Integrated stress response plasticity governs normal cell adaptation to chronic stress via the PP2A-TFE3-ATF4 pathway.

The integrated stress response (ISR) regulates cell fate during conditions of stress by leveraging the cell's capacity to endure sustainable and efficient adaptive stress responses. Protein phosphatase 2A (PP2A) activity modulation has been shown to be successful in achieving both therapeutic efficacy and safety across various cancer models; however, the molecular mechanisms driving its selective antitumor effects remain unclear. Here, we show for the first time that ISR plasticity relies on PP2A activation to regulate drug response and dictate cellular fate under conditions of chronic stress. We demonstrate that genetic and chemical modulation of the PP2A leads to chronic proteolytic stress and triggers an ISR to dictate cell fate. More specifically, we uncovered that the PP2A-TFE3-ATF4 pathway governs ISR cell plasticity during endoplasmic reticular and cellular stress independent of the unfolded protein response. We further show that normal cells reprogram their genetic signatures to undergo ISR-mediated adaptation and homeostatic recovery thereby successfully avoiding toxicity following PP2A-mediated stress. Conversely, oncogenic specific cytotoxicity induced by chemical modulation of PP2A is achieved by activating chronic and irreversible ISR in cancer cells. Our findings propose that a differential response to chemical modulation of PP2A is determined by intrinsic ISR plasticity, providing a novel biological vulnerability to selectively induce cancer cell death and improve targeted therapeutic efficacy.

Effects of Two Group Prenatal Care Interventions on Mental Health: An RCT.

INTRODUCTION: Perinatal depression and anxiety cost the U.S. health system $102 million annually and result in adverse health outcomes. Research supports that cognitive behavioral therapy improves these conditions, but barriers to obtaining cognitive behavioral therapy have prevented its success in pregnant individuals. In this study, the impact of a cognitive behavioral therapy-based intervention on anxiety, depression, stress, healthy lifestyle beliefs, and behaviors in pregnant people was examined. STUDY DESIGN: This study used a 2-arm RCT design, embedded in group prenatal care, with one arm receiving a cognitive behavioral therapy-based Creating Opportunities for Personal Empowerment program and the other receiving health promotion content. SETTING/PARTICIPANTS: Black and Hispanic participants (n=299) receiving prenatal care from 2018 to 2022 in New York and Ohio who screened high on 1 of 3 mental health measures were eligible to participate. INTERVENTION: Participants were randomized into the manualized Creating Opportunities for Personal Empowerment cognitive behavioral therapy-based program, with cognitive behavioral skill-building activities delivered by advanced practice nurses in the obstetrical setting. MAIN OUTCOME MEASURES: Outcomes included anxiety, depression, and stress symptoms using valid and reliable tools (Generalized Anxiety Disorder scale, Edinburgh Postnatal Depression Scale, and Perceived Stress Scale). The Healthy Lifestyle Beliefs and Behaviors Scales examined beliefs about maintaining a healthy lifestyle and reported healthy behaviors. RESULTS: There were no statistically significant differences between groups in anxiety, depression, stress, healthy beliefs, and behaviors. There were significant improvements in all measures over time. There were statistically significant decreases in anxiety, depression, and stress from baseline to intervention end, whereas healthy beliefs and behaviors significantly increased. CONCLUSIONS: Both cognitive behavioral therapy and health promotion content embedded in group prenatal care with advanced practice nurse delivery improved mental health and healthy lifestyle beliefs and behaviors at a time when perinatal mood generally worsens. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov NCT03416010.

Depression, anxiety, and stress in pregnant Black people: A case for screening and evidence-based intervention.

BACKGROUND: Guidelines call for pregnant people to be screened for depression and anxiety. Screening may be particularly important for pregnant Black individuals who are reported to be more likely than non-Hispanic White pregnant people to experience prenatal stress, anxiety, and depressive symptoms. The purpose of this study was to determine if depression, anxiety, and stress co-occur in pregnant Black people and to identify which demographic factors are related to these mental health concerns. METHODS: A subset analysis of an ongoing randomized controlled trial examined the risk of coexisting mental health conditions in pregnant Black people who screened eligible to participate (that is, they had high levels of depression, anxiety, and/or stress) in two urban clinics using a descriptive correlational design. RESULTS: Of the 452 pregnant Black people who were screened for eligibility, 194 (42.9%) had elevated scores on depression, anxiety, and/or stress measures and were enrolled in the larger study. The average scores of the 194 enrolled participants were anxiety, mean (M) = 9.16 (standard deviation [SD] = 4.30); depression, M = 12.80 (SD = 4.27); and stress, M = 21.79 (SD = 4.76). More than one-third (n = 70, 36.1%) experienced two symptoms and 64 (33.0%) reported all three symptoms. CONCLUSION: Pregnant Black individuals experience high levels of comorbid mental health distress including depression, anxiety, and stress. The findings indicate that treatment for mental health concerns needs to be broad-based and effective for all three conditions. Prenatal interventions should aim to address mental health distress through screening and treatment of depression, anxiety, and stress, especially for pregnant Black individuals. This study furthers understanding of the prevalence of prenatal mental health conditions in pregnant Black people.

A generic approach to construct pseudo components for oil weathering models.

Oil weathering models are essential for predicting the behavior of spilled oil in the environment. Most models use a "Pseudo Component" (PC) approach to represent the wide range of compounds found in petroleum products. Within the approach, rather than modeling each individual compound in an oil, a manageable number of PCs are developed that represent whole classes of compounds. However, previous studies focused mainly on traditional crude oils and did not develop a generic approach to create an optimal set of PCs for a variety of oils. In developing the updates to the NOAA oil weathering model, we propose herein a generic approach to construct PCs using oil distillation data to capture the complexity of oil evaporative weathering. We validated our approach with 899 oils from the Automated Data Inquiry for Oil Spills (ADIOS) oil library and found that an optimal set of sixteen PCs should be used. These PCs include two with low boiling point (below 144 °C), one with a high boiling point (above 400 °C), and thirteen constructed within a middle range of boiling points with a temperature resolution of 20 °C. Our simulation tests suggested that this set of sixteen PCs adequately characterizes oil evaporation processes for a wide variety of oils.

Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance.

Loss of the tumor suppressive activity of the protein phosphatase 2A (PP2A) is associated with cancer, but the underlying molecular mechanisms are unclear. PP2A holoenzyme comprises a heterodimeric core, a scaffolding A subunit and a catalytic C subunit, and one of over 20 distinct substrate-directing regulatory B subunits. Methylation of the C subunit regulates PP2A heterotrimerization, affecting B subunit binding and substrate specificity. Here, we report that the leucine carboxy methyltransferase (LCMT1), which methylates the L309 residue of the C subunit, acts as a suppressor of androgen receptor (AR) addicted prostate cancer (PCa). Decreased methyl-PP2A-C levels in prostate tumors is associated with biochemical recurrence and metastasis. Silencing LCMT1 increases AR activity and promotes castration-resistant prostate cancer growth. LCMT1-dependent methyl-sensitive AB56αCme heterotrimers target AR and its critical coactivator MED1 for dephosphorylation, resulting in the eviction of the AR-MED1 complex from chromatin and loss of target gene expression. Mechanistically, LCMT1 is regulated by S6K1-mediated phosphorylation-induced degradation requiring the ß-TRCP, leading to acquired resistance to anti-androgens. Finally, feedforward stabilization of LCMT1 by small molecule activator of phosphatase (SMAP) results in attenuation of AR-signaling and tumor growth inhibition in anti-androgen refractory PCa. These findings highlight methyl-PP2A-C as a prognostic marker and that the loss of LCMT1 is a major determinant in AR-addicted PCa, suggesting therapeutic potential for AR degraders or PP2A modulators in prostate cancer treatment.

PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis.

Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by "switching" interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak double-knockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.

Small-Molecule-Mediated Stabilization of PP2A Modulates the Homologous Recombination Pathway and Potentiates DNA Damage-Induced Cell Death.

High-grade serous carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP inhibitors (PARPi) have become the mainstay of HGSC-targeted therapy, given that these tumors are driven by a high degree of genomic instability (GI) and homologous recombination (HR) defects. Nonetheless, approximately 30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a small-molecule activator of protein phosphatase 2A (PP2A; SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in patient-derived HGSC cells and xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56α, B56γ, and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061-induced stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient HGSC cells and PDX models. Our studies identify PP2A as a novel regulator of HR and indicate PP2A modulators as a therapeutic therapy for HGSC. In summary, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi resistance driven by BRCA1/2 mutation reversions.

Factors influencing the participation of Black and White Americans in Alzheimer's disease biomarker research.

Introduction: Alzheimer's disease (AD) is a public health priority. AD biomarkers may vary based on race, but the recruitment of diverse participants has been challenging. Methods: Three groups of Black and White participants with and without prior research advocacy or participation were interviewed individually or in focus groups to better understand perspectives related to AD biomarker research participation. A rapid qualitative data analytic approach was used to analyze the data. Results: Identified barriers to AD biomarker research participation included hesitancy due to fear, distrust of research and researchers, lack of relevant knowledge, and lack of research test results disclosure. Drivers for engagement in biomarker research procedures included knowledge about research, AD, and related clinical procedures, perceived benefits of participation, and outreach from trusted sources. Discussion: Participants' comments related to the need for diversity in research and desire for results disclosure suggest opportunities to engage Black individuals. Highlights: Black Americans experience more salient barriers to Alzheimer's disease (AD) biomarker research participation.Concerns about research diversity influence research participation decisions.Research test disclosure may affect research participation and retention.

Biased holoenzyme assembly of protein phosphatase 2A (PP2A): From cancer to small molecules.

Protein phosphatase 2A (PP2A) is a family of serine threonine phosphatases responsible for regulating protein phosphorylation, thus opposing the activity of cellular kinases. PP2A is composed of a catalytic subunit (PP2A Cα/ß) and scaffolding subunit (PP2A Aα/ß) and various substrate-directing B regulatory subunits. PP2A biogenesis is regulated at multiple levels. For example, the sequestration of the free catalytic subunit during the process of biogenesis avoids promiscuous phosphatase activity. Posttranslational modifications of PP2A C direct PP2A heterotrimeric formation. Additionally, PP2A functions as a haploinsufficient tumor suppressor, where attenuated PP2A enzymatic activity creates a permissive environment for oncogenic transformation. Recent work studying PP2A in cancer showed that its role in tumorigenesis is more nuanced, with some holoenzymes being tumor suppressive, while others are required for oncogenic transformation. In cancer biology, PP2A function is modulated through various mechanisms including the displacement of specific B regulatory subunits by DNA tumor viral antigens, by recurrent mutations, and through loss of carboxymethyl-sensitive heterotrimeric complexes. In aggregate, these alterations bias PP2A activity away from its tumor suppressive functions and toward oncogenic ones. From a therapeutic perspective, molecular glues and disruptors present opportunities for both the selective stabilization of tumor-suppressive holoenzymes and disruption of holoenzymes that are pro-oncogenic. Collectively, these approaches represent an attractive cancer therapy for a wide range of tumor types. This review will discuss the mechanisms by which PP2A holoenzyme formation is dysregulated in cancer and the current therapies that are aimed at biasing heterotrimer formation of PP2A for the treatment of cancer.

Comparison of transversus abdominis plane blocks with liposomal bupivacaine versus ropivacaine in open total abdominal hysterectomy.

Regional anesthesia is frequently employed in efforts to improve postoperative analgesia and reduce opioid requirements following abdominal surgery. The purpose of the current analysis was to determine if there was a difference in postoperative pain and opioid consumption between patients who underwent open total abdominal hysterectomy (TAH) and received ultrasound-guided bilateral transversus abdominis plane (TAP) blocks using either liposomal bupivacaine or ropivacaine. A single-center retrospective analysis was conducted of 215 patients from November 2018 through March 2020 who underwent an open TAH and received bilateral TAP blocks with either liposomal bupivacaine or ropivacaine. The primary outcome measure was opioid consumption at regular intervals until discharge, and the secondary outcome measures included pain scores, incidence of nausea/vomiting, and use of antiemetics at the same time intervals. Intraoperative opioid consumption and postanesthesia recovery unit opioid requirements were similar between the two groups. Opioid requirements at 24 hours (P < 0.04) and 48 hours (P < 0.01), as well as total morphine equivalent requirements (P < 0.05), were significantly lower in the liposomal bupivacaine group compared to the ropivacaine group. Patients undergoing open TAH who received liposomal bupivacaine TAP blocks required fewer postoperative opioids to achieve similar pain scores when compared to patients who received ropivacaine TAP blocks.

Proactive, Recovery-Oriented Treatment Navigation to Engage Racially Diverse Veterans in Mental Healthcare (PARTNER-MH), a Peer-Led Patient Navigation Intervention for Racially and Ethnically Minoritized Veterans in Veterans Health Administration Mental Health Services: Protocol for a Mixed Methods Randomized Controlled Feasibility Study.

BACKGROUND: Mental health care disparities are persistent and have increased in recent years. Compared with their White counterparts, members of racially and ethnically minoritized groups have less access to mental health care. Minoritized groups also have lower engagement in mental health treatment and are more likely to experience ineffective patient-provider communication, which contribute to negative mental health care experiences and poor mental health outcomes. Interventions that embrace recovery-oriented practices to support patient engagement and empower patients to participate in their mental health care and treatment decisions may help reduce mental health care disparities. Designed to achieve this goal, the Proactive, Recovery-Oriented Treatment Navigation to Engage Racially Diverse Veterans in Mental Healthcare (PARTNER-MH) is a peer-led patient navigation intervention that aims to engage minoritized patients in mental health treatment, support them to play a greater role in their care, and facilitate their participation in shared treatment decision-making. OBJECTIVE: The primary aim of this study is to assess the feasibility and acceptability of PARTNER-MH delivered to patients over 6 months. The second aim is to evaluate the preliminary effects of PARTNER-MH on patient activation, patient engagement, and shared decision-making. The third aim is to examine patient-perceived barriers to and facilitators of engagement in PARTNER-MH as well as contextual factors that may inhibit or promote the integration, sustainability, and scalability of PARTNER-MH using the Consolidated Framework for Implementation Research. METHODS: This pilot study evaluates the feasibility and acceptability of PARTNER-MH in a Veterans Health Administration (VHA) mental health setting using a mixed methods, randomized controlled trial study design. PARTNER-MH is tested under real-world conditions using certified VHA peer specialists (peers) selected through usual VHA hiring practices and assigned to the mental health service line. Peers provide PARTNER-MH and usual peer support services. The study compares the impact of PARTNER-MH versus a wait-list control group on patient activation, patient engagement, and shared decision-making as well as other patient-level outcomes. PARTNER-MH also examines organizational factors that could impact its future implementation in VHA settings. RESULTS: Participants (N=50) were Veterans who were mostly male (n=31, 62%) and self-identified as non-Hispanic (n=44, 88%) and Black (n=35, 70%) with a median age of 45 to 54 years. Most had at least some college education, and 32% (16/50) had completed ≥4 years of college. Randomization produced comparable groups in terms of characteristics and outcome measures at baseline, except for sex. CONCLUSIONS: Rather than simply documenting health disparities among vulnerable populations, PARTNER-MH offers opportunities to evaluate a tailored, culturally sensitive, system-based intervention to improve patient engagement and patient-provider communication in mental health care for racially and ethnically minoritized individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT04515771; https://clinicaltrials.gov/ct2/show/NCT04515771. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37712.

Oil biodegradation in permeable marine sediments: Effects of benthic pore-water advection and solute exchange.

Oil spills have been recognized as among the worst kinds of environmental disasters, causing severe coastal ecological and economic damages. Although benthic flow and solute fluxes are known to have strong impacts on fate and transport of oil deposited within marine sediments, their endogenous mechanisms still remain to be uncovered. In this paper, simulations of flow and solute transport processes along with hydrocarbon biodegradation were conducted in a cylindrical benthic chamber system to investigate influences of benthic hydrodynamics on oil biodegradation in permeable marine sediments. Results show that ripple-flow interactions create subsurface recirculation cells whereby seawater infiltrates into the benthic sediments at ripple troughs while groundwater discharges near the crests. It results in a spatially varied oil biodegradation rate in marine sediments. Significant oil biodegradation occurs near sediment ripple troughs due to direct oxygen recharge, while biodegradation of oil deposited uphill becomes slow due to limited oxygen replenishment. Oil biodegradation decreases subsurface oxygen content, and consequently impedes discharge of oxygen from benthic sediments. Our results reveal a dynamic interaction between oil biodegradation and benthic flow and solute transport processes, which has strong implications for predicting oil persistence and biodegradation within marine sediments and its associated impacts on benthic biogeochemical processes.

Targeting Ribonucleotide Reductase Induces Synthetic Lethality in PP2A-Deficient Uterine Serous Carcinoma.

Uterine serous carcinoma (USC) is a highly aggressive endometrial cancer subtype with limited therapeutic options and a lack of targeted therapies. While mutations to PPP2R1A, which encodes the predominant protein phosphatase 2A (PP2A) scaffolding protein Aα, occur in 30% to 40% of USC cases, the clinical actionability of these mutations has not been studied. Using a high-throughput screening approach, we showed that mutations in Aα results in synthetic lethality following treatment with inhibitors of ribonucleotide reductase (RNR). In vivo, multiple models of Aα mutant uterine serous tumors were sensitive to clofarabine, an RNR inhibitor (RNRi). Aα-mutant cells displayed impaired checkpoint signaling upon RNRi treatment and subsequently accumulated more DNA damage than wild-type (WT) cells. Consistently, inhibition of PP2A activity using LB-100, a catalytic inhibitor, sensitized WT USC cells to RNRi. Analysis of The Cancer Genome Atlas data indicated that inactivation of PP2A, through loss of PP2A subunit expression, was prevalent in USC, with 88% of patients with USC harboring loss of at least one PP2A gene. In contrast, loss of PP2A subunit expression was rare in uterine endometrioid carcinomas. While RNRi are not routinely used for uterine cancers, a retrospective analysis of patients treated with gemcitabine as a second- or later-line therapy revealed a trend for improved outcomes in patients with USC treated with RNRi gemcitabine compared with patients with endometrioid histology. Overall, our data provide experimental evidence to support the use of ribonucleotide reductase inhibitors for the treatment of USC. SIGNIFICANCE: A drug repurposing screen identifies synthetic lethal interactions in PP2A-deficient uterine serous carcinoma, providing potential therapeutic avenues for treating this deadly endometrial cancer.

Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors.

FTO catalyzes the Fe(II) and 2-oxoglutarate (2OG)-dependent modification of nucleic acids, including the demethylation of N6-methyladenosine (m6A) in mRNA. FTO is a proposed target for anti-cancer therapy. Using information from crystal structures of FTO in complex with 2OG and substrate mimics, we designed and synthesized two series of FTO inhibitors, which were characterized by turnover and binding assays, and by X-ray crystallography with FTO and the related bacterial enzyme AlkB. A potent inhibitor employing binding interactions spanning the FTO 2OG and substrate binding sites was identified. Selectivity over other clinically targeted 2OG oxygenases was demonstrated, including with respect to the hypoxia-inducible factor prolyl and asparaginyl hydroxylases (PHD2 and FIH) and selected JmjC histone demethylases (KDMs). The results illustrate how structure-based design can enable the identification of potent and selective 2OG oxygenase inhibitors and will be useful for the development of FTO inhibitors for use in vivo.

Pre-implementation Evaluation of PARTNER-MH: A Mental Healthcare Disparity Intervention for Minority Veterans in the VHA.

To design PARTNER-MH, a peer-led, patient navigation program for implementation in Veterans Health Administration (VHA) mental health care settings, we conducted a pre-implementation evaluation during intervention development to assess stakeholders' views of the intervention and to explore implementation factors critical to its future adoption. This is a convergent mixed-methods study that involved qualitative semi-structured interviews and survey data. Data collection was guided by the Consolidated Framework for Implementation Research (CFIR). We interviewed and administered the surveys to 23 peers and 10 supervisors from 12 midwestern VHA facilities. We used deductive and inductive approaches to analyze the qualitative data. We also conducted descriptive analysis and Fisher Exact Test to compare peers and supervisors' survey responses. We triangulated findings to refine the intervention. Overall, participants viewed PARTNER-MH favorably. However, they saw the intervention's focus on minority Veterans and social determinants of health framework as potential barriers, believing this could negatively affect the packaging of the intervention, complicate its delivery process, and impact its adoption. They also viewed clinic structures, available resources, and learning climate as potential barriers. Peers and supervisors' selections and discussions of CFIR items were similar. Our findings informed PARTNER-MH development and helped identify factors that could impact its implementation. This project is responsive to the increasing recognition of the need to incorporate implementation science in healthcare disparities research. Understanding the resistance to the intervention's focus on minority Veterans and the potential barriers presented by contextual factors positions us to adjust the intervention prior to testing, in an effort to maximize implementation success.

Women Construct Their Birth Narratives and Process Unplanned Cesarean Births Through Storytelling.

OBJECTIVE: To examine birth narratives of primiparous women who experienced unplanned cesarean births to improve nursing care. DESIGN: Descriptive, qualitative. SETTING: The family/newborn units of a large teaching hospital in the Northeast United States. PARTICIPANTS: Fourteen women who experienced unplanned cesarean births of singleton infants at term. METHODS: We used semistructured interviews to analyze the participants' birth narratives. Within 48 hours of birth, participants answered the prompt: "Tell us your birth story." Four perinatal nurse experts in consultation with a qualitative research expert ordered, analyzed, and coded data into themes and subthemes. RESULTS: We identified the following four themes: Changing Reality: Transition to Labor, Expectations Meeting Reality: Navigating the Unknown, Transition to Motherhood: The Cesarean Birth Experience, and Accepting the New Reality. CONCLUSION: Childbearing women need time immediately after birth to process their experiences. Our findings highlight avenues for changes in clinical care to optimize women's experiences of unplanned cesarean births. Participants wanted clearer communication with the maternity care team, voices in the decision-making process, and inclusion of support persons to optimize their birth experiences. Because negative birth experiences affect maternal and child well-being, it is important to understand women's perceptions and develop strategies to assist them in the construction of their birth narratives.

The SRG rat, a Sprague-Dawley Rag2/Il2rg double-knockout validated for human tumor oncology studies.

We have created the immunodeficient SRG rat, a Sprague-Dawley Rag2/Il2rg double knockout that lacks mature B cells, T cells, and circulating NK cells. This model has been tested and validated for use in oncology (SRG OncoRat®). The SRG rat demonstrates efficient tumor take rates and growth kinetics with different human cancer cell lines and PDXs. Although multiple immunodeficient rodent strains are available, some important human cancer cell lines exhibit poor tumor growth and high variability in those models. The VCaP prostate cancer model is one such cell line that engrafts unreliably and grows irregularly in existing models but displays over 90% engraftment rate in the SRG rat with uniform growth kinetics. Since rats can support much larger tumors than mice, the SRG rat is an attractive host for PDX establishment. Surgically resected NSCLC tissue from nine patients were implanted in SRG rats, seven of which engrafted and grew for an overall success rate of 78%. These developed into a large tumor volume, over 20,000 mm3 in the first passage, which would provide an ample source of tissue for characterization and/or subsequent passage into NSG mice for drug efficacy studies. Molecular characterization and histological analyses were performed for three PDX lines and showed high concordance between passages 1, 2 and 3 (P1, P2, P3), and the original patient sample. Our data suggest the SRG OncoRat is a valuable tool for establishing PDX banks and thus serves as an alternative to current PDX mouse models hindered by low engraftment rates, slow tumor growth kinetics, and multiple passages to develop adequate tissue banks.

Randomized controlled trial of the COPE-P intervention to improve mental health, healthy lifestyle behaviors, birth and post-natal outcomes of minority pregnant women: Study protocol with implications.

BACKGROUND: Emotionally distressed pregnant minority women experience multiple adverse outcomes, including pre-eclampsia, preterm birth, operative deliveries and low birth weight. Although the United States Preventive Services Task Force recommends screening in pregnant women, many practices do not screen because efficacious interventions and systems are not in place to treat them. AIM: Purpose of this randomized controlled trial (RCT) is to test a group delivered manualized cognitive-behavioral skills building intervention entitled COPE-P versus an attention control program on the mental health, birth and postpartum outcomes of minority pregnant women experiencing depressive, anxiety and stress symptoms. METHODS: Design is a longitudinal randomized block RCT with repeated measures (beginning with screening prior to 18 weeks, group prenatal care in both groups from 16 + 1 to 31 + 1 weeks and ending at 6 months postpartum) at two study sites (New York city and Columbus, Ohio). Race/ethnicity is being blocked to ensure equal numbers of Hispanic and Black women. 384 women are being recruited from antenatal clinics if they are: between 18 and 40 years; in an uncomplicated singleton pregnancy <18 weeks; and self-identify as Black or Hispanic. Valid and reliable measures are being used to assess healthy lifestyle behaviors and mental health outcomes immediately following the interventions, six - eight weeks postpartum and at the children's six-month well baby visit. Birth and delivery outcomes also are being assessed. CONCLUSION: If found to be efficacious, the COPE-P intervention could be a key solution to managing those with emotional distress and improving their outcomes.

Splice of Life for Cancer: Missplicing of PPP2R5A by Mutant SF3B1 Leads to MYC Stabilization and Tumorigenesis.

Although mutations in SF3B1 are the most common RNA-splicing factor mutations in cancer, determining the downstream missplicing events that drive tumorigenesis has remained challenging. Liu and colleagues present a model by which mutant SF3B1 tumors displayed high levels of oncogenic MYC activity through the missplicing of PP2A-B56α, a key post-translational regulator of MYC stability, providing a new therapeutic target and driver of SF3B1-mediated tumorigenesis.See related article by Liu et al., p. 806.

Selective PP2A Enhancement through Biased Heterotrimer Stabilization.

Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to dephosphorylate hundreds of proteins is regulated by over 40 specificity-determining regulatory "B" subunits that compete for assembly and activation of heterogeneous PP2A heterotrimers. Here, we reveal how a small molecule, DT-061, specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate selective substrates, such as its well-known oncogenic target, c-Myc. Our 3.6 Å structure identifies molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme and highlight inherent mechanisms of PP2A complex assembly. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for therapeutic targeting, and aid in the development of phosphatase-based therapeutics tailored against disease specific phospho-protein targets.