bluuebunny/crossref_metadata_2025 huggingface dataset:
Downregulations of Aldolase C Are Correlated with IDH1 Wild‐type Overexpressions and Predict Significant Poor Prognosis in Glioblastoma Patients
Authors: Tsai Hsing Fang , Chang Yu Chan , Tsai Wen Chiuan , Hsiao Michael
Published: June 2021

Background

Aldolases family is the one of the main enzymes involved in the process of glycolysis. The expression of aldolases family is tissue‐specific, and Aldolase C (ALDOC) is found expressed mainly in the normal brain especially in the adult brain and is also found important in the brain development of infant. ALDOC catalyzes the reversible conversion of fructose‐1,6‐bisphosphate to glyceraldehydes‐3‐phosphate (G3P), or glyceraldehyde, and dihydroxyacetone phosphate (DHAP) by aldol cleavage to exert it function in brain hippocampus and purkinje cells. However, the role of ALDOC in glioblastoma remains unclear.

Design

In this study, we data‐mined the in silico databases to evaluate the RNA expression of aldolase family members in glioblastoma (GBM) patient cohorts to determine its prognostic values. We further performed Immunohistochemical staining (IHC) analysis to evaluate protein expression levels of ALDOC in GBM patients. The correlation of ALDOC and GBM patient survival were examined.

Results

Our results from TCGA database analyses showed higher expression of ALDOC RNA expression levels in the normal brain tissue compared to GBM (P=0.0004). Expression levels of ALDOC were found significantly downregulated in high grade GBM compared to low grade glioma. In addition, the expression level of ALDOC is associated with molecular subtypes (proneural, neural, classical and mesenchymal) and recurrent status in several GBM datasets. The expression level of other Aldolase family members ALDOA and ALDOB have no significant prognostic impacts in the GBM cohorts. We further examined the correlations of wild‐type IDH1, one of the most significant poor prognostic markers in GBM, with ALDOC in GBM patient cohorts. Interestingly, our results showed there was a strong negative correlation between IDH1 and ALDOC expression in RNA levels at TCGA cohorts as well as in protein expression levels in our GBM patient cohorts. Combination of low ALDOC and high IDH1 wilt‐type expressions predicts a stronger poor significance in GBM patient compared to ALDOC or wild‐type IDH alone. Moreover, we found there is also a strong IDH1 mutant expression with increase ALDOC expression levels that predicts a significant good prognosis in GBM patient cohorts. The plausible ALDOC and IDH1 regulatory mechanism was further elucidated.

Conclusion

These results indicate ALDOC downregulation correlates with IDH1 wild‐type overexpression and predicts stronger poor prognosis in glioblastoma patients. ALDOC may play critical roles in inhibiting IDH1 functions to inhibit the progression of glioblastoma.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Brain Cancer: Failure of Resolution of Inflammation?
Authors: Hallisey Victoria , Barksdale Chantal A , Chang Jaimie , Sulciner Megan L , Bielenberg Diane R. , Schmidt Brigitta A , Keiran Nicholas , Haung Sui , Serhan Charles N , Keiran Mark W , Panigrahy Dipak
Published: June 2021

Medulloblastoma therapy, including radiation and chemotherapy, induces cell death resulting in tumor cell debris assumed to be inert or inhibitory to tumor growth. However, tumor cell death (debris) produced by cytotoxic therapy can accelerate tumor progression through the inflammatory response, suggesting that every attempt to kill tumor cells is a double‐edged sword. Inflammation is regulated by endogenous specialized pro‐resolving lipid mediators (SPMs), such as resolvins and protectins, which are present in the brain and CSF. These lipid autacoids stimulate the clearance of cellular debris by macrophages, resulting in reduced localized pro‐inflammatory cytokines. A loss of SPMs is associated with several neurodegenerative diseases but has not been studied in brain cancer. We hypothesize that reduced levels of SPMs correlate with brain cancer progression and that control of tumor cell debris‐mediated inflammation through resolvins and protectins represents a novel approach to brain cancer treatment. Here, we show that SPM receptors are expressed by human brain tumors including glioblastoma and medulloblastoma. Medulloblastoma tumor cell debris generated by front‐line chemotherapy or targeted therapy stimulates primary tumor growth when co‐injected with a subthreshold (non‐tumorigenic) inoculum of tumor cells by triggering the release of pro‐inflammatory cytokines. Stimulation of the resolution of inflammation via protectins and resolvins suppressed orthotopic medulloblastoma. Protectins and resolvins down‐regulated proinflammatory cytokine release in debris‐activated microglia and stimulate the clearance of tumor debris by inducing macrophage phagocytosis of apoptotic tumor cells. Histological analysis of SPM‐treated medulloblastoma and glioblastoma tumors revealed suppressed Ki‐67‐stained tumor cell proliferation. Thus, brain tumor progression results from a loss of resolution of tumor debris‐associated inflammation. Enhancing endogenous clearance of tumor cell debris via protectins and resolvins is a novel biological target to complement current cytotoxic brain cancer therapy and addresses the intrinsic limitation of current cancer therapy involving cell death. Our studies provide a new strategy for the prevention and treatment of therapy‐induced resistance in medulloblastoma and other brain cancers.

Support or Funding Information

This work was supported by the National Cancer Institute grant RO1 01CA170549‐02 (D.P.); ROCA148633‐01A4 (D.P.); and the Credit Unions Kids at Heart Team (D.P.)

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Investigating Novel Roles for Hedgehog Co‐Receptors During Craniofacial Development
Authors: Echevarria‐Andino Martha Luz , Allen Benjamin
Published: June 2021

Hedgehog (HH) signaling is essential for correct patterning of vertebrate embryos, including during craniofacial development. HH ligands signal through the canonical receptor Patched1 (PTCH1), and three co‐receptors–growth arrest specific 1 (GAS1), cell adhesion molecule‐related/down‐regulated by oncogenes (CDON), and brother of CDON (BOC). Together, these co‐receptors are required during embryogenesis to mediate proper HH signaling. However, recent genetic studies suggest tissue‐specific, antagonistic roles for these proteins. For example, Gas1 restricts the HH pathway during mouse tooth development, while Boc antagonizes HH signaling during zebrafish jaw formation. Here I explored possible antagonistic roles for GAS1, CDON and BOC in HH‐dependent mammalian craniofacial development. Genetic deletion of these co‐receptors results in variable holoprosencephaly (HPE) phenotypes (failure to divide the forebrain into two cerebral hemispheres). Gas1 mutant mice display a spectrum of HPE phenotypes, and significant patterning defects in the neural tube and limb. In contrast, genetic deletion of Boc does not perturb patterning in any of these tissues. Strikingly, the combined deletion of Boc and Gas1 results in more severe neural tube and limb patterning defects than those observed in Gas1 single mutants. However, the Gas1 craniofacial phenotype is partially ameliorated in Gas1;Boc double mutant embryos as determined by the levels of NKX2.1, Gli1, Ptch1 and internasal distance quantitation. Micro‐computed tomography and skeletal analyses reveal that the rescue of the craniofacial defects in Gas1;Boc double mutants is restricted to the nasal bone and nasal capsule; other craniofacial bones are more severely affected, similar to what is observed in the neural tube and the limb. This effect does not appear to be due to differential GAS1 and BOC function in the forebrain neuroepithelium as overexpression of these co‐receptors in the developing chicken forebrain both promote HH signaling. Instead, I hypothesize that these co‐receptors have distinct, tissue‐specific functions in the craniofacial mesenchyme or the surface ectoderm. To further explore an antagonistic role for BOC during craniofacial development, I am currently deleting Boc in a sensitized HH genetic background through breeding with Ptch1 and Shh heterozygous mutant animals. These findings suggest that GAS1 and BOC do not function simply as redundant HH co‐receptors, but instead display distinct, tissue‐specific functions, particularly during craniofacial development.

Support or Funding Information

National Sciences Foundation Graduate Research Fellowship Program (DGE 1256260), Rackham Pre‐Candidate Graduate Student Research Grant, Bradley Merill Patten Fellowship and Organogenesis Training Grant (NIH T32HD007505)

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The intersection of chimpanzee science, ethics and policy: The rapid reformation of a research landscape
Authors: Ross Steve
Published: June 2021

Chimpanzees, along with bonobos, are the closest living relatives of human beings. As such, this species shares myriad genetic, physiological, anatomical, behavioral and cognitive traits with our own species and has served as a research proxy for humankind for over a hundred years. While much of the history of chimpanzee research is focused use as biomedical subjects, the past two decades of policy reform have radically reshaped when and how we utilize chimpanzees in research settings. In this talk, I will examine these historical trends and characterize the unprecedented way in which the research community has shaped and been shaped by these changes. Focusing on the growth of non‐traditional research venues such as zoos and sanctuaries, I will illustrate new opportunities for the study of chimpanzee biology, behavior and cognition while highlighting the inherent challenges that arise from a rapid restructuring of research paradigms.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Genetic or Pharmacological Induction of the Hypoxia Response Enhances Functional Regeneration Following Peripheral Nerve Injury
Authors: Smaila Brittney D , Erskine Erin L , Holland Seth D , Hunter Diana V , Babaeijandaghi Farshad , Rossi Fabio M , Ramer Matt S
Published: June 2021

Peripheral nerve injuries (PNIs) occur in 1–3% of patients with traumatic injuries. While peripheral axons have the ability to regenerate at ~1mm/day, the distance over which they must do so means lengthy recovery times, which are associated with regenerative failure due to a decline in supporting cells' ability to maintain axon growth. Successful axonal regeneration depends heavily upon the neuronal response to injury, as well as that of myeloid cells recruited to the damaged nerve. In injured neurons, transcriptomic changes occur which mirror those observed in hypoxia. Hypoxia inducible factors (HIFs) effect these transcriptomic changes; these are governed in turn by prolyl hydroxylase domain (PHD) proteins. Under normoxic conditions, PHDs act as master regulators of the hypoxia response, targeting HIFs for proteasomal degradation. We hypothesize that deleting any or all of the PHDs (PHD1, 2, and 3), or inhibiting PHDs pharmacologically, will induce the hypoxia response and enhance axonal regeneration and functional recovery following PNI. We used global PHD1 knockout, global PHD3 knockout, and heterozygous PHD2 transgenic mice, as well as non‐transgenic mice treated with DMOG, a pan‐PHD inhibitor. We used a sciatic nerve crush model of injury and assessed functional recovery at various time points post‐injury using toe pinch and grasping tests, and electromyography. Using immunohistochemistry we characterized macrophage and axon densities in the nerves after injury. We also assessed DMOG‐induced changes in macrophage phenotype using FACS, RT‐PCR and immunohistochemistry. We found that deletion of PHD1 or PHD3, or inhibition of all three PHDs resulted in earlier functional recovery after injury, increased macrophage infiltration in the injured nerve, an M2‐skewed macrophage phenotype, and enhanced axonal regrowth. In addition, deletion of any of the PHDs, or their inhibition by DMOG, resulted in improved electromyographical responses of the nerve one month post injury. Our findings suggest that functional recovery after peripheral nerve injury can be aided by hypoxia‐independent induction of the hypoxia response.

Support or Funding Information

Wings for Life; ICORD Blusson Integrated Cures Partnership

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Prosecting Human Cadaveric Donors in Stages to Mimic Dissection
Authors: Curran Shannon
Published: June 2021

Gross anatomy lab contact hours are decreasing for many health professions students, yet the quantity and importance of the anatomical information they are required to learn remains the same. In an attempt to maintain the benefits of cadaver‐based study, many programs are using prosections as an alternative to dissection when student lab time is limited. Although prosection‐based instruction is a valuable and time‐efficient method for students, students can struggle to understand important anatomical relationships that are typically mastered during dissection. Creating prosections that mimic the progressive stages of dissection, presented in a sequential and structured manner, can maximize learning while mitigating the challenges of prosection use. Whole human cadaveric donors were prosected to demonstrate either superficial or deep structures for first year Physician Assistant students. Superficial preparations demonstrated superficial relationships. Generally, these donors had no muscles reflected, no organs removed, and limited amounts of fat and fascia removed. Deep preparations demonstrated intermediate and deep relationships for the different systems and regions of the body. Generally, these donors had muscles reflected and fat and fascia removed to show all neurovasculature. To maximize donor use and student learning opportunities, different organs and muscles were removed and different regions were hemisected on the deep preparations to provide several deep views and relationships. By prosecting in this way, the layers and steps of dissection from superficial to deep were represented and anatomical relationships that are frequently lost while preparing prosections were maintained. Students were able to appreciate anatomical relationships and variability from human cadaveric donors in a way similar to dissection while accounting for reduced gross anatomy lab instruction time.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Meniscofemoral Ligaments: Under Emphasized in Anatomy Literature Despite Being Evolutionarily Preserved and Surgically Repaired
Authors: Stevens Kelsey , Immonen Jessica , Gilmer Les , Albin Alexa
Published: June 2021

Purpose and Background

Anatomical literature, including medical hallmarks such as Gray's Anatomy, variably discuss the location and prevalence of the anterior and posterior meniscofemoral ligaments (aMFL, pMFL). These ligaments can be seen in an intracapsular knee joint dissection emerging from the posterior horn of the lateral meniscus and flanking the posterior cruciate ligament (PCL) anteriorly and posteriorly. Anatomical teaching resources including some of the most widely used textbooks and atlases for students of allied health professions typical make no mention of the aMFL and variably label the pMFL in medical images.

Methods

66 cadaveric knee joints were dissected using a novel approach that improves preservation of the aMFL and pMFL. Prevalence of the meniscofemoral ligaments were recorded individually and together. Current and popular medical resources were reviewed for the presence of information on the meniscofemoral ligaments.

Results

It was determined that 100% of cadaveric knee joints possess at least one of the meniscofemoral ligaments hence, these structures have been evolutionarily preserved to carry out a significant function. One of the most convincing hypotheses on the function of the aMFL and pMFL claims they serve to guide the movements of the lateral meniscus during joint flexion and extension. Other hypotheses state these ligaments may function to oppose the popliteus' pull on the lateral meniscus to prevent tears, structurally reinforce the PCL or provide proprioceptive feedback. Large structures that currently do not possess concrete functional descriptions should not be left out of the anatomical literature as this promotes confusion and decreases the potential for future practitioner innovation.

Conclusions

New aMFL and pMFL prevalence data and the hypothesized biomechanical functions of the ligaments should be receiving more attention in the medical research and teaching literature. Select orthopedic surgeons perform surgical repairs of the meniscofemoral ligaments and their associated structures. The posterior horn of the lateral meniscus may also be surgically excised after tear although it is the origin of the meniscofemoral ligaments. A more thorough surgical attempt to repair posterior horn tears prior to meniscectomy should become the gold standard of practice as the fields of surgery and orthopedics advance and make final conclusions on the role of the meniscofemoral ligaments. Currently anatomical literature should more consistently address and discuss the anatomy of these ligaments.

Support or Funding Information

Internal Grant from Rocky Mountain University of Health Professions

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Granzyme K: An Important Mediator of Cutaneous Inflammation and Re‐epithelialization
Authors: Richardson Katlyn , Turner Chris , Zeglinski Matthew , Zhao Hongyan , Shen Yue , Granville David
Published: June 2021

Background

Granzyme K (GzmK) is a serine protease traditionally thought as having a role in immune cell‐mediated killing. However, recent evidence has challenged this paradigm. We now believe GzmK is a mediator of inflammation. GzmK is elevated in plasma from patients with a variety of pro‐inflammatory disorders, including allergic asthma, endotoxemia, and sepsis. In addition, culture of endothelial cell, lung fibroblasts and activated macrophages with purified GzmK induces the secretion of pro‐inflammatory cytokines. In the present study we hypothesized that GzmK is elevated in cutaneous inflammation and contributes to impaired reepithelialization of cutaneous wounds.

Methods

GzmK expression was evaluated histologically in tissue from patients with a variety of inflammatory skin diseases and compared to healthy skin controls. Using a murine model of skin injury and repair, the role of GzmK was investigated. Wound severity was assessed macroscopically, comparing onset, severity and wound resolution between GzmK−/− and wildtype mice. Wound tissue was isolated and examined histologically, including wound morphometry (wound area, re‐epithelialization, epidermal thickness), GzmK expression, collagen organization (Masson's Trichrome, picosirius red, Collage I/III), inflammation (markers of T‐cells, macrophages, NK cells), angiogenesis (CD31) and fibrosis (α‐SMA). To further verify the role of GzmK in cutaneous inflammation, cultured keratinocytes and skin fibroblasts were exposed to GzmK and cytokine expression, cellular proliferation and viability were assessed.

Results

GzmK was markedly increased in biopsies from patients with skin wounds compared to normal skin, with negligible levels observed. Macrophages, namely classically activated M1, were identified as the predominant cell type responsible for GzmK expression and secretion. GzmK−/− mice exhibited expedited wound closure and wound maturation compared to equivalent wounds in wild‐type mice. Re‐epithelialization had the greatest disparity between GzmK−/− and wild‐type mice; vastly accelerated epithelialization observed in GzmK−/− mice suggests that keratinocytes may be particularly sensitive to GzmK insult. Additionally, in vitro cultured keratinocytes exhibited impaired wound healing, including decreased cell migration and viability, and an increase in pro‐inflammatory cytokines when exposed to GzmK.

Conclusion

GzmK is an important mediator of cutaneous inflammation and epithelialization; functioning to enhance the pro‐inflammatory phase of wound repair whilst simultaneously hindering re‐epithelialization.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Role of Mitochondrial Peroxide Release in the Mechanisms Underlying Age‐Related Sarcopenia
Authors: Van Remmen Holly , Pharaoh Gavin , Ahn Bumsoo
Published: June 2021

Age related loss of muscle mass and function (sarcopenia) is a major contributor to reduced quality of life in the elderly. Previous studies from our laboratory have shown that denervation induced alterations in muscle mitochondrial reactive oxygen species (ROS) generation is an integral player in this process. To specifically determine the role of mitochondrial function, generation of ROS and lipid peroxides in denervation atrophy, we utilized two transgenic mouse models with increased expression of the hydrogen peroxide scavengers catalase or peroxiredoxin 3, specifically in skeletal muscle. First, we asked whether these mitochondrial antioxidants can reduce denervation induced changes in muscle mitochondrial ROS production and reduce muscle atrophy in a surgical denervation model. Gastrocnemius mass is significantly reduced (~20%) at 7 days post‐sciatic nerve transection in wildtype, skmPrdx3 and skmMCAT mice, i.e., there was no protective effect of hydrogen peroxide scavengers on denervation atrophy. ROS production measured using the fluorescent probe Amplex Red was elevated in permeabilized muscle fibers and isolated mitochondria from denervated hindlimb 7 days post transection and neither Prdx3 or MCAT expression inhibits the signal. This data supports that the Amplex Red signal does not represent hydrogen peroxide alone, but includes the response from other lipid peroxide species and suggests that hydrogen peroxide scavenging is not sufficient to reduce denervation induced atrophy. Next, we asked whether Prdx3 muscle specific expression can modulate the sarcopenia phenotype in an established mouse model of accelerated sarcopenia, mice lacking CuZnSOD (Sod1KO/skmPrdx3Tg mice). ROS generation is significantly elevated in isolated muscle mitochondria from Sod1KO mice, and normalized by Prdx3 overexpression in the Sod1KO/skmPrdx3Tg mice. The oxygen consumption rate is reduced in skeletal muscle mitochondria isolated from Sod1KO muscle and restored by Prdx3 overexpression. We also found that in vitro contractile force generation was decreased by ~20% in Sod1KO mice, and the force reduction wwas rescued in Sod1KO/skmPrdx3Tg mice. Importantly, the muscle atrophy that occurs in the Sod1KO mice is fully restored by Prdx3 overexpression. This finding demonstrates a direct role of skeletal muscle‐specific mitochondrial H2O2 in promoting contractile abnormalities and muscle atrophy. Together these results implicate mitochondrial H2O2 generation as a novel therapeutic target to ameliorate skeletal muscle pathologies and support further studies to elucidate the role of lipid peroxide mediators released by mitochondria in denervation induced atrophy.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Transcriptional Activation of Lipogenic Genes by Insulin/Feeding
Authors: Sul Hei Sook
Published: June 2021

Insulin treatment or feeding a high carbohydrate diet causes a marked increase in fatty acid and fat synthesis and enzymes involved in lipogenesis are coordinately induced. We are studying transcriptional activation of lipogenic genes, employing fatty acid synthase (FAS) as a model system. We defined insulin response element at ‐65 E‐box and USF binding at this site for transcriptional activation by insulin. USF and SREBP‐1c, by binding at adjacent sites, directly interact and function together. We identified various other components of the USF complex and their posttranslational modifications by feeding/insulin treatment. USF‐1 recruits and is phosphorylated by DNA‐PK allowing recruitment and acetylation by P/CAF, resulting in the FAS promoter activation, whereas, in fasting, USF‐1 is deacetylated by HDAC9. USF also recruits Brg1/Brm‐associated factor (BAF) 60c that functions as a specific chromatin‐remodeling component for lipogenic gene transcription. In response to insulin, BAF60c is phosphorylated at S247 by atypical PKCζ/λ, which causes translocation of BAF60c to the nucleus, allowing a direct interaction with USF‐1. Thus, BAF60c is recruited to form the lipoBAF complex to remodel chromatin structure. Recently, we also found that by direct interaction USF‐1 recruits specific histone demethylase for histone modification and transcriptional activation of various lipogenic genes.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hepatic Oleate Deficiency Represses De Novo Lipogenesis and Enhances Systemic Glucose Utilization Through FGF21 During High Carbohydrate Feeding
Authors: Ntambi James Mukasa , Aljohani Ahmed , Bonneville Abram , Bond Laura
Published: June 2021

Increased carbohydrate consumption and subsequently increased hepatic de novo lipogenesis have been linked to the development of chronic metabolic diseases including hepatic steatosis and insulin resistance. Stearoyl CoA desaturase 1 (SCD1) is a critical lipogenic enzyme that catalyzes the synthesis of monounsaturated fatty acids, oleate and palmitoleate, from saturated fatty acids, stearate and palmitate, respectively. SCD1 deficient mouse models exhibit protection against diet induced adiposity, hepatic steatosis, and hyperglycemia. However, the mechanism of this protection in response to SCD1 deficiency is not fully understood. Using a liver specific SCD1 knockout (LKO) mouse model fed a high carbohydrate low fat diet, we show that hepatic SCD1 deficiency decreases de novo lipogenesis and glycogen accumulation but instead increases tissue glucose uptake and utilization. Reduced hepatic oleate levels led to increased expression of GLUT4 and adiponectin expression in WAT and BAT. High molecular weight plasma adiponectin species were also increased. Glut‐1 expression was increased in the liver, small intestine, spleen and brain. The induction of glucose utilization in LKO mice correlated with higher hepatic expression and plasma levels of fibroblast growth factor 21 (FGF21), a hepatokine known to increase systemic insulin sensitivity and regulate whole body glucose and lipid metabolism. Feeding LKO mice with a diet rich in oleate, but not stearate reduced hepatic FGF21 expression and plasma levels. Consistently, inhibition of SCD1 activity in primary hepatocytes induced FGF21 expression which was repressed by treatment with oleate but not palmitoleate. These data suggest that hepatic oleate regulates systemic glucose metabolism either directly or through modulating plasma FGF21 and adiponectin.

Support or Funding Information

NIH, ADA

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Emodin, a natural anthraquinone, may help protect gastrointestinal health during chemotherapy treatment by decreasing inflammation of the gastric mucosa and preserving gut morphology
Authors: Sougiannis Alexander T. , Kelley Brittany , Velazquez Kandy E. , Enos Reilly T. , Bader Jackie E. , Chatzistamou Ioulia , Pena Marjorette M. , Nagarkatti Mitzi , Carson sJames A. , Fan Daping , Murphy E. Angela
Published: June 2021

The clinical utility of 5‐fluorouracil (5FU) chemotherapy remains hampered by hematopoietic and gastrointestinal toxicities. Emodin, a natural anthraquinone, has been shown to have anti‐inflammatory potential and may be effective as a complementary therapeutic used during chemotherapy treatments. The purpose of this study was to evaluate the efficacy of emodin on reducing the non‐specific toxicities associated with 5FU treatment. 50 C57BL/6 were randomized into four groups; Control + Vehicle (n=5), Control + Emodin (n=5), 5FU + Vehicle (n=20), 5FU + Emodin (n=20). 5FU was administered via I.P. over 3 cycles of the following regime: 5 consecutive days of 5FU at 35mg/kg followed by 9 days of recovery. Emodin was administered via oral gavage 3x/week at 40mg/kg through the entire 3 cycles of 5FU treatment. 5FU + Emodin treated mice showed improved muscular strength (p<0.05), fun‐to‐fatigue time (P<0.05), and peripheral nociception (p<0.05) compared to 5FU + Vehicle treated mice. 5FU + Emodin treated mice did not show recovery of decreased circulating immune cells and red blood cells that is common with 5FU treatment. 5FU + Vehicle treated mice did show slightly increased splenic CD11b+ F4/80+ macrophages (6.8%) vs. control mice (4.3%), a phenotype that was not decreased in 5FU + Emodin treated mice (6.5%). 5FU treatment shows classic inflammatory damage to the gastric mucosa. 5FU + Vehicle treated mice show decreased villus length (p<0.05) compared to control mice. 5FU + Emodin treated mice showed increased villus length (p<0.05) compared to 5FU + Vehicle treated mice but remained shorter (p<0.05) than control mice. Further, small intestine tissue shows increased TNFα expression in 5FU + Vehicle treated mice which was decreased (p<0.05) in 5FU + Emodin treated mice. Similar increases in inflammatory gene expression are seen in the colon tissue of 5FU + Vehicle treated mice. 5FU + Emodin treated mice show decreased colonic TNFα expression (p<0.05) and trending decrease in MCP‐1 (p=0.052) and NOS2 (p=0.065) expression compared to 5FU + Vehicle treated mice. Taken together, Emodin treatment may contribute to improved GI health by reducing damaging inflammation which may contribute to improved overall quality of life. Future analysis will expand on the inflammatory signaling pathways involved in emodin signaling and will investigate the potential role of the gut microbiome in reducing GI inflammation in this model of 5FU treatment.

Support or Funding Information

1F31AT009820 to ATS.1RO1CA218578 to EAM. 1R41AT009964 to EAM. 5R21CA191966 to EAM.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
GUT BACTERIA MODULATE T CELL RESPONSES AND ADVERSE CARDIAC REMODELING IN PRESSURE OVERLOAD INDUCED HEART FAILURE
Authors: Carrillo‐Salinas Francisco J , Ngwenyama Njabulo , Anastasiou Marina , Kaur Kuljeet , Aronovitz Mark , Alcaide Pilar
Published: June 2021

Changes in the bacterial composition of the gut, defined as gut dysbiosis, are recently becoming associated with the pathogenesis of heart failure (HF), a leading cause of mortality worldwide. Certain bacteria promote T cell activation, and T cell activation contributes to adverse cardiac remodeling and cardiac dysfunction in HF. We tested the hypothesis that gut dysbiosis modulates cardiac remodeling and function in a T cell‐dependent manner. C57/BL6 mice were orally treated with a wide spectrum antibiotic cocktail (ABX) and subjected to transverse aortic constriction (TAC), a stablished model of HF. ABX was present during the 4 week duration of TAC, thus sterilizing the gut completely, or during 3 weeks before TAC followed by removal during the 4 weeks of TAC duration to allow spontaneous reconstitution of the gut microbiota. We report that gut microbiota depletion results in reduced T cell activation in the mediastinal lymph nodes, heart T cell infiltration, and prevents cardiac fibrosis and cardiac hypertrophy in response to TAC. However, gut dysbiosis induced by bacterial reconstitution after ABX removal, only partially recovered this phenotype. We used 16S RNA sequencing to characterize the bacterial populations in Sham, TAC, and in ABX treated TAC mice after ABX removal and spontaneous bacterial colonization in the gut (TAC‐REC). TAC induced changes in the gut microbiota compared to Sham surgery, which at the genus level resulted in a higher relative abundance of Bacteroides (p=0.048) and lower relative abundance of Coprococcus (p=0.024), Lactobacillus (p=0.021) and Bifidobacterium (p=0.042), these last two normally associated to an anti‐inflammatory response. Bacterial reconstitution in TAC‐REC mice started after 2 weeks of ABX removal, but was incomplete even by 4 weeks post ABX removal, as reflected by the different relative bacterial abundance between TAC and TAC‐REC 4 weeks post TAC. Several genera were identified as colonizing the gut in TAC‐REC mice that could potentially be associated with cardiac dysfunction. Ongoing studies are focused on the characterization of bacterial populations responsible for this effect and on determining the type of T cell response involved.

Support or Funding Information

This work was supported by the NIH‐R01‐HL123658.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
β1‐Blockers Provide Cardioprotection, Attenuation of Intramyocardial Inflammation and Leukocyte Endothelial Transmigration in Septic Mice
Authors: Mansart Arnaud , Efthimiadi Laurie , Vinit Stéphane , Fayssoil Abdallah , Annane Djillali
Published: June 2021

Septic cardiac dysfunction is a key feature of severe sepsis and septic shock, contributing to multiorgan dysfunction syndrome and death. Persistent β adrenergic stimulation is detrimental in sepsis, and specific β1 blockade mitigates excessive systemic inflammation and seems to improve myocardial function. The aim of this study was to investigate the effects of the specific β1 blocker atenolol on the septic mouse myocardium. We also evaluated the survival of septic mice and systemic inflammation in response to atenolol treatment.

Mice were rendered septic using intraperitoneal injection of lipopolysaccharide (LPS). The effects of atenolol on the myocardium were assessed by a microarray technique and were confirmed by subsequent western blot, elisa protein assays and confocal microscopy. Infusion of atenolol significantly reduced the intramyocardial production of the proinflammatory cytokines tumor necrosis factor α (TNF‐α), interleukin 1β (IL‐1β) and interleukin‐6 (IL‐6) in the septic model. Cell adhesion molecules and local myocardial chemotaxis were down‐regulated, with a significant reduction in the myocardial levels of angiopoietin 2 (Ang‐2), monocyte chemoattractant protein 1 (MCP‐1), macrophage inflammatory protein 1α (MIP‐1α), MIP‐2, E‐selectin, P‐selectin, intracellular adhesion molecule 1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1). Furthermore, atenolol significantly improved left ventricular ejection fraction, arterial pressure and aortic blood flow in septic mice. The median survival time was increased by atenolol in septic model, and the plasma levels of lactate, TNF‐α, IL‐1β, IL‐6, MCP‐1 and MIP‐1α were significantly reduced in response to atenolol treatment.

In mice with experimentally induced septic shock, the β1 adrenergic blocker atenolol exerts cardioprotective effects through the tempering of both systemic and local inflammation and by reducing intramyocardial chemotaxis and the synthesis of endothelial transmigration proteins.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cutaneous and Gastrointestinal Dysbiosis in Immunodeficient Mice
Authors: Fowlkes Natalie Wall , Swain Jody , Gagea Mike , Lockworth Cynthia , Tinkey Peggy , Jensen Vanessa , Whitley Elizabeth
Published: June 2021

The health of immunodeficient rodent strains used for tumor modeling is often challenged by increased susceptibility to overgrowth of organisms which are not normally pathogenic in immunocompetent mice. Herein, we describe spontaneously occurring skin and gastrointestinal lesions in a cohort of immunodeficient mice. In the current case series, NOD‐SCID‐gamma and athymic nude mice presented clinically moribund with thickened, scaly, erythematous cutaneous lesions covering the head, neck, and trunk. Examination of hematoxylin and eosin (H&E) stained sections revealed marked acanthosis and orthokeratotic hyperkeratosis with large numbers of coccobacilli in the lamellar layers of keratin of epidermis in affected animals. Variable mild dermal inflammation was present. Gram‐positive pleomorphic rods were cultured from skin and identified as Corynebacterium bovis via qPCR. Staphylococcus xylosus was also cultured in a case that had abundant Gram‐positive cocci bacteria in the skin. C. bovis and S. xylosus have been associated with a “scaly skin” syndrome in immunodeficient mice. Acanthosis and hyperkeratosis with coccobacilli were also present in the keratinized portion of the stomach. Additionally, affected mice frequently had massive proliferation of segmented filamentous bacteria (SFB) in the small intestine. Impaired immune responses in immunodeficient strains may lead to a constellation of clinical signs and pathology which represent a form of dysbiosis. Investigation of dysbiosis in immunodeficient mice used in cancer research is important for maintaining the health of the colony and for accurate interpretation of research outcomes.

Support or Funding Information

Supported by the NIH/NCI under award number P30CA016672 and the Research Animal Support Facility‐Houston.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effect of Different Auditory Stimuli on Laparoscopic Skill Acquisition
Authors: Grant Sara , Singh Aman , Roach Victoria
Published: June 2021

INTRODUCTION

Literature suggests that listening to music decreases the time required for a surgeon to perform surgical skills, and improves their overall performance. However, little is known about how the surgeon's preference or response to that particular music affects the rate at which they learn a novel skill. The primary goal of this study is to explore how different auditory conditions impact the rate of acquisition of an introductory surgical skill, the intracorporeal knot.

METHODS

Participants will be naïve to surgical skills (medical students), and prescreened for demographics, history of musical experiences, and their use of music as a study aid. A cognitive pre‐test will be employed to assess baseline participant performance with, and without the presence of music. This will serve to stratify individuals into two groups: those whose performance thrives, or declines, in the presence of music. An equal proportion of individuals from each group will be randomly assigned to one of four auditory training conditions: participant‐preferred music, randomized music, ambient noise, and silence. Participants will watch an instructional video on the technique of the intracorporeal knot and will have 80 minutes to practice the task to proficiency. Proficiency is defined in the literature by the Fundamentals of Laparoscopic Surgery as a maximum of 112 seconds with no knots occurring outside of 1mm. Learning curves will be analyzed to determine the rate of acquisition for each group.

ANTICIPATED RESULTS

We anticipate that participants will master the intracorporeal knot tying task fastest under the preferred music condition, and slowest in the randomized music condition.

CONCLUSION

When the music is reflective of the surgeon's personal taste, it could be beneficial for the acquisition of new surgical skills. However, non‐preferred music could negatively impact skill acquisition and would suggest that minimizing of the use of music in operating rooms when residents are present would generate a more efficient learning environment.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Long Arm of Anatomy Education Outreach Programs: From NYC to Tanzania and Brasil
Authors: Marquez Samuel , Mtui Estomih , Curcio Daniella F , Laitman Jeffrey T
Published: June 2021

Anatomy education outreach programs have been the focus of three directors of anatomy from different medical institutions who together have collaborated locally, and have continued their work individually, to target underrepresented population groups from NYC to Tanzania and Brasil. Márquez of Downstate created Anatomy Education Day (AED), a powerful education outreach program that centers on the exposure of underrepresented youth to the Allied Health Sciences as a means of increasing diversity in medicine and related healthcare fields. Mtui of Weill Cornell Medicine returns yearly to his native country of Tanzania performing lectures and dissection demonstrations to stimulate the young minds of first‐ and second‐year medical students. His motivation can be linked to when he grew up in the rural Marangu‐Kilimanjaro Tanzania, when a doctor came to visit to talk about health care practices and how these behaviors actually helped the people of this settlement. That education outreach visit sparked an interest in him that eventually took him to UPenn, Galway in the Republic of Ireland and ending at Cornell where he is the Professor and Chief of the Division of Anatomy. Laitman and Curcio of Mount Sinai have been building bridges between Brasil and the US in anatomical education focusing on students who although disadvantaged inresources more than compensates for it with their enthusiasm, dedication, and strong work ethic. Curcio, a native of São Paulo, has witnessed first hand the impact the outreach has had not only on her countrymen but also on her ‐ reinvigorating and motivating her in bridging the gap between the immediate needs of students and easy access to educational resources. The different education outreach approaches employed by the authors are designed to maximize exposure to a range of healthcare pathways, in a concerted effort to inspire and prepare students to pursue careers in medicine and medical research.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Student perceptions of the importance of diversity and inclusion in anatomical dissection teams
Authors: Alsup B. Kathleen , Fox Glenn M.
Published: June 2021

There is a marked increase of diversity and inclusivity teaching initiatives at the University of Michigan. Based on these programs and the goal of the Division of Anatomical Sciences' faculty to best provide a safe and productive environment for all learners, a research plan was developed to investigate what aspects of diversity and inclusion are of most importance to students participating in a dissection‐ and team‐based Anatomy course (DENT 545). Results indicate that the majority of students considered the Anatomy curriculum to be inclusive (53.2% pre‐ and 56.8% post‐survey), based on the University of Michigan's definition of inclusive teaching. However, student viewpoints differed considerably in the importance of diversity within a dissection team, and what aspects of diversity and inclusion are of greatest importance.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Growth vs. Fixed Mindset and Perceived Stress in First and Second Year Medical Students
Authors: Roth Alex R , Schaefer Audra F
Published: June 2021

Burnout in medical professions is a growing concern, and as such, factors associated with burnout, such as stress, are being examined as early as medical school matriculation. By understanding the stress levels of medical students in their preclinical years, faculty can potentially assist students in the development of stress management techniques early on, enabling students to better handle the stress of medical school and in their careers as future physicians. A factor that has implications for how students approach the academic setting and how they manage stress is an individual's mindset. A person with a fixed mindset believes their intelligence is a static trait that will only be documented rather than be further developed. In comparison, individuals with a growth mindset believe they can change their intelligence through hard‐work. Growth mindset has been shown to be associated with greater academic success and resilience enduring stress.

The goal of this study was first to determine first and second‐year medical students' perceived stress levels and whether the students held a fixed or a growth mindset. Additionally, this study aimed to determine if there is a relationship between perceived stress, mindset and academic performance during the preclinical years of medical school. In this pilot study, with IRB approval, first and second year medical students at a regional campus of a large Midwestern medical school completed the Perceived Stress scale, a 10 question Likert‐type inventory, as well as a 20 question Likert‐type scale to determine students' predominant mindset (growth versus fixed). Additionally, the relationships between mindset and scores on NBME subject exams in the preclinical years and USMLE Step 1, as well as perceived stress scores and NBME scores and USMLE Step 1 scores will be examined. Preliminary results showed that 12% of students had a strong growth mindset, and 70% of students had a growth mindset with some fixed ideas. The perceived stress scale scores ranged from 2–38 (40 max), with an average score of 12.9.

A better understanding of students' perceived stress and their mindset about learning in medical school can provide potentially useful insight for instructors into the mindset of their students, allowing instructors to help guide students through the learning process and managing the stress that often accompanies this difficult academic path.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.