ileal glucagon‐like‐peptide‐1 expression and significantly down‐regulated the level of hepatic pSer307 IRS‐1/IRS‐1 ratio (insulin receptor substrate 1), which are associated with improved glucose tolerance and impaired insulin signaling, respectively.Taken together, these data showed a potential anti‐inflammatory effect of blueberry supplementation associated with improved glucose tolerance. These effects may result from the alleviation of metabolic endotoxemia and intestinal inflammation and the modulation of gut microbiota.Support or Funding InformationThis material is based upon work that is supported by the National Institute of Food and Agriculture, USDA, under award number 2014‐67017‐21757.
F93D Mutation in HDAC4 N‐Terminal Glutamine‐Rich Domain and its Effect on Photoreceptor Survival
Authors: Juarez Michelle C. , Sample Vedangi , Cepko Constance 
Published: November 2023

Over 60 genes have been associated with Retinitis Pigmentosa (RP), making it the most common form of retinal disease. There is currently no cure for RP but gene therapy approaches appear to be promising. HDAC4 has been shown to regulate the survival of photoreceptors in normal and RP diseased mouse models. HDAC4 has multiple binding domains, and truncations within these different domains suggest that residues 1–118 of HDAC4 are sufficient to promote rod survival. The two characterized domains within this 1–118 region are the C‐terminal binding protein (CTBP) domain and part of the glutamine rich region. Crystal structure of the N‐terminal glutamine rich domain reveals 4 monomers assembled into a tetramer, with a central hydrophobic core that function in stability of the tetramer complex. A point mutation in the 93rd residue from Phenylalanine to Aspartic Acid disrupts this hydrophobic core and the tetramer stability. We report expression of our F93D mutant construct through electroporations of mice models in attempts to identify whether this key residue of HDAC4 is important in rescuing diseased rod photoreceptors.Support or Funding InformationHoward Hughes Medical Institute, EXROP program
Validation of a Quantitative Polymerase Chain Reaction (qPCR)‐based Method for Detecting Lymph Node Metastasis by Melanoma Cells
Authors: Goodloe Travis Bedsole , Hargadon Kristian M 
Published: November 2023

Melanoma, a cancer of pigment‐producing melanocytes in the skin, is a highly lethal type of cancer because of its propensity to metastasize to several vital organs, including the lungs, brain, bone, and kidneys. Melanoma has also been shown to metastasize to tumor‐draining lymph nodes, and such lymph node metastasis correlates with dysfunctional anti‐tumor immunity and poor patient prognosis. In order to better understand 1) how melanomas spread to regional lymph nodes and 2) how lymph node involvement by melanomas contributes to immune suppression and disease progression, a model system for detecting melanoma cell invasion of local lymph nodes is sorely needed. Therefore, the goal of this study was to develop a quantitative Reverse Transcription‐Polymerase Chain Reaction (qRT‐PCR)‐based approach to assess melanoma metastasis to tumor‐draining lymph nodes by measuring in lymph node cell populations expression of the tyrosinase‐related protein‐2 (Trp2) gene that is involved in the melanin biosynthesis pathway. We demonstrate in both a primary tumor and lung metastasis model of murine melanoma that this approach is a highly sensitive system for the detection of melanoma cells in tumor‐draining lymph nodes.Support or Funding InformationCommonwealth Health Research BoardVirginia Academy of Science Jeffress Memorial FellowshipVirginia Foundation for Independent Colleges Mednick Memorial FellowshipHampden‐Sydney College Student‐Faculty Research FundSigma Xi Grants‐In‐Aid of ResearchHampden‐Sydney College Faculty‐Student ResearchFund Hampden‐Sydney College Department of Biology
Vasculogenic mimicry in non‐functioning pituitary adenomas: fact or fallacy?
Authors: Rotondo Fabio , Di Michele Joseph , Kovacs Kalman , Syro Luis V , Yousef George M , Cusimano Michael D , Di Ieva Antonio 
Published: November 2023

IntroductionVasculogenic mimicry (VM) refers to the formation of vascular channels within genetically dysregulated tumor cells. It occurs de novo without the presence of an endothelial cell lining. Since its introduction in 1999, it has been observed in several tumor types and is proposed to be an alternative means of providing blood perfusion to tumors. Pituitary tumors are generally slow growing, benign adenomas. To date, VM in pituitary adenomas has not been described. Herein, we studied whether these channels occur in clinically non‐functioning pituitary adenomas (NFPA).Materials and MethodsWe studied the presence of VM in 49 randomly selected cases of surgically‐removed clinically NFPA using CD34 and Periodic Acid‐Schiff (PAS). Tumors were divided into 2 groups (19 recurring and 30 non‐recurring). 10 surgically removed and 5 autopsy‐obtained non‐tumorous pituitaries from patients with no endocrine diseases and no hormone treatment were also included.To demonstrate vascular change, CD34‐PAS double immunostaining on paraffin‐embedded sections was used. Slides were assessed for the presence of CD34‐negative and PAS‐positive channels indicating that they were not lined by endothelial cells. Immunohistochemical findings were evaluated under low and high magnification.ResultsImmunopositivity for CD34 demonstrated endothelial cells lined blood vessels, which were localized in all 49 cases of clinically NFPA. The PAS‐ positive pattern, which stained sub‐endothelial matrix, was also visible in all cases. Slides were assessed for the presence of CD34‐negative and PAS‐positive channels indicating that they were not lined by endothelial cells. This staining pattern suggestive of VM was observed in 22/49 (45%) of the clinically NFPA. The amount of staining pattern varied both from case to case and within groups. No statistically significant correlation was found between the presence of this staining pattern within each group and the gender of the patients. An intriguing finding was the correlation between staining pattern and age. In 22 cases studied where the staining was identified, 14 cases (64%) were in the age range between 52–59 yrs while the remainder of the cases were equally distributed between the age range 25–75 yrs. In 27 cases where the staining pattern was not identified, 12 cases (44%) were in the age range between 51–57 yrs and 22/27 (81%) of the negative cases in the age range between 31–57 yrs. This was an intriguing finding since cases studied were randomly selected.ConclusionThis finding carries potential clinical implications with respect to patient response to therapy as well as clinical course. More work is needed to prove that the presence of sub‐endothelial matrix without endothelial lining represents VM.Support or Funding InformationAcknowledgement Authors are grateful to the Jarislowsky and Lloyd Carr‐Harris Foundations for their generous support.
CD44, CD133 and Lgr5 as biomarkers for early detection of H. pylori‐associated gastric cancer
Authors: Walker Rachel , Mejia Jaime , Enderling Heiko , Pimiento Jose M , Malafa Mokenge , Coppola Domenico 
Published: November 2023

BackgroundGastric cancer remains the second most common cause of cancer deaths worldwide, yet specific biomarkers for early detection remain elusive. The present work proposes an increase in stem cell prevalence during the progression through the Correa pathway from normal gastric mucosa (NM) to inflammation and intestinal metaplasia (IM), dysplasia (DS) and gastric cancer (GC), and identifies several stem cell biomarkers which demonstrate increased expression throughout this pathway.MethodsRetrospective gastric tissue samples were obtained from a cohort of 63 patients from Colombia, a region where virulent CagA+ H. pylori infection and associated gastric cancer is highly prevalent. We measured variations in expression of stem cell markers CD44 (antibody #HPA005785, Sigma Aldrich, St. Louis, MO), CD133 (antibody MAB4399, Millipore, Billerica, MA) and Lgr5 (antibody ab75850, Abcam, Cambridge, MA) during disease progression. Samples were divided as follows: 10 NM; 17 IM; 10 DS and 26 GC. All cases were stained using the Ventana automated immunostainer Discovery XT (Ventana, Tucson, AZ). Scoring was conducted using the Allred scoring system featuring a proportion score and an intensity score to give a total score between 0 and 8.ResultsA significant increase in expression of all three stem cell markers (CD44, CD133 and Lgr5) was observed during each progression stage (NM to IM, IM to DS, and DS to GC). Statistical analysis of overall correlation between respective biomarker expression and disease stage is provided in Table 1. Expression increase between each individual stage of progression is demonstrated in Figure 1 for all 3 markers: CD44 (green), CD133 (blue) and Lgr5 (red). Statistical significance of increase at each stage is indicated by asterisks: p < 0.05 (*), p < 0.01 (**), p < 0.001 (***).ConclusionStem cell dynamics as represented by common epithelial stem cell markers may allow early detection of the transition from to GC in patients at increased risk for gastric cancer.

Statistical analysis of correlation between respective markers and disease stage.

Marker
Spearman correlation
T value
P value

CD44
0.771
8.9828
9.148e‐13

CD133
0.818
9.3961
1.827e‐13

Lgr5
0.834
9.3466
2.216e‐13
Control of Breast Cancer through the Resolution of Inflammation
Authors: Vatnick Donna Rachel , Lehner Kristen , Gilligan Molly , Panigrahy Dipak , Gus‐Brautbar Yael , Ramon Sesquile , Huang Sui , Serhan Charles 
Published: November 2023

BackgroundCurrent breast cancer therapies, including chemotherapy and targeted therapy, reduce tumor burden by killing tumor cells. However, they result in apoptotic and necrotic cell bodies, or “tumor cell debris,” which may act as a source of tumor stimulation by promoting inflammation. Thus, chemotherapy and targeted therapy may be a double‐edged sword. Enhancing clearance of tumor debris by specialized pro‐resolving mediators (SPMs) may target the endogenous mechanisms driving tumor growth, resistance, and dormancy escape. Maresin 1 (MaR1), a key mediator of resolution, is biosynthesized by human macrophages from endogenous docosahexaenoic acid. We hypothesize that maresins represent a novel modality in breast cancer treatment by resolving inflammation and enhancing endogenous clearance of tumor cell debris by macrophage phagocytosis.MethodsTrypan blue assay and flow cytometry confirmed generation of breast tumor estrogen receptor positive (ER+) and estrogen receptor negative (ER−) tumor cells with chemotherapy or anti‐hormone therapy (cisplatin, tamoxifen or fulvestrant). Macrophage phagocytosis of tumor cell debris following resolvin or maresin treatment was quantified. Cytokine/chemokine levels were measured via cytokine array and ELISA.ResultsChemotherapy and anti‐hormone therapy generated tumor cell debris. We demonstrate that tamoxifen‐induced debris stimulates primary breast tumor growth in vivo, and that systemic administration of MaR1 inhibits debris‐stimulated breast cancer tumors. MaR1 promotes the clearance of tumor debris by stimulating macrophage phagocytosis of apoptotic tumor cells, and by counter‐regulating critical pro‐inflammatory cytokines, as well as stimulating endogenous anti‐inflammatory cytokines (i.e. IL‐1ra).ConclusionsMaresins suppress primary breast tumor growth via stimulating the uptake of apoptotic tumor cells by macrophages and endogenous anti‐inflammatory cytokines. Thus, the maresin pathway or the enhancement of endogenous resolution processes offers an entirely novel approach for controlling chronic inflammation as a modality of cancer treatment, complementing current approaches that focus on pro‐inflammatory mediators.
Breast Cancer Emergence from Dormancy can be Activated by Hepatic Stellate Cells
Authors: Khazali Ahmad Suhail , Clark Amanda , Wheeler Sarah , Wells Alan 
Published: November 2023

Tumor dormancy is a well‐known clinical phenomenon. Studies have shown that in breast cancer survivors, the cancer recurs within 5–10 years (up to 20%) and more than 10 years (up to 11%) post initial treatment. Liver is one of the main metastatic sites for breast cancer recurrence as 60% of breast cancer patients had liver metastases at autopsy and 5–14% of the patients had liver metastases 4–10 years after radical mastectomy suggesting tumor dormancy. The factors and mechanisms for tumor outgrowth in the liver still remain unclear. Inflammation may increase the risk of breast cancer recurrence as increased levels of inflammation markers have been correlated with poor disease‐free and overall survival. We hypothesized that inflammatory signals from activated liver non‐parenchymal cells (NPC) can stimulate dormant micrometastatic cancer cells to grow and form macrometastases. In this study, we performed co‐culture experiments of breast cancer cell lines with hepatic stellate cell lines. Transwell assay was performed to determine whether soluble factors contribute to tumor growth. Protein array and luminex assays were conducted to determine the soluble factors secreted by the stellate cells. Finally, induction of breast cancer growth by these chemokines was validated in both in‐vitro and ex‐vivo. Human and rat hepatic stellate cell lines promoted significant breast cancer cells (MCF‐7) growth in‐vitro. Transwell assay indicated that MCF‐7 growth was due to soluble factors. IL‐8 and MCP‐1 were highly secreted by the stellate cells in‐vitro as well as by primary human NPC in a 3D ex‐vivo microphysiologic system, Liverchip. In‐vitro and ex‐vivo assays verified that IL‐8, but not MCP‐1, could directly stimulate breast cancer cell proliferation. These data suggest that activated NPC may mediate breast cancer escape from dormancy in the liver by secreting inflammatory signals. Disrupting inflammation might be an ideal therapeutic alternative to prevent tumor escape from dormancy in the liver.Support or Funding InformationJoint support by the NIH (UH3TR000496), NCATS and NCI