Guidance of Developing Motor Neurons into the Periphery

Motor neurons (MNs) are a diverse class of cells that originate in the central nervous system and project to muscles in the periphery. The development of all MNs subtypes begins with Sonic Hedgehog (Shh) signaling in the spinal cord and then progresses to increasingly specific guidance signaling systems. MN subtypes are classified by the combined activities of transcription factors and molecular signaling systems that determine axon trajectory. Molecular cues have been attributed to the organization of MNs into columns within the spinal cord and then into specific motor pools. These cues have also been shown to be responsible for axon guidance into the periphery and important for axons to innervate the correct targets. Despite advances in research on specific guidance cues used by different subdivisions of MNs, it is still not fully understood how signaling systems work with one another in the same environment to guide different classes of MNs to their respective muscle targets

Inhibition of the Redox Function of APE1/Ref-1 in Myeloid Leukemia Cell Lines Results in a Hypersensitive Response to Retinoic Acid-induced Differentiation and Apoptosis

Objective The standard of care for promyelocytic leukemia includes use of the differentiating agent all-trans retinoic acid (RA) and chemotherapy. RA induces cell differentiation through retinoic acid receptor (RAR) transcription factors. Because redox mechanisms influence how readily transcription factors bind to DNA response elements (RARE), the impact of small molecule (E3330) inhibition of the redox regulatory protein, apurinic-apyrimidinic endonuclease/redox effector factor (APE1/Ref-1) on RAR DNA binding and function in RA-induced myeloid leukemia cell differentiation and apoptosis was investigated. Materials and Methods The redox function of APE1 was studied using the small molecule inhibitor E3330 in HL-60 and PLB acute myeloid leukemia cells. Electrophoretic mobility shift assays were employed to determine effect of inhibitor on APE1/Ref-1 redox signaling function. Trypan blue assays, Annexin-V/propidium iodide and CD11b staining, and real-time polymerase chain reaction analyses were employed to determine survival, apoptosis, and differentiation status of cells in culture. Results RARα binds to its RARE in a redox-dependent manner mediated by APE1/Ref-1 redox regulation. Redox-dependent RAR-RARE binding is blocked by E3330, a small molecule redox inhibitor of APE1/Ref-1. Combination treatment of RA + E3330 results in a profound hypersensitivity of myeloid leukemia cells to RA-induced differentiation and apoptosis. Additionally, redox inhibition by E3330 results in enhanced RAR target gene, BLR-1, expression in myeloid leukemia cells. Conclusions The redox function of APE1/Ref-1 regulates RAR binding to its DNA RAREs influencing the response of myeloid leukemia cells to RA-induced differentiation. Targeting of APE1/Ref-1 redox function may allow manipulation of the retinoid response with therapeutic implications

Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic

Reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease (Ref-1/APE1) is a critical node in tumor cells, both as a redox regulator of transcription factor activation and as part of the DNA damage response. As a redox signaling protein, Ref-1/APE1 enhances the transcriptional activity of STAT3, HIF-1α, nuclear factor kappa B, and other transcription factors to promote growth, migration, and survival in tumor cells as well as inflammation and angiogenesis in the tumor microenvironment. Ref-1/APE1 is activated in a variety of cancers, including prostate, colon, pancreatic, ovarian, lung and leukemias, leading to increased aggressiveness. Transcription factors downstream of Ref-1/APE1 are key contributors to many cancers, and Ref-1/APE1 redox signaling inhibition slows growth and progression in a number of tumor types. Ref-1/APE1 inhibition is also highly effective when paired with other drugs, including standard-of-care therapies and therapies targeting pathways affected by Ref-1/APE1 redox signaling. Additionally, Ref-1/APE1 plays a role in a variety of other indications, such as retinopathy, inflammation, and neuropathy. In this review, we discuss the functional consequences of activation of the Ref-1/APE1 node in cancer and other diseases, as well as potential therapies targeting Ref-1/APE1 and related pathways in relevant diseases. APX3330, a novel oral anticancer agent and the first drug to target Ref-1/APE1 for cancer is entering clinical trials and will be explored in various cancers and other diseases bringing bench discoveries to the clinic

Ref-1/APE1 as Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia

The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets, but have yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pathways in T-ALL, we investigated the multi-functional protein redox factor-1 (Ref-1/APE1), which acts as a signaling "node" by exerting redox regulatory control of transcription factors important in leukemia. Leukemia patients' transcriptome databases showed increased expression in T-ALL of Ref-1 and other genes of the Ref-1/SET interactome. Validation studies demonstrated that Ref-1 is expressed in high-risk leukemia T-cells, including in patient biopsies. Ref-1 redox function is active in leukemia T-cells, regulating the Ref-1 target NF-kB, and inhibited by the redox-selective Ref-1 inhibitor E3330. Ref-1 expression is not regulated by Notch signaling, but is upregulated by glucocorticoid treatment. E3330 disrupted Ref-1 redox activity in functional studies and resulted in marked inhibition of leukemia cell viability, including T-ALL lines representing different genotypes and risk groups. Potent leukemia cell inhibition was seen in primary cells from ALL patients, relapsed and glucocorticoid-resistant T-ALL cells, and cells from a murine model of Notch-induced leukemia. Ref-1 redox inhibition triggered leukemia cell apoptosis and down-regulation of survival genes regulated by Ref-1 targets. For the first time, this work identifies Ref-1 as a novel molecular effector in T-ALL and demonstrates that Ref-1 redox inhibition results in potent inhibition of leukemia T-cells, including relapsed T-ALL. These data also support E3330 as a specific Ref-1 small molecule inhibitor for leukemia

Disparities in eating disorder risk and diagnosis among sexual minority college students: Findings from the national Healthy Minds Study

ObjectiveTo examine differences in eating disorder (ED) risk and diagnosis by sexual orientation in a national sample of college students.MethodData from 178 U.S. colleges and universities participating in the Healthy Minds Study between 2016 and 2019 were analyzed (36,691 cisgender men, 81,730 cisgender women; 15.7% self‐identifying as sexual minorities). Outcomes were ED risk (≥2 on the SCOFF) and self‐reported lifetime ED diagnosis. Prevalence estimates adjusted for demographics and weight status were computed via logistic regression.ResultsHigher proportions of questioning (29.1%), bisexual (26.3%), and gay men (30.9%) exhibited elevated risk than heterosexual men (14.3%), and a higher proportion of gay men exhibited elevated risk than bisexual men. Higher proportions of questioning (34.5%) and bisexual women (34.6%) exhibited elevated risk than heterosexual women (27.6%); proportions of lesbian (28.1%) and heterosexual women were similar. Among those with elevated risk, higher proportions of bisexual (5.0%) and gay men (7.1%) and of questioning (14.7%), bisexual (18.1%), and lesbian women (19.6%) had been diagnosed relative to heterosexual men (2.0%) and heterosexual women (10.3%), respectively.DiscussionQuestioning and bisexual individuals appear to be particularly vulnerable; they may experience elevated ED risk relative to their heterosexual peers yet underdiagnosis relative to their gay or lesbian peers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162796/2/eat23304_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162796/1/eat23304.pd

Spenders and Tightwads Among Newlyweds: Perceptions of Partner Financial Behaviors and Relational Well-Being

Finances, and how couples manage their finances, can have important implications for couples’ relational well-being. Using data from 1,585 couples that participated in the CREATE study (a nationally representative dyadic dataset of U.S. newlywed couples), we examined how perceiving one’s spouse as a financial spender (i.e., spending more than they ideally would) or financial tightwad (i.e., spending less than they ideally would) was associated with several measures of relational well-being (i.e., satisfaction, commitment, and power) through actor-partner interdependence structural equation models. Results showed that perceiving one’s partner as a spender was detrimental for both the individual’s and the partner’s marital satisfaction, marital commitment, and marital power. Perceiving one’s partner as a tightwad was detrimental for both the individual’s and the partner’s marital commitment and marital power. The findings suggest that interventions focused on perceptions of financial management behaviors may help strengthen relational well-being among newlyweds

Effects of Exposure to Community Violence and Family Violence on School Functioning Problems among Urban Youth: The Potential Mediating Role of Posttraumatic Stress Symptoms

Adolescents who are exposed to violence during childhood are at an increased risk for developing posttraumatic stress (PTS) symptoms. The literature suggests that violence exposure might also have negative effects on school functioning, and that PTS might serve as a potential mediator in this association. The purpose of the current study was to replicate and extend prior research by examining PTS symptoms as a mediator of the relationship between two types of violence exposure and school functioning problems among ado- lescent youth from an urban setting. Participants included a sample of 121 junior high and high school students (M = 15 years; range = 13–16 years; 60 males, 61 females) within high-crime neighborhoods. Consistent with our hypotheses, community violence and fam- ily violence were associated with PTS symptoms and school functioning problems. Our data suggest that community and family violence were indirectly related to school func- tioning problems through PTS symptoms. Findings from this study demonstrate that PTS symptoms potentially mediate the relationship between violence exposure and school functioning problems across two settings (community and home). Future research should further examine protective factors that can prevent youth violence exposure as well as negative outcomes related to violence

Activation of the integrated stress response (ISR) pathways in response to Ref-1 inhibition in human pancreatic cancer and its tumor microenvironment

Pancreatic cancer or pancreatic ductal adenocarcinoma (PDAC) is characterized by a profound inflammatory tumor microenvironment (TME) with high heterogeneity, metastatic propensity, and extreme hypoxia. The integrated stress response (ISR) pathway features a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) and regulate translation in response to diverse stress conditions, including hypoxia. We previously demonstrated that eIF2 signaling pathways were profoundly affected in response to Redox factor-1 (Ref-1) knockdown in human PDAC cells. Ref-1 is a dual function enzyme with activities of DNA repair and redox signaling, responds to cellular stress, and regulates survival pathways. The redox function of Ref-1 directly regulates multiple transcription factors including HIF-1α, STAT3, and NF-κB, which are highly active in the PDAC TME. However, the mechanistic details of the crosstalk between Ref-1 redox signaling and activation of ISR pathways are unclear. Following Ref-1 knockdown, induction of ISR was observed under normoxic conditions, while hypoxic conditions were sufficient to activate ISR irrespective of Ref-1 levels. Inhibition of Ref-1 redox activity increased expression of p-eIF2 and ATF4 transcriptional activity in a concentration-dependent manner in multiple human PDAC cell lines, and the effect on eIF2 phosphorylation was PERK-dependent. Treatment with PERK inhibitor, AMG-44 at high concentrations resulted in activation of the alternative ISR kinase, GCN2 and induced levels of p-eIF2 and ATF4 in both tumor cells and cancer-associated fibroblasts (CAFs). Combination treatment with inhibitors of Ref-1 and PERK enhanced cell killing effects in both human pancreatic cancer lines and CAFs in 3D co-culture, but only at high doses of PERK inhibitors. This effect was completely abrogated when Ref-1 inhibitors were used in combination with GCN2 inhibitor, GCN2iB. We demonstrate that targeting of Ref-1 redox signaling activates the ISR in multiple PDAC lines and that this activation of ISR is critical for inhibition of the growth of co-culture spheroids. Combination effects were only observed in physiologically relevant 3D co-cultures, suggesting that the model system utilized can greatly affect the outcome of these targeted agents. Inhibition of Ref-1 signaling induces cell death through ISR signaling pathways, and combination of Ref-1 redox signaling blockade with ISR activation could be a novel therapeutic strategy for PDAC treatment

The Grizzly, February 10, 1997

Medical Ethicist to Speak on Campus • Gender Studies May Replace Women\u27s Studies • ECBA Candidate Speaks on Technology • Opinion: Code of Silence?; What I Think II; Politics Gone Wild; Big Brenneman is Watching, but not Paying Attention • Spirit of Life Ensemble Performs for Diversity Week • Mass Media and Society Brings Internet to the Classroom • Gymnastics Team Wins Second Straight Meet • Women Hoopsters Go 1-1 for the Week • Ursinus Men\u27s Basketball Team Downed at Pallestra • UC Wrestlers Split with Elizabethtown and Nationally Ranked Lycoming • Swimming Team Suffers Two Losseshttps://digitalcommons.ursinus.edu/grizzlynews/1396/thumbnail.jp

The Grizzly, April 23, 1982

Recurring Thefts Plague New Men\u27s Dorm • Final Forum Discusses Use of Photography in Space • Too Much Grass on Campus? • Letters to the Editor • Congress Puts Hold on Financial Aid Cuts • Reagan\u27s Change of Style • Vanities Well Received by Community • Hooters Reggae Keeps UC Jumping • UC Baseball Splits With Widener • Men\u27s Tennis Top Widener • Bear Blades Finish Season Strong • Women\u27s Tennis Head to MACs • Women\u27s Track Club Earns First Place • Temple Dumps Women\u27s Lacrosse • Men\u27s Lacrosse is on Trackhttps://digitalcommons.ursinus.edu/grizzlynews/1079/thumbnail.jp