bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diet Quality Indexes and Colorectal Cancer Risk: the Multiethnic Cohort Study
Authors: Park Song‐Yi , Boushey Carol , Wilkens Lynne , Haiman Christopher , Le Marchand Loïc 
Published: November 2023

Healthy eating patterns assessed by diet quality indexes have been related to lower risk of colorectal cancer. Previous studies have been performed mostly among whites. We investigated the associations between four diet quality indexes, the Healthy Eating Index 2010 (HEI‐2010), the Alternative Healthy Eating Index 2010 (AHEI‐2010), the alternate Mediterranean diet (aMED) score, and the Dietary Approaches to Stop Hypertension (DASH) score, and colorectal cancer risk in a multiethnic population. We performed a prospective analysis using data from 190,949 adults aged 45–75 years who enrolled the Multiethnic Cohort Study by completing a self‐administered questionnaire in 1993–1996. Participants were African Americans, Native Hawaiians, Japanese Americans, Latinos and whites living in Hawaii and California. During an average 16 years of follow‐up, 4,770 invasive colorectal cancer cases were identified. Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs). Both in men and women, all four scores were inversely associated with risk of colorectal cancer adjusting for age and race/ethnicity in a dose‐dependent manner. In multivariate models, further adjustment for covariates slightly weakened the associations, especially in women, and the associations with the AHEI‐2010 and aMED score were no longer statistically significant. Tests for heterogeneity did not show statistically significant differences in the associations between men and women (P's for heterogeneity > 0.13). In men, the risk reductions were greater for the HEI‐2010 (HR=0.69, 95% CI: 0.59–0.80 for quintile 5 vs. 1), AHEI‐2010 (HR=0.75, 95% CI: 0.65–0.85), and DASH score (HR=0.75, 95% CI: 0.66–0.86) than for the aMED score (HR=0.84, 95% CI: 0.73–0.97). Associations were stronger for the left colon and rectum than for the right colon for all indexes. The inverse associations were less strong in African Americans than in the other four racial/ethnic groups for all four indexes. Our findings support that high diet quality is associated with a lower risk of colorectal cancer in most racial/ethnic subgroups.Support or Funding InformationThis work was supported by the National Institutes of Health (U01 CA164973, NCI HHSN261201200423P, P30 CA071789).
Potential Roles of Lutein in Mammary Gland Development and Breast Cancer Cell Growth
Authors: Yuan Yan , Harrison Earl 
Published: November 2023

Breast cancer is the most common form of malignancy and the second leading cause of cancer mortality in women. The most recent epidemiological studies have shown an inverse relationship between the blood lutein concentration and breast cancer risk, particularly for estrogen receptor negative (ER−) tumors. However, it is currently unclear whether it is the lutein itself, or a metabolite of lutein that plays a role in breast tissue protection, or whether lutein is a biomarker of another exposure. To better understand the impact of dietary lutein on breast development, we performed an in vivo feeding study by using a modified AIN‐93G diet, to which lutein was added at a concentration of 0.01%. C57/BL6 virgin female mice were fed with diets with or without lutein supplementation. Plasma, mammary gland, and liver were collected after 5, 10, and 15 weeks of feeding. Plasma lutein levels were determined by HPLC. Whole mount staining and immunohistochemistry (IHC) analyses were conducted to evaluate the development of mammary glands. To investigate the function of lutein on breast cancer risk, we also performed an in vitro study by using both ER+ and ER− human breast cancer cell lines (T47D, SKBR3, ZR‐751, MCF7, MDA‐MB‐231) treated with 10 uM lutein, or 10 uM β‐carotene, and assessed cell growth with MTT assay. Whole mount staining and IHC showed no difference in proliferation and branching of the glands between two dietary groups. Our in vitro studies showed there was no significant effect of lutein on cell growth, in contrast to β‐carotene which led to a 30% decrease in cell growth. Thus, the association between plasma lutein and breast cancer risk may result from lutein being a biomarker of vegetable intake, or a marker of other phytochemicals, and not a direct effect of lutein itself.Support or Funding InformationNIH Grant R01‐HL49879
The Unfolded Protein Response Regulates Pancratic Neuroendocrine Tumor Growth
Authors: Oakes Scott A. , Qi Jenny Y. , Moore Paul C , Warren Rachel A. , Thamsen Maike , Ghosh Rajarshi , Gliedt Micah J. , Maly Dustin J. , Backes Bradley J , Papa Feroz R. 
Published: November 2023

The Unfolded Protein Response (UPR) is an intracellular signaling pathway that communicates the protein folding status of the endoplasmic reticulum (ER) to the nucleus to maintain ER homeostasis. Hypoxia, nutrient deprivation, proteasome dysfunction, sustained demands on the secretory pathway or somatic mutations in its client proteins‐‐conditions often encountered by cancer cells—can lead to the accumulation of misfolded proteins in the ER and cause “ER stress.” However, the precise role of UPR signaling in the development and maintenance of cancer remains controversial. We reasoned that pancreatic neuroendocrine tumors (PanNETs) might be one class of solid tumor that may be particularly sensitive to protein folding stress due to their high secretory activity.The Master UPR regulator IRE1 (Inositol requiring enzyme 1 alpha) is an ER transmembrane kinase/endoribonuclease (RNase) that acts as a critical life‐death switch depending on the level of ER stress. We analyzed primary human PanNET samples for activation of UPR components and found strong evidence of ER stress and IRE1 hyperactivation in this tumor type. We used a variety of chemical‐genetic tools to selectively manipulate IRE1's homeostatic and apoptotic outputs in a PanNET xenograft model and found that the precise balance of IRE1 signaling is critical for tumor growth in vivo. Disrupting this balance by pushing the pathway in either direction is detrimental to PanNET growth and survival. Moreover, targeting IRE1 with highly selective small molecules in a preclinical mouse model phenocopied the results of genetic manipulation. Our results indicate that IRE1 is an important regulator of PanNET cell survival and growth and provide a strong rationale for therapeutically targeting this kinase/RNase in PanNETs and other cancers that experience high levels of ER stress.Support or Funding InformationThis work was supported by an American Cancer Society Research Scholar Award, American Association for Cancer Research‐Caring for Carcinoid Foundation Award, Harrington Discovery Institute Scholar‐Innovator Award, and the National Institutes of Health: R01CA136577, R01DK095306, U01DK108332.
Targeting debris‐stimulated angiogenesis and primary tumor growth by resolvin mediated clearance
Authors: Chang Jaimie , Gilligan Molly , Sulciner Megan , Huang Sui , Kieran Mark , Serhan Charles , Panigrahy Dipak 
Published: November 2023

BackgroundStandard cancer therapy reduces tumor burden by killing tumor cells, yet simultaneously creates tumor cell debris and associated inflammation in the tumor microenvironment. Thus, cancer therapy is inherently a double‐edged sword. Since tumor growth is angiogenesis‐dependent, we hypothesize that the accumulation of chemotherapy‐generated debris, stimulates tumor growth via tumor angiogenesis. ω‐3 fatty acid‐derived lipid autacoids termed ‘Specialized pro‐resolving mediators’ (SPMs), including resolvins, stimulate the resolution of inflammation by activating macrophage clearance of cell debris and promote wound healing and regeneration. While SPMs inhibit VEGFA‐mediated corneal and retinal neovascularization, the role of SPMs in tumor angiogenesis had not been studied to date. Thus, resolvins may represent a novel therapeutic approach to cancer through inhibition of tumor angiogenesis.ResultsHere, we show that co‐injecting tumor debris generated by the chemotherapeutic agent 5‐Fluorouracil (5‐FU), with living murine colon carcinoma (CT26) cells stimulated tumor growth in a dose‐dependent manner up to 100‐fold. In contrast, tumor cell debris alone did not produce any visible tumors, even at 100 days post‐injection. Next, we titrated the number of living tumor cells to a fixed quantity of 5‐FU‐generated tumor cell debris. The presence of debris promoted CT26 tumor growth even at an inoculum of 1×102 or 1×103 living tumor cells, which do not result in a visible tumor when injected alone, even at 150 days post‐injection. Tumor cell debris stimulated angiogenesis in a matrigel plug assay as measured by increased infiltration of CD31+ endothelial cells via flow cytometry analysis. 5‐FU‐generated debris also stimulated macrophage production of the pro‐angiogenic factors, MIP‐1α, serpin E1, and osteopontin. We also detected increased osteopontin levels in the plasma of mice bearing debris‐stimulated tumors compared to mice injected with living tumor cells alone. Systemic administration of resolvins inhibited primary growth of human colon xenografts (CCL‐188) via reduced microvessel density (as measured by CD31+ endothelial cells). Resolvins also stimulated macrophage phagocytosis of tumor cell debris.ConclusionsWe show that chemotherapy‐generated tumor cell debris stimulates tumor angiogenesis and primary tumor growth. Stimulating the clearance of tumor cell debris via SPMs, such as resolvins, represents a novel approach to preventing tumor growth and progression by inhibiting tumor angiogenesis.Support or Funding InformationR01‐170549
The effect on the content of Nogo‐A in the damage area of the rats brain with Fasudil after traumatic brain injury
Authors: Duan Hubin , Hao Chunyan , Liu Cuiming , Li Shuzhen , Gao Ling , Zheng Xiaojun 
Published: November 2023

ObjectiveTo explore the nerve regeneration mechanism after traumatic brain injury (TBI) by detecting the content of the Nogo‐A in the damage area of the rats brain and the intervention experiment with Fasudil after traumatic brain injury.MethodsThe rats model with TBI was prepare by Feeney's methods. 45 male SD rats were randomly divided into Sham operation group(Sham group), traumatic brain injury group (TBI group) and Fasudil treatment group(F group). Fasudil treatment group rats were immediately given Fasudil (9mg/kg, Qd) after TBI for 3 days. Immunohistochemistry measurement was used to detect the content of the Nogo‐A in the damage area of the rats brain. Using electron microscope to observe the ultrastructure changes of the damage area and the surrounding tissue in each group.ResultsNuclei deformation, shrivel and irregular were observed in the cells of damage area of the TBI group and F group rats brain. Scattered nucleoli, increased chromatin, mitochondria scattered distribution, edema, mitochondrial crest disappear were also observed in above cells. Furthermore, these phenomena in TBI group rats brain were more serious than F group rats brain. There are significant difference among the Nogo‐A protein content in the damage area of rats brain tissue in Sham group, TBI group and F group (P<0.05). The Nogo‐A protein content in TBI group is the highest and the one in Sham group is lowest(P<0.05).ConclusionCraniocerebral trauma can cause brain damage, including the nucleus, mitochondria and other structural damage, cell edema, NOGO ‐ A content increased, which inhibite the nerve regeneration. Fasudil can block the Rho/ROCK signaling pathways, dilate cerebrovascular, increase the blood flow in the cerebrovascular, and promote nerve regeneration and functional recovery.Support or Funding InformationThis study was supported by the National Natural Science Foundation Youth (Fund No.30600637), China Postdoctral Foundation (Fund No.2014M561207), Research Project Supported by Shanxi Scholarship Council of China(Fund No. 2011‐096 and Key projects No.4)
Autoantigen‐specific T and B Cell Cross‐reactivity to a Gut Commensal in Antiphospholipid Syndrome
Authors: Dehner Carina Anja , Ruff William , Vieira Silvio Manfredo , Goodman Andrew , Kriegel Martin Alexander 
Published: November 2023

The microbiota provides an enormous antigenic challenge to the adaptive immune system. We hypothesized that a homeostatic adaptive immune response to commensals can trigger and sustain autoreactive T and B cells via cross‐reactivity with autoantigens in an HLA‐susceptible host. We used antiphospholipid syndrome (APS), an autoimmune clotting disorder targeting the plasma protein b2‐glycoprotein I (b2GPI), as a human model.Protein BLAST and Clustal Omega queries revealed that the human gut commensal Roseburia intestinalis contains peptide sequences with high homology to the immunodominant b2GPI T and B cell epitopes. Patient PBMCs proliferated significantly more to R. intestinalis protein extracts compared to phylogenetically closely related Eubacterium rectale, which lacks homologous sequences. We next established a MHCII tetramer for a major pathogenic T cell epitope in domain V of b2GPI, which shares a highly homologous region with an unrelated R. intestinalis protein. Sorting on tetramer‐positive CD4 memory T cells, we sought to determine if clones cross‐react with R. intestinalis proteins and peptides. Tetramer‐positive T cells proliferated significantly more to heat‐killed whole R. intestinalis bacteria in a dose‐responsive manner compared to controls. Cytokine measurements revealed a heterogeneous but pathogen‐associated phenotype. Tetramer positive clones showed an increase in GM‐CSF, TNF‐α IL‐9, IL‐13, and IL‐21.To demonstrate cross‐reactivity functionally in vivo, BALB/c mice were immunized with whole heat‐killed R. intestinalis and proliferation studies using splenocytes and lymphocytes were performed. Lymphocytes from draining lymph nodes and splenocytes showed significant proliferation in response to b2GPI compared to littermate mice immunized with adjuvant alone. Furthermore, ELISA revealed significant anti‐b2GPI titers in 1 of 3 R. intestinalis‐immunized animals compared to controls. In vitro, immunoblotting using APS patient plasma and an RGGMR epitope‐specific monoclonal antibody showed strong reactivity with R. intestinalis proteins including one at 24 kDa at the size of the major mimic‐containing candidate protein.In summary, we have identified human epitope‐specific b2GPI‐reactive CD4 memory T cell clones, which have a pathogen‐associated phenotype and cross‐react to whole heat‐killed R. intestinalis. Additionally, immunization of BALB/c mice with R. intestinalis produces human b2GPI‐reactive lymphocytes and autoantibodies, the latter are also supported in vitro by an epitope‐specific monoclonal anti‐human b2GPI antibody binding to R. intestinalis protein. To our knowledge this work represents the first study to demonstrate b2GPI‐specific T and B cell cross‐reactivity to a common human‐commensal bacterium. Further studies to determine the R. intestinalis proteins and epitopes recognized by the patients' adaptive immune system are ongoing.Support or Funding InformationNIH/NIAID
Retrieval Practice is a Superior Method for Learning Anatomy and Physiology Information
Authors: Dobson John 
Published: November 2023

Retrieval practice is a learning strategy that was developed by cognitive scientists and is based on the act of recalling information after exposure. Although dozens of studies have demonstrated meaningful learning advantages with retrieval practice, most educators and students are not familiar with the strategy. The purpose of this presentation is to share five studies in which our lab found that retrieval practice resulted in superior learning when compared to more commonly‐used strategies such as reading/rereading. These advantages included superior recall and a greater ability to synthesize complex information that is typically found in anatomy & physiology, structural kinesiology and exercise physiology courses.Support or Funding InformationNone
Modeling human lumbar spinal osteoarthritis and low back pain through preclinical studies
Authors: Little Joshua W 
Published: November 2023

Low back pain (LBP) is a prevalent condition and the primary cause for global disability. This is likely a result, in part, of poor pain management that stems from a lack of understanding of the pathophysiological mechanisms that contribute to this complex condition. To better understand the underlying mechanisms of LBP, we use preclinical animal pain models to mimic the human condition and examine the neurobiological processes induced from spine‐related tissues that contribute to pain. We are currently investigating two common causes for LBP, lumbar facet joint degeneration and muscle pain. Facet joint degeneration that is consistent with spinal osteoarthritis (OA) has distinctive patterns of histopathological findings. We wanted to determine if a rat model of lumbar vertebral segmental hypomobility induces degeneration that replicates these characteristic findings to mimic spinal OA. We performed time‐dependent investigations to determine the location, severity, and progression of histopathological changes to the articular cartilage following the onset of hypomobility. Our findings suggest that lumbar spine hypomobility induces facet joint histopathological changes that mimic spinal OA histopathology, location (patterning), and progression. We have also identified the potential contribution of adjacent joint tissues including the synovium, capsule, and subchondral bone in the onset and progression of OA. The low back muscles are also a clinically relevant source of LBP. We are investigating a rat model to mimic chronic low back muscle pain (LBPm) using nerve growth factor (NGF), a critical regulator of pain signaling and essential to muscle pain including LBPm. Repeated lumbar paraspinal intramuscular NGF injections in rats induce prolonged pain behavioral responses (e.g., paraspinal mechanical hyperalgesia) and enhanced response profiles of dorsal horn nociceptive neurons. These findings are consistent with central (spinal) sensitization, a pathophysiological state implicated in chronic pain. Central sensitization is associated with a glial cell mediated inflammatory process called neuroimmune activation, which is defined experimentally as glial cell hyperactivation with the release of proinflammatory cytokines. We hypothesized that repeated NGF paraspinal muscle injections contribute to persistent mechanical hyperalgesia and central sensitization, in part, through spinal cord neuroimmune activation. Our time course studies revealed that the development of NGF induced LBPm is associated with lumbar spinal cord dorsal horn microglial hyperactivation; suggesting that neuroimmune activation contributes to LBPm. Collectively, these models are promising and may provide a better mechanistic understanding to develop therapeutic approaches that offer meaningful LBP relief.Support or Funding InformationSLU Center for Neuroscience and NCMIC
Are Early Eocene Asiadapid Primates Primitive or Derived? Implications for Behavior and Morphology of the Ancestral Euprimate
Authors: Dunn Rachel 
Published: November 2023

The oldest known primates of modern aspect (euprimates) appear at the beginning of the Eocene across the Holarctic. At the time of their appearance they are already clearly divided into two distinct clades: Adapoidea (basal members of Strepsirrhini, lemurs, lorises, and bushbabies) and Omomyidae (basal Haplorhini, tarsiers, monkeys, and apes). However, postcranial remains from these earliest euprimates are rare and fragmentary, and most of our knowledge of postcranial adaptations within euprimate groups is based on younger, more derived fossils, which show postcranial specializations for leaping. This evidence has led researchers to suggest that leaping played a key role in the evolution of euprimates as a clade. Fossil adapoids (family Asiadapidae) and omomyids (the genus Vastanomys) from the early Eocene of India are among the earliest fossil euprimates for which well‐preserved postcrania are known, making them ideal for addressing the question of the ancestral euprimate locomotor mode. These early euprimates are represented mostly by teeth and jaws that clearly place them within adapodiea or omomyidae, but the isolated postcranial elements are unique in showing little specialization for leaping. While it is generally accepted that the Indian primate postcrania lack derived traits seen in younger fossils, there is disagreement about whether the lack of specialization in asiadapids, specifically, reflects the ancestral euprimate condition or represents a reversal from a more specialized leaping ancestor. This talk reviews functional and comparative analyses of the Indian primate postcrania in a phylogenetic context to assess whether asiadapid morphology is likely due to plesiomorphy or homoplasy. The assertion that the non‐specialized morphology in asiadapids is due to homoplasy requires assumptions that are not well supported by the fossil record (that asiadapids evolved from a large‐bodied ancestor) and that reversals occur in body size and across the skeleton in both asiadapids and Vastanomys; however, it is consistent with previous conceptions of the ancestral euprimate as a specialized leaper. If asiadapids are considered to represent an ancestral morphology, this would suggest that the ancestral euprimate was small, and that the early divergence of strepsirhines and haplorhines was driven by differences in hind‐limb behaviors, both of which are supported by our current knowledge of the fossil record. However, this scenario suggests that the ancestral euprimate was a generalized arboreal quadruped, rather than a specialized leaper, which necessitates an alternative explanation for the evolution of traits uniting euprimates.Support or Funding InformationNational Geographic Society, Leakey Foundation, Belgian Science Policy Office, Wadia Institute of Himalayan Geology
X‐Ray Computed Tomography Reveals Hidden Morphology in an Extinct Mammalian Relative
Authors: Wallace Rachel Veronica Simon 
Published: November 2023

High Resolution X‐ray computed tomography is commonly used to study internal structures of fossil skulls. CT allows inference about the structure of brain surface morphology, the inner ear, and internal bony elements such as turbinates. Computed tomography data is frequently published in figures as isosurface renderings of either the segmented endocranial volume or of the surface of the specimen. Here I demonstrate how CT improves upon superficial anatomical understanding of fossils in a Late Triassic early mammal relative from the Ischigualasto Formation in Argentina. When the specimen, PVSJ 882, was first discovered and initially described, it was assumed to be closely related to mammals on account of the perceived absence of two circumorbital bones, the prefrontal and postorbital. It was not until the specimen could be viewed non‐destructively in cross section that the prefrontal and postorbital were identified to be present. However, other derived early mammalian features grew apparent, including a fusion of the prootic and opisthotic to form the petrosal, as well as cochlea housed within a bony promontorium. The discovery of primitive orbital elements in a specimen with such a derived ear is new to mammal paleontology. The superficial morphology of other derived mammal relatives is encouraged to be studied with CT. Furthermore, I demonstrate how adjusted volume renderings can more accurately communicate the morphology of the specimen in question, while isosurfaces can be misleading for the same reasons that photos of the specimen in rock matrix can be misleading. While isosurface renderings have advantages in figures depicting CT data, they should not be used to the exclusion of volume renderings when volume renderings can depict subtle sutures, unprepared foramina, and deep, delicate bone buried under rock matrix.Support or Funding InformationThe Jackson School of Geosciences at the University of Texas at Austin