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Although psychotherapy research has traditionally focused on decrease in distress, emotion research suggests the important role of positive emotional experience in healing and growing.

Sexual and gender minority (SGM)-identifying adolescents are particularly vulnerable to negative psychological outcomes, including engagement in nonsuicidal self-injury (NSSI). However, little is known about why these relationships exist. We used experimental methods to test the psychological mediation framework in an online sample of 328 adolescents who reported female sex at birth and a range of sexual and gender identities. Participants reported on depressive symptoms, self-criticism (both self-report and implicit), NSSI, and discrimination. They also completed a discrimination-based mood induction to test emotional reactivity. At baseline, SGM participants reported higher levels of implicit and self-reported self-criticism, depressive symptoms, discrimination, and higher rates of NSSI compared with cisgender, heterosexual participants (ps < .03). Following the discrimination induction, SGM-identifying participants exhibited larger emotional reactivity compared with cisgender heterosexual participants, as measured by change in negative mood, F(1, 326) = 7.33, p = .01, ηp2 = .02, and state self-criticism, F(1, 326) = 4.67, p = .03, ηp2 = .014, but not implicit affect toward the self. This effect was associated with baseline depressive symptoms, self-criticism, NSSI history, and discrimination. Post hoc analyses revealed that participants who tended to reframe experiences of discrimination as opportunities for growth exhibited attenuated emotional reactivity to the induction; findings remained significant after adjusting for SGM status and event severity (ps < .001). Results indicate that adolescents identifying as SGM may experience elevated psychological distress compared with their cisgender heterosexual peers and that stigma-related stressors may increase emotion dysregulation and maladaptive cognitive styles, paralleling previously proposed psychological mediation models. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Results of Kinase Inhibitor Screen including compound names, IC50s, and fold change compared to vehicle.

Viability assays, Soft agar, Immunoprecipitation, Kinase inhibitor screen, and Patient outcome data

Results of the Phosphokinase Array with phosphorylation sites, fold change relative to vehicle, and Kmeans clustering.

Supplemental Figures S1-S9. S1: Kinase inhibitor screen and response of OP449 and INK128. S2: CI values for DT1154 combined with INK128 and viability curves. S3: Kmeans clusters and signaling in response to PP2A activators and INK128. S4: Oncoprint and survival curves of patients with alterations in the MYC/mTOR pathway. S5: pT58 MYC expression levels in PDA cells treated with DT1154 and INK128. S6: Signaling with B56a knockdown or T58A MYC overexpression in response to DT1154 and INK128 treatment. S7: Signaling showing decreased expression of MYC increases the efficacy of INK128. S8: Treatment of KPC and KPCM/+ cell lines with BEZ235, Dasatinib, and Sunitinib. S9: Endpoint analysis of long- and short-term in vivo treatment with DT1154 and INK128.

In cancer, kinases are often activated and phosphatases suppressed, leading to aberrant activation of signaling pathways driving cellular proliferation, survival, and therapeutic resistance. Although pancreatic ductal adenocarcinoma (PDA) has historically been refractory to kinase inhibition, therapeutic activation of phosphatases is emerging as a promising strategy to restore balance to these hyperactive signaling cascades. In this study, we hypothesized that phosphatase activation combined with kinase inhibition could deplete oncogenic survival signals to reduce tumor growth. We screened PDA cell lines for kinase inhibitors that could synergize with activation of protein phosphatase 2A (PP2A), a tumor suppressor phosphatase, and determined that activation of PP2A and inhibition of mTOR synergistically increase apoptosis and reduce oncogenic phenotypes in vitro and in vivo. This combination treatment resulted in suppression of AKT/mTOR signaling coupled with reduced expression of c-MYC, an oncoprotein implicated in tumor progression and therapeutic resistance. Forced expression of c-MYC or loss of PP2A B56α, the specific PP2A subunit shown to negatively regulate c-MYC, increased resistance to mTOR inhibition. Conversely, decreased c-MYC expression increased the sensitivity of PDA cells to mTOR inhibition. Together, these studies demonstrate that combined targeting of PP2A and mTOR suppresses proliferative signaling and induces cell death and implicates this combination as a promising therapeutic strategy for patients with PDA.Significance:These findings present a combinatorial strategy targeting serine/threonine protein phosphatase PP2A and mTOR in PDA, a cancer for which there are currently no targeted therapeutic options.

Introduction There is a concomitant rise in suicide rates with the prevalence of opioids involved in overdose deaths, especially among adolescents and young adults. However, there are limited studies on whether opioid use prospectively predicts suicidal behavior in youth. Methods Our sample included 183 psychiatric patients (18-30 years) admitted for a suicide attempt (SA), have current suicidal ideation (SI), and psychiatric controls without ideation or attempt (PC). Suicidal behavior was assessed using the Columbia Suicide Severity Rating Scale. We also recruited a healthy control group (HC; n = 40). Patients and controls were followed over a year. ANOVA, regression, and cox regression were used. Results Suicide attempt (β = 0.87, CI [0.1-1.6], p = 0.02) and SI [(β = 0.75, CI [0.03-1.5], p = 0.04) were significantly more likely than HCs to have used opioids in the past year at baseline. Opioid use was associated with increased anxiety symptoms (β = 0.75, CI [0.001-1.5], p = 0.05), PTSD symptoms (β = 3.90, CI [1.1-6.7], p = 0.01), and aggression (β = 0.02, CI [0.01-0.04], p = 0.02). Opioid use in the month prior to hospitalization predicted SA at 6 months (OR = 1.87, CI [1.06-3.31], p = 0.032). Conclusions Opioid use is a proximal predictor for SA. These findings may help clinicians better identify patients at risk for suicidal behavior, allowing for more personalized treatment approaches.

Background: Recent studies have demonstrated equivalent short-term results when comparing arthroscopic versus open anterior shoulder stabilization. However, none have evaluated the long-term clinical outcomes of patients after arthroscopic or open anterior shoulder stabilization, with inclusion of an assessment of preoperative glenoid tracking. Purpose: To compare long-term clinical outcomes of patients with recurrent anterior shoulder instability randomized to open and arthroscopic stabilization groups. Additionally, preoperative magnetic resonance imaging (MRI) studies were used to assess whether the shoulders were “on-track” or “off-track” to ascertain a prediction of increased failure risk. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A consecutive series of 64 patients with recurrent anterior shoulder instability were randomized to receive either arthroscopic or open stabilization by a single surgeon. Follow-up assessments were performed at minimum 15-year follow-up using established postoperative evaluations. Clinical failure was defined as any recurrent dislocation postoperatively or subjective instability. Preoperative MRI scans were obtained to calculate the glenoid track and designate shoulders as on-track or off-track. These results were then correlated with the patients’ clinical results at their latest follow-up. Results: Of 64 patients, 60 (28 arthroscopic and 32 open) were contacted or examined for follow-up (range, 15-17 years). The mean age at the time of surgery was 25 years (range, 19-42 years), while the mean age at the time of this assessment was 40 years (range, 34-57 years). The rates of arthroscopic and open long-term failure were 14.3% (4/28) and 12.5% (4/32), respectively. There were no differences in subjective shoulder outcome scores between the treatment groups. Of the 56 shoulders, with available MRI studies, 8 (14.3%) were determined to be off-track. Of these 8 shoulders, there were 2 surgical failures (25.0%; 1 treated arthroscopically, 1 treated open). In the on-track group, 6 of 48 had failed surgery (12.5%; 3 open, 3 arthroscopic [ P = .280]). Conclusion: Long-term clinical outcomes were comparable at 15 years postoperatively between the arthroscopic and open stabilization groups. The presence of an off-track lesion may be associated with a higher rate of recurrent instability in both cohorts at long-term follow-up; however, this study was underpowered to verify this situation.

Transgender adolescents (TGAs) face many of the same sociocultural and biological influences on body dissatisfaction and disordered eating as cisgender peers. Additionally, TGAs experience unique body- and gender-related concerns. The purpose of this study is to explore the nuances of gender identity, gender transitioning, body image, and disordered eating among TGAs. Case summaries and a synthesis of key themes are presented from interviews with nine TGAs aged 16 to 20 (M(age) = 17). All participants reported engaging in at least one behavior to change their weight or shape. Consistent with a theoretical biopsychosociocultural model we proposed, TGAs described body dissatisfaction and disordered eating related to transgender-specific factors (e.g., behaviors aimed at minimizing secondary sex characteristics) and broader developmental and sociocultural factors. Some participants reported improvements in body image and disordered eating following gender transition. The interviews highlight complex associations among gender identity, gender transitioning, body image, and disordered eating during adolescence, suggesting that disentangling transgender-specific factors from other individual factors is difficult. These findings may guide future research on the prevalence and functions of disordered eating among TGAs and point to a unique set of needs for effective detection and treatment of concurrent gender incongruence, body dissatisfaction, and disordered eating.

Objective Adolescence is a developmental period of increased risk for disordered eating. Gender minority adolescents (GMAs), or those whose gender identity does not align with their sex assigned at birth, may experience body image concerns related to unique gender-related stressors. GMAs may use disordered eating to affirm a feminine, masculine, or nonbinary gender identity. However, little is known about differences in disordered eating between GMAs and cisgender adolescents. Therefore, this study had two primary goals: (a) to compare disordered eating between GMAs and cisgender adolescents by examining the role of gender identity and sex assigned at birth; and (b) within GMAs, to examine associations between gender identity congruence and disordered eating. Method A large U.S. sample of GMAs and cisgender adolescents (n = 1,191 GMAs; 919 cisgender; Mage = 15.93 years) reported their disordered eating on an anonymous online survey. Results A MANOVA revealed a significant interaction between gender identity and sex assigned at birth. Follow-up ANOVAs demonstrated that purging, caloric restriction, excessive exercise, and muscle building differed as a function of gender identity and sex assigned at birth. Among GMAs, a multiple multivariate regression model demonstrated that disordered eating was lower among participants who reported greater gender identity congruence. Discussion GMAs should not be considered a homogenous group, as differences in gender identity may lead to the internalization of different appearance ideals and disparate eating disorder symptomatology. Results suggest that clinicians working with GMAs consider the unique body image concerns that could accompany a specific gender identity.

Accelerated experiential dynamic psychotherapy (AEDP; Fosha, 2000, 2021b) is an integrative, healing-oriented, mind-body, affect-focused therapy. A posttreatment outcome study demonstrated AEDP's effectiveness (Iwakabe et al., 2020) on a variety of measures of psychological functioning. This study sought to address AEDP's long-term effectiveness. As previously reported, 63 adult patients completed a 16-session AEDP treatment with qualified therapists in private practice in the United States, Canada, Israel, Japan, and Sweden. Forty patients responded to 6-month follow-up and 52 responded to 12-month follow-up. Results indicate that patients maintained their posttreatment therapeutic gains, both 6 and 12 months later. Large effect sizes (

Transgender adolescents (TGAs) have high risk for experiencing mental health problems, but little is known about how aspects of gender identity relate to their mental health symptoms. Evidence from child and adult samples of transgender individuals indicates making progress in gender transition milestones and higher levels of congruence between gender identity and gender expression are related to fewer mental health problems. We examined associations between perceived transition progress, gender congruence, and mental health symptoms in a diverse, nationwide sample of TGAs.TGAs (n = 1,943) participated in a cross-sectional online survey. Perceived gender transition progress, gender congruence, and depressive and anxiety symptoms were assessed. Path analysis was conducted to examine whether transition progress was related to mental health symptoms via higher levels of gender congruence.Most TGAs had undertaken at least one social transition step (98%), but only 11% had taken medical transition steps. Higher gender congruence was associated with lower mental health symptoms. Greater transition progress was associated with higher gender congruence, and perceived transition progress evidenced negative indirect associations with mental health symptoms. TGAs identifying with binary identities (transmasculine and transfeminine youth) reported lower levels of transition progress and gender congruence compared to other subgroups of TGAs.Higher levels of perceived transition progress and gender congruence are related to lower mental health symptoms among TGAs. Mental health interventions tailored to the unique developmental needs of TGAs are needed given high risk for mental health problems within this population, and interventions addressing transition progress and gender congruence should be examined.

BACKGROUND. The COVID-19 pandemic is the most serious global public health crisis since the 1918 influenza pandemic. This study is the first to assess its mental health impact across the lifespan in the US in adults, adolescents, and health care workers (HCWs). METHODS. We recruited 4909 participants through an online survey advertising on Facebook and Instagram to assess exposure to COVID-19 and psychiatric symptoms from April 27 to July 13. We also recruited through the University of Pittsburgh, University of Pittsburgh Medical Center (UPMC), and other health care systems around Pittsburgh. The primary outcomes were clinically significant depression, anxiety, and posttraumatic stress disorder symptoms, suicidal ideation or behavior, and grief reactions since COVID-19. RESULTS. Adolescents were significantly more likely to report moderate to severe symptoms of depression (55% vs. 29%, χ(2)=122, df=1, p

The health of transgender adolescents (i.e., those identifying with a gender other than their sex assigned at birth) is gaining attention from researchers, yet little work has examined normative sexual behaviors among this population. Self-identified gender minority adolescents, including those identifying as trans boys, trans girls, nonbinary, and questioning their gender identity (age range 14–18, M(age) = 16.0, n = 1,223) from all 50 U.S. states responded to anonymous online surveys. Participants reported on their age of initiation and number of sexual partners for four sexual behaviors ranging in intimacy (i.e., sexual touching, oral sex, vaginal sex, and anal sex). Participants also indicated the gender of their sexual partners and experiences with sexually transmitted infections (STIs), STI tests, and pregnancy. Overall, transgender adolescents’ age of initiating sexual behaviors and number of sexual partners are similar to those observed in prior studies of cisgender adolescents. No differences were found between gender identity subgroups on ever engaging, age of initiation, number of partners, and gender of partners across the four sexual behaviors, with some exceptions for anal sex. Participants reported low rates of STIs and pregnancy, but also low rates of STI testing. Implications for sex education and health care are discussed.

Objective Sexual and gender minority (SGM) adolescents report elevated risk for psychopathology. Identifying as a racial/ethnic minority and sexual minority (SM) or gender minority (GM) may lead to greater stress/discrimination and psychopathology. We examined nonsuicidal self-injury, suicide ideation, and suicide attempts (i.e., self-injurious thoughts and behaviors [SITBs]) and depressive symptoms across intersections of sexual orientation, gender, and race/ethnicity. Method Study participants consisted of a large (n = 2,948; 59% GM) sample of adolescents aged 14-18 who were recruited online to complete a cross-sectional survey. SGM status, race/ethnicity, and their interactions were used to predict depressive symptoms and SITBs. Associations among race/ethnicity and GM-specific psychosocial factors were assessed. Results SM (B = 3.75) and GM (B = 8.81) participants reported higher depressive symptoms and SITB histories (odds ratios [ORs] from 1.92 to 2.43 and 2.87 to 5.44, respectively). Asian participants were less likely to report nonsuicidal self-injury (OR = 0.45), and Latinx participants were more likely to report suicide attempts (OR = 1.50). Although omnibus tests of interactions were largely insignificant, exploratory analyses revealed fewer depressive symptoms (B = -8.40) and SITBs (ORs from -0.95 to -2.05) among Black SM participants and, at times, Black GM participants. This protective effect may relate to lower self-reported expectations of rejection due to gender. Conclusions GM participants reported the highest risk for depressive symptoms and SITBs. Contrary to hypotheses, multiple minority identification was not associated with greater psychopathology. Future research, assessing specific sexual and gender identities across diverse samples, is needed to highlight how race affects psychopathology risk across these identities. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Recent research has documented significant mental health disparities for transgender adolescents. However, the extant literature is hindered by vague operationalizations of gender identity and limited measurement of trans-specific stressors. In this article, we (1) introduce and describe the Gender Minority Youth (GMY) Study, a large-scale study of transgender youth disparities; and (2) provide evidence of the feasibility of using social media to recruit a diverse sample of U.S. transgender and cisgender youth. Facebook and Instagram advertisements targeted 14–18-year-old adolescents to complete an online survey. Participants (N = 3318) self-reported gender assigned at birth and current gender identity, mental health symptoms, and transgender-specific stressors and milestones. Adolescents included 1369 cisgender (n = 982 cisgender female; n = 387 cisgender male), 1938 transgender (n = 986 transgender male; n = 132 transgender female; n = 639 nonbinary assigned female at birth; n = 84 nonbinary assigned male at birth; n = 84 questioning gender identity assigned female at birth; n = 13 questioning gender identity assigned male at birth), and 11 intersex youth. The GMY Study is the first nationwide sample of U.S. adolescents recruited specifically for a study of mental health disparities between transgender and cisgender youth. We demonstrate the feasibility of using social media advertisements and a waiver of parental permission to recruit a large sample of adolescents, including subsamples of gender minority youth. We remedied limitations in the existing literature by including appropriate measures of gender assigned at birth, current gender identity, and detailed questions about transgender-specific stressors and transition milestones.

Non-alcoholic steatohepatitis (NASH) is a progressive and severe liver disease, characterized by lipid accumulation, inflammation, and downstream fibrosis. Despite its increasing prevalence, there is no approved treatment yet available for patients. This has been at least partially due to the lack of predictive preclinical models for studying this complex disease. Here, we present a 3D in vitro microtissue model that uses spheroidal, scaffold free co-culture of primary human hepatocytes, Kupffer cells, liver endothelial cells and hepatic stellate cells. Upon exposure to defined and clinically relevant lipotoxic and inflammatory stimuli, these microtissues develop key pathophysiological features of NASH within 10 days, including an increase of intracellular triglyceride content and lipids, and release of pro-inflammatory cytokines. Furthermore, fibrosis was evident through release of procollagen type I, and increased deposition of extracellular collagen fibers. Whole transcriptome analysis revealed changes in the regulation of pathways associated with NASH, such as lipid metabolism, inflammation and collagen processing. Importantly, treatment with anti-NASH drug candidates (Selonsertib and Firsocostat) decreased the measured specific disease parameter, in accordance with clinical observations. These drug treatments also significantly changed the gene expression patterns of the microtissues, thus providing mechanisms of action and revealing therapeutic potential. In summary, this human NASH model represents a promising drug discovery tool for understanding the underlying complex mechanisms in NASH, evaluating efficacy of anti-NASH drug candidates and identifying new approaches for therapeutic interventions.

* Abbreviations: AAP — : American Academy of Pediatrics EMR — : electronic medical record SGM — : sexual and gender minority In this issue of Pediatrics , Luk et al1 describe the risk of suicidal behavior within a 7-year nationally representative longitudinal sample of US adolescents. They found that sexual minority adolescents had an earlier onset of suicidality and faster progression from suicide ideation to a suicide plan, compared with that of heterosexual adolescents. The increased risk for suicidal ideation and behavior among this vulnerable population of youth is well described.2 The findings in this report regarding the early emergence and rapid progression of suicide risk among sexual minority adolescents suggest that early identification of risk and implementation of risk reduction interventions are critical. Rates of suicide3 and suicide-related emergency department visits4 are increasing among adolescents in the United States. Screening for depression is currently recommended at annual visits from the age of 12 years,5 and the American Academy of Pediatrics (AAP) has developed resources, tool kits, and trainings to facilitate this activity.6,7 In recent research, it is suggested that screening for depression alone may not capture many suicidal youth8,9 because 32% of patients at risk for suicide in an inpatient medical sample were not identified by depression screening. In other reviews,10,11 authors cite accumulating evidence that suicide risk is better captured by direct questions about suicidal ideation. Validated instruments to identify suicide risk are available, and accurate identification of risk allows referral for emergency consultation or treatment that has the potential to prevent suicidal behavior. In addition to screening all youth for depressive symptoms and … Address correspondence to: Dr Pamela Murray, Boston Children’s Hospital, 333 Longwood Ave, Boston, MA 02215. E-mail: pamela.murray{at}childrens.harvard.edu

Pancreatic ductal adenocarcinoma (PDAc) ranks among the top three most aggressive cancers in the United States and is projected to increase in incidence over the next few years. Standard of care treatment for PDAc consists of a cocktail of harsh chemotherapies, which have improved overall survival by only a few percentage points—to a 5-year survival rate of 11%. One commonly deregulated pathway in PDAc is c-MYC (MYC), a potent transcription factor. MYC plays an important role in tumor progression and its deregulation has been correlated with tumor aggressiveness and therapeutic resistance in PDAc and other cancers. Recently, oncogenic MYC expression has been shown to regulate elements of the tumor microenvironment (TME) in mouse models of multiple cancers. In PDAc, MYC’s expression has been linked to a desmoplastic immune suppressive TME, yet the specific mechanism has yet to be described. Here, we present a novel genetically engineered mouse model (GEMM) of PDAc that can be used to better model the disease and to interrogate questions of how MYC regulates the tumor immune and stromal microenvironments. Our KMCERT2 model has inducible Cre-driven expression of both mutant Kras and low deregulated Myc in the pancreas. We show that deregulated MYC cooperates with KRASG12D in the adult pancreas to drive PDAc, and our model recapitulates inter- and intra-tumoral heterogeneity seen within clinical PDAc populations. Currently, a majority of murine studies of PDAc are performed using an embryonic KrasG12D- and p53 loss/mutant-driven PDAc model (KPC). RNA- and DNA sequencing on both microdissected autochthonous tumor specimens and KMCERT2 tumor-derived cell lines was conducted to further understand the mechanisms underlying our observed phenotypes. In contrast to the KPC model, our inducible KMCERT2 model of PDAc displays genetic changes, such as CDKN2A and SMAD4 loss, comparable to human disease. Interestingly, multiplexed immunohistochemistry analysis of immune cell composition of spontaneous KMCERT2 tumors compared to the commonly used KPC shows an increased density of antigen presenting cells (APCs) within MYC-driven tumors. Human PDAc is often resistant to standard of care therapies such as gemcitabine and FOLFIRINOX. Orthotopic therapeutic studies using our KMCERT2 tumor-derived cell lines demonstrate a similar resistance to these therapies, allowing us to use this model to better understand the mechanisms leading to therapeutic resistance and to test new therapies. In addition, we find consistent metastasis to the liver in both spontaneous and orthotopic transplant settings. Together, this work investigates the role of deregulated MYC expression in metastatic behavior, immune phenotypes, and therapeutic response in murine PDAc. It also provides both spontaneous and orthotopic mouse models of PDAc that recapitulate the heterogeneous and highly metastatic nature of the human disease, allowing for important therapeutic testing opportunities. Citation Format: Isabel A. English, Patrick J. Worth, Amy S. Farrell, Brittany L. Allen-Petersen, Vidhi Shah, Courtney Betts, Carl Pelz, Xiaoyan Wang, Colin J. Daniel, Mary C Thoma, Lisa M Coussens, Ellen M Langer, Rosalie C Sears. Myc drives phenotypic heterogeneity, metastasis, and therapy resistance in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A067.

Protein phosphatase 2A (PP2A) is a major serine-threonine phosphatase that regulates many cellular pathways including KRAS, whose oncogenic mutation is prevalent in 95% of patients with Pancreatic Ductal Adenocarcinoma (PDAC). Previous research has identified a decrease in global PP2A activity and an increase in the expression of PP2A inhibitors in PDAC cell lines, suggesting that suppression of PP2A activity may be pertinent in PDAC maintenance. Importantly, PP2A has low mutation rates in PDAC, making it a viable target for therapeutic reactivation. While PP2A has been shown to have global tumor suppressive capabilities, the regulation of specific pathways by PP2A can be altered based on PP2A holoenzyme composition. Therefore, there is a critical need to understand the mechanisms by which oncogenic KRAS can affect PP2A function and differential substrate targeting in PDAC. The PP2A holoenzyme consists of 3 subunits: the scaffolding subunit (A), the catalytic subunit (C), and the regulatory subunit (B). There are 16 different B subunits that can be incorporated into the PP2A holoenzyme that are responsible for substrate specificity. The B56α subunit of PP2A has been shown to negatively regulate cellular transformation. Our research aims to investigate the mechanisms by which PP2A-B56α is regulated through oncogenic KRAS and how suppression of B56α impacts the initiation and progression of PDAC. To determine how oncogenic KRAS alters the dynamics of PP2A-B56α and overall PP2A activity we utilized tet-inducible KRASG12D cell lines to allow direct manipulation of KRAS mutational activation. Using this system, we have identified time dependent alterations in cancerous inhibitor of PP2A (CIP2A) following induction of KRASG12D expression, indicating that PP2A suppression may be an early event in PDAC initiation. Consistent with this hypothesis, we characterized changes in the acceleration of PDAC formation in vivo using the Ptf1a-Cre; LSL- KRASG12D (KC) genetic mouse model combined with a B56α hypomorph model (KCBhm/hm). Our data show that the loss of B56α accelerates PDAC initiation, with an increase in pancreatic precursor lesion (PanIN) number and a decrease in healthy acinar area. In response to B56α loss, similar acceleration of acinar to ductal metaplasia (ADM) kinetics were observed in a 3D-cultured ADM Assay. Furthermore, when 3D-cultured acinar cells were treated with a small molecule activator of PP2A (SMAP), SMAP treatment resulted in smaller and fewer ductal structures, preventing the ADM process. Collectively, these data suggest that PP2A-B56α plays a regulatory role in cellular plasticity and loss contributes to PDAC initiation. Future studies will investigate how mutant KRAS-mediated CIP2A expression effects overall PP2A phosphatase activity and how subsequent sequestration of B56α contributes to development of PDAC. Together, these studies identify PP2A as a critical regulator of KRAS-induced cellular plasticity and support reactivation of PP2A as a novel therapeutic strategy in PDAC patients. Citation Format: Samantha L Tinsley, Rebecca A. Shelley, Gagan K. Mall, Ella Rose D. Chianis, Mary C. Thoma, Marina Pasca di Magliano, Goutham Narla, Rosalie C. Sears, Brittany L. Allen-Petersen. The role of PP2A-B56α in KRAS-mediated pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B064.

This paper explores core adaptive emotions, both negative and positive, and investigates their respective roles in the transformation of emotional suffering into flourishing. We do so through the l...

In cancer, kinases are often activated and phosphatases suppressed, leading to aberrant activation of signaling pathways driving cellular proliferation, survival, and therapeutic resistance. Although pancreatic ductal adenocarcinoma (PDA) has historically been refractory to kinase inhibition, therapeutic activation of phosphatases is emerging as a promising strategy to restore balance to these hyperactive signaling cascades. In this study, we hypothesized that phosphatase activation combined with kinase inhibition could deplete oncogenic survival signals to reduce tumor growth. We screened PDA cell lines for kinase inhibitors that could synergize with activation of protein phosphatase 2A (PP2A), a tumor suppressor phosphatase, and determined that activation of PP2A and inhibition of mTOR synergistically increase apoptosis and reduce oncogenic phenotypes in vitro and in vivo. This combination treatment resulted in suppression of AKT/mTOR signaling coupled with reduced expression of c-MYC, an oncoprotein implicated in tumor progression and therapeutic resistance. Forced expression of c-MYC or loss of PP2A B56α, the specific PP2A subunit shown to negatively regulate c-MYC, increased resistance to mTOR inhibition. Conversely, decreased c-MYC expression increased the sensitivity of PDA cells to mTOR inhibition. Together, these studies demonstrate that combined targeting of PP2A and mTOR suppresses proliferative signaling and induces cell death and implicates this combination as a promising therapeutic strategy for patients with PDA. Significance: These findings present a combinatorial strategy targeting serine/threonine protein phosphatase PP2A and mTOR in PDA, a cancer for which there are currently no targeted therapeutic options.

Lesbian, gay, and bisexual (LGB) individuals are less healthy than heterosexual individuals, and minority stress endured by LGB individuals contributes to these health disparities. However, within-groups differences in minority stress experiences among LGB individuals remain underexplored. Individuals are more likely to be categorized as LGB if they exhibit gender nonconformity, so gender nonconformity could influence concealability of sexual orientation among LGB individuals, carrying important implications for the visibility of their stigmatized sexual orientation identity and for how they experience and cope with minority stress. Through a meta-analytic review, we examined how gender nonconformity was associated with minority stress experiences among LGB individuals. Thirty-seven eligible studies were identified and included in analyses. Results indicate gender nonconformity is associated with experiencing more prejudice events, less concealment of sexual orientation, lower internalized homonegativity, and higher expectations of rejection related to sexual orientation among LGB individuals. Gender nonconformity is more strongly associated with experiencing prejudice events among gay and bisexual men than among lesbian and bisexual women. Gender nonconformity is systematically associated with minority stress experiences among LGB individuals, and future research must measure and examine gender nonconformity when investigating the role of minority stress in degraded health outcomes among LGB populations.