Search

International audience; Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.

Supplementary Methods, Figures 1-6 from The Adaptor Protein AMOT Promotes the Proliferation of Mammary Epithelial Cells via the Prolonged Activation of the Extracellular Signal-Regulated Kinases

Knowledge of which pulmonary function tests are commonly performed in primary care and interpretation of their results is integral for the diagnosis, care, and management of those with pulmonary symptoms. This article provides an overview of the most common pulmonary function tests and interpretation of their results.

OBJECTIVE To compare postoperative gluteal and posterior thigh pain, device performance, and perioperative complications in women undergoing sacrospinous ligament fixation with an anchor-based compared with a suture-capturing device. METHODS This was a single-center, patient-blinded, parallel, superiority trial of patients undergoing native-tissue pelvic organ prolapse repair through sacrospinous ligament fixation with an anchor-based compared with suture-capturing device using randomized-block randomization. The primary outcome was the increase in gluteal and posterior thigh pain from baseline to 1-week postoperation using the numerical rating scale. Pain was also assessed at postoperative day 1, week 6, and a summarized assessment for the first postoperative week. Intraoperative device performance, home opioid pain medication use, and changes in prolapse symptom scores were also analyzed. To provide 80% power to detect a pain difference of 2.5 points between the groups with an SD of 2.8 and a 15% dropout estimate using a two-sided 5% significance level, 24 patients were required per group. Analysis with Student's t test, Wilcoxon rank-sum tests, and Fisher exact tests were performed as well as an analysis of covariance for the primary outcome. RESULTS Between September 2018 and June 2020, 47 patients (24 anchor-based and 23 suture-capturing) were included in the study. There was no significant difference between the anchor-based and suture-capture groups in mean change in gluteal and posterior thigh pain from baseline to 1-week postoperation (-0.4, 95% CI -1.6 to 2.3). The highest pain increase from baseline during the first postoperative week was also similar between the two groups (up 4.00 and up 4.74, respectively) with no significant difference between the anchor-based and suture-capture groups (-0.7, 95% CI -1.4 to 2.8). There were no differences in changes in pain at any of the other timepoints, in opioid pain medication utilization, device performance, or in prolapse symptom scores. CONCLUSION An anchor-based device did not reduce postoperative gluteal and posterior thigh pain compared with a suture-based device after sacrospinous ligament fixation. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT03565640. FUNDING SOURCE Supported by Neomedic via Adler Instruments. Neomedic provided funding for this principal investigator-initiated study. Funding went to providing small value gift cards to patients for study completion, office supplies for the study, and funding the data analysis collaboration with the Wake Forest Baptist Health CTSI Biostatistics Department. Neomedic did not have any direct role in study design, patient recruitment, study execution, data analysis, or manuscript writing or editing.

We describe how an online graduate nurse practitioner program combined psychiatric mental health nurse practitioner and primary care advanced practice registered nurse (AGNP/FNP/PNP) tracks into an integrated curriculum. Student evaluations and assessments, along with board certification scores, demonstrated improvement in identifying and managing behavioral health problems, as well as increased competence and collaboration with other nurse practitioner students. Details of the integrated curriculum are provided.

Eating disorders (EDs) are characterized by altered eating behaviors and valuation of self-image, as well as difficulty establishing supportive social relationships. This pilot study evaluated feasibility, acceptability, and clinical responses to a novel and brief group-therapy intervention for EDs, the Self-Blame and Perspective-Taking Intervention (SBPI). The SBPI consisted of four sessions of experiential art therapy activities in conjunction with psychoeducation targeting interpersonal attributions and mentalization. Twenty-four outpatient, treatment-seeking women with EDs participated in the SBPI, with 87.5% completing the intervention and 94% rating their participation positively. Eating disorder symptoms, depression, anxiety, self-attribution bias, and self-esteem were assessed before (T1) and after participation (n = 20 at T2; n = 18 at T3). Separate repeated measures MANOVAs were performed to assess these clinical and self-concept variables. Relative to baseline, participants demonstrated significant improvements in all self-concept measures: self-attribution bias, trait self-esteem and state self-esteem at T2. ED, depression, and anxiety symptoms were significantly decreased at both T2 (1-4 weeks post) and T3 (3-5 months post). The SBPI altered self-concept targets acutely with sustained clinical improvements. Future work is needed to evaluate how self-concept and social constructs are related to clinical symptom expression in EDs.

Background Problems in social cognition and social support contribute to eating disorders (ED). Group therapy provides an ideal format to create an experiential learning environment focused on understanding social interactions. This pilot study examined the qualitative content of the participants’ experiences in the Self-Blame and Perspective-Taking Intervention (SBPI) for ED. Methods The SBPI was a 4-week group therapy intervention involving art therapy and psychoeducation that focused on social behaviors in ED patients. Participants received surveys immediately after the intervention and at 1 to 4 weeks after the post-intervention. Thematic analyses of qualitative feedback were performed using Braun and Clarke’s thematic analysis framework. Results Inductive analyses revealed three main themes: (1) Developing self-acceptance through emotional reflection, (2) Changing expectations with neurosocial knowledge, and (3) Bonding and vulnerability in social interactions; all concepts intentionally targeted by the SBPI. Participants varied in their support of a guideline to exclude personal discussion of ED-related cognitions and behaviors in the group. Conclusions As a whole, patients valued the combination of psychosocial education with group experientials focused on social behavior. Positive feedback from the SBPI suggests that adjunctive treatments that target mental-wellness constructs indirectly related to ED pathology may be helpful by allowing patients to see themselves as separable from the illness. Trial registration ClinicalTrials.gov, NCT0487758. Registered 7 May 2021—Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT04877158., Plain English summary Adult patients with eating disorders frequently report challenges in developing and maintaining supportive social relationships. A group therapy intervention utilizing structured art tasks in conjunction with psychoeducation about interpersonal relationships was piloted in twenty-four women with eating disorders. Participants provided written feedback about their experiences in the intervention. These responses were coded by three raters to identify consistent themes related to those experiences. Participants reported benefits related to self-acceptance and emotional regulation, valued learning about their brain and behaviors, and appreciated peer interactions in this setting. In sum, this adjunctive and structured outpatient group targeting social interactions was acceptable to outpatients with eating disorders.

Ureteral injury during gynecological surgery can be managed in a variety of ways, from endoscopic stent placement to ureteroneocystotomy with accompanying psoas hitch and/or Boari flap. The majority of these occur during hysterectomy; therefore, gynecologic surgeons may not be as familiar with repair in women with intact uteri. Herein we present our technique for delayed robotic-assisted ureteral reimplant and psoas hitch in a woman with a ureteral injury sustained during cesarean section, which initially presented as a uretero-cervical fistula.In this video, we describe the evaluation and surgical management of a patient with delayed recognition of a left distal ureteral injury sustained during cesarean section. We present necessary modifications to robotic-assisted laparoscopic ureteroneocystostomy and psoas hitch to accommodate an intact uterus including the need for uterine manipulation, division of the round ligament, bladder mobilization from the lower uterine segment and development of the retropubic space, reimplantation steps, and psoas hitch.Simple modifications to a traditional technique of robotic-assisted ureteroneocystotomy effectively compensate for the presence of a uterus. Obstetricians should maintain a high index of suspicion for ureteral injury in women with new-onset severe urinary leakage post-cesarean section.

Dissection provides a unique opportunity to integrate anatomical and clinical education. Commonly, cadavers are randomly assigned to courses, which may result in skewed representation of patient populations. The primary aim of this study was to determine if the anatomical donors studied by students at the University of Massachusetts Medical School (UMMS) accurately represent the disease burden of the local patient population. This cross-sectional study compared the University of Massachusetts Memorial Medical Center patient claims data and body donation data from the UMMS Anatomical Gift Program (AGP). This study examined age, race, sex, and morbidities within a 10-year timeframe in 401,258 patients and 859 anatomical donors who met inclusion criteria. An independent t test was conducted to compare the mean ages of the two populations. Chi square analysis was conducted on race, sex, and 10 morbidity categories. A Fischer's exact test was conducted for two morbidity categories with n

Impetigo, a bacterial skin infection that involves the superficial layers of the skin, is one of the most common skin infections in children ages 2 to 5 but can occur in individuals across the lifespan. This article discusses the diagnosis and management of impetigo in primary care.

INTRODUCTION AND OBJECTIVES:The Boari Flap has been in the urologist’s armamentarium for tension free reconstruction of mid and proximal ureteral defects for over 70 years. However, complications c...

Background: Poor utilization of standardized outcome measures for monitoring patient care and progress in mental health services is evident. The objective of this work was to implement computerized diagnostic and history assessments for outpatient mental health visits in the ambulatory psychiatric clinic of a large pediatric health system. Methods: A computerized assessment system was created for the iPad to administer and score a series of validated diagnostics before new patient and follow-up appointments with a psychiatry provider. Outcome measures were a percentage of completed assessments, provider satisfaction, and patient satisfaction. Results: Across all outpatient psychiatry clinics, screener completion rate for new patients increased from 0% to 90% within 1 year of implementation and sustained within 3σ process control limits for 2 years. Return visit assessment completion increased from 0% to 80%. The most substantial completion rate increase was related to scheduling assessment time as part of the visit. Assessment of provider and patient satisfaction through surveys before and after the implementation showed 94% of providers felt that visit efficiency had improved, and overall opinion of the system was highly positive. Patients also reported high satisfaction with the assessment process (4.1 on Likert scale 0–5, 5 = very positive). Conclusions: This quality improvement program demonstrates strategies for overcoming barriers to the use of standardized assessments in outpatient psychiatry. We show that a large pediatric mental health system can achieve systematic outcome data collection with minimal disruption to routine clinical care.

Study of the female urinary microbiome is a relatively new focus of research. The female microbiome and its interaction with the body as a whole has the potential to explain a variety of clinical conditions, including recurrent urinary tract infections, urinary incontinence, and interstitial cystitis/bladder pain syndrome. In this chapter, we will explore the available literature linking the female microbiome to urinary incontinence and pathologic lower urinary tract symptoms.

Chronic pelvic pain syndrome (CPPS) is defined as pain perceived within the structures of the male or female pelvis of at least 6-month duration. The management of CPPS in both men and women poses a challenge to both the clinician and the patient. Botulinum toxin type A (BoNT-A) is known to block the release of neurotransmitters at the neuromuscular junction but also appears to have anti-nociceptive and anti-inflammatory effects. BoNT-A has been used for over two decades to treat conditions associated with pathological muscle hyperactivity. There is emerging evidence that BoNT-A may play a role in treating CPPS when alternate treatments and more conservative measures have been ineffective. Moving forward, well-designed clinical trials are needed to further investigate the utility of BoNT-A use in the treatment of CPPS.

CONTEXT Social norms and stigma may play important roles in reproductive health behavior and decision making among young women in the U.S. South, who disproportionately experience unintended pregnancies. No research has described the presence and manifestations of social norms and stigmas associated with unintended pregnancy and related decision making from the perspective of this population. METHODS Six focus groups and 12 cognitive interviews were conducted between December 2013 and July 2014 with 46 low-income women aged 19–24 living in Birmingham, Alabama; respondents were recruited from two public health department centers and a community college. Semistructured interview guides were used to facilitate discussion about social perceptions of unintended pregnancy and related pregnancy decisions. Sessions were audio-recorded, and transcripts were analyzed using a theme-based approach. RESULTS Participants described community expectations that pregnancy occur in the context of monogamous relationships, in which both partners are mature, educated and financially stable. However, respondents reported that unintended pregnancy outside of these circumstances was common, and that the community expected young women faced with unintended pregnancies to bear and raise their children. Women who chose to do so were viewed more positively than were women who chose abortion or adoption. The community generally considered these alternatives to parenting unacceptable, and participants discussed them in terms of negative labels, social judgment and nondisclosure. CONCLUSIONS Findings suggest a need to reduce stigma and create a social environment in which young women are empowered to make the best reproductive decisions for themselves.

Supplemental Digital Content is Available in the Text., Background: Internalization of HIV-related stigma may inhibit a person's ability to manage HIV disease through adherence to treatment regimens. Studies, mainly with white men, have suggested an association between internalized stigma and suboptimal adherence to antiretroviral therapy (ART). However, there is a scarcity of research with women of different racial/ethnic backgrounds and on mediating mechanisms in the association between internalized stigma and ART adherence. Methods: The Women's Interagency HIV Study (WIHS) is a multicenter cohort study. Women living with HIV complete interviewer-administered questionnaires semiannually. Cross-sectional analyses for the current article included 1168 women on ART for whom data on medication adherence were available from their last study visit between April 2013 and March 2014, when the internalized stigma measure was initially introduced. Results: The association between internalized stigma and self-reported suboptimal ART adherence was significant for those in racial/ethnic minority groups (AOR = 0.69, P = 0.009, 95% CI: 0.52 to 0.91), but not for non-Hispanic whites (AOR = 2.15, P = 0.19, 95% CI: 0.69 to 6.73). Depressive symptoms, loneliness, and low perceived social support mediated the association between internalized stigma and suboptimal adherence in the whole sample, as well as in the subsample of minority participants. In serial mediation models, internalized stigma predicted less-perceived social support (or higher loneliness), which in turn predicted more depressive symptoms, which in turn predicted suboptimal medication adherence. Conclusions: Findings suggest that interconnected psychosocial mechanisms affect ART adherence, and that improvements in adherence may require multifaceted interventions addressing both mental health and interpersonal factors, especially for minority women.

Rheumatoid arthritis (RA) is one of the most common inflammatory conditions in the United States affecting approximately 1 million adults. This article briefly reviews the evidence-based diagnosis of RA, mainstays of treatment to prevent joint destruction, and pain management.

Adult asthma is a prevalent chronic medical condition that is associated with high morbidity, mortality, and cost. Early identification, evidence-based diagnosis, and step-wise management can lead to improvements in patient outcomes, decrease exacerbations, and eliminate respiratory function decline as the patient ages.

This article discusses the physiology of normal hearing, the pathophysiology and differential diagnoses of sudden sensorineural hearing loss, and an approach for definitive diagnosis and treatment. A focus is placed on idiopathic sudden sensorineural hearing loss in the adult population in a primary care setting.

Dissection provides a unique opportunity to integrate anatomical and clinical education. Commonly, cadavers are randomly assigned to courses, which may result in skewed representation of patient populations. The primary aim of this study was to determine if the anatomical donors studied by students at the University of Massachusetts Medical School (UMMS) accurately represent the disease burden of the local patient population. This cross-sectional study compared the University of Massachusetts Memorial Medical Center patient claims data and body donation data from the UMMS Anatomical Gift Program (AGP). This study examined age, race, sex, and morbidities within a 10-year timeframe in 401,258 patients and 859 anatomical donors who met inclusion criteria. An independent t test was conducted to compare the mean ages of the two populations. Chi square analysis was conducted on race, sex, and 10 morbidity categories. A Fischer's exact test was conducted for two morbidity categories with n 10. Demographic analysis showed a significant difference in age, and racial representation between the populations. No statistical difference was found regarding sex. Morbidities were separated into 22 ICD-10 categories. Twelve categories were excluded and 10 were analyzed for population comparison. Two categories were over represented and seven were under-represented in the AGP population. One category showed no significant difference between populations. Targeted selection of cadavers in anatomy courses would improve morbidity variability in the anatomy lab. In addition, AGP acceptance guidelines should be evaluated to increase disease variation among the donor population. Clin. Anat. 31:250-258, 2018. © 2017 Wiley Periodicals, Inc.

Background: The development of a comprehensive and structured clinical curriculum map can outline the specific content covered throughout a nurse practitioner program and provide a method for identifying redundancy and omissions in the didactic clinical content. Method: A curriculum map outlining the specific clinical content covered in each didactic course in a Master of Science in Nursing and Doctor of Nursing Practice advanced practice program was created. The curriculum map incorporated accreditation standards, certification testing domains, and common primary care diagnoses. Results: A curriculum map supported the development of organized, consistent, and transparent clinical didactic content across courses and the program. The curriculum map allows for frequent curriculum and course review and updates to help meet program and accreditation standards. Conclusion: The development and implementation of the clinical didactic curriculum map facilitates the integration of core clinical content in an organized manner that builds learning and prepares future nurse practitioners. [ J Nurs Educ. 2018;57(7):440–445.]

Purpose Despite following standard treatment, Pseudomonas keratitis can continue to progress and result in loss of vision or of the eye. Our cases demonstrate that the Morgan Lens can be an effective topical antibiotic delivery vehicle in advanced keratitis. Methods Two patients (3 eyes) with Pseudomonas keratitis were included in this report after failing to respond to intense inpatient topical treatment. Because loss of the eyes was imminent, the Morgan Lenses were used for continuous lavage with ceftazidime (50 mg/mL), in conjunction with other conventional treatment. Results Three days after lavage, corneal cultures became negative in all eyes. Infusion was continued for at least a week to ensure sterilization of the infection before switching to standard topical therapy. The infection in both cases was promptly eradicated and the eyes were rescued. Conclusions The Morgan Lens can be a viable alternative in treating severe and aggressive infectious keratitis or sclerokeratitis. Application of the Morgan Lens is noninvasive and requires minimal training. Intravenous tubing connectors allow for easy swapping between medications, simultaneous administration of multiple medications, and titration of dosing. Additionally, it is cost-effective as the low demand for nursing care essentially eliminates the need for intensive care unit admission.

Internalized stigma related to HIV is associated with poorer outcomes for people living with HIV (PLWH). However, little is known about the association between experiences of daily acts of discrimination by others and the activation of internalized stigma, including factors that may moderate this association. One hundred nine men living with HIV responded to experience sampling method (ESM) questions 3 times a day for 7 days via smart-phones. ESM questions included experiences of recent acts of discrimination, internalized HIV stigma, avoidance coping with HIV, and recent social support. We also administered several traditional questionnaire measures assessing psychosocial constructs. In Hierarchical Linear Modeling analyses controlling for age, race, socioeconomic status, and time on antiretroviral therapy, experiencing discrimination predicted internalized stigma within-persons. Individuals higher on attachment-related avoidance, attachment-related anxiety, avoidance coping, perceived community stigma, and helplessness, and individuals lower on social support, had stronger associations between discrimination and current internalized stigma. Similarly, results from two state moderator variables supported our trait analyses: State-level (ESM) social support and avoidance coping were significant moderators. Thus, when PLWH experience incidents of discrimination due to HIV, this may lead to increased feelings of internalized stigma. We extend the literature by demonstrating that the associations between experienced and internalized stigma are not just at the generalized trait level, but also occur at the state-level, accounting for within person variability. Results provide implications for interventions aiming to modify maladaptive interpersonal traits as well as interventions to increase social support to reduce the impact of discrimination on PLWH.

We examined disparities in prenatal care utilization (PNCU) among U.S. and foreign-born women with chronic conditions. We performed a cross-sectional analyses using data from 2011 to 2012 National Center for Health Statistics Natality Files (n = 6,644,577) to examine the association between maternal nativity (U.S. vs. foreign-born), presence of a chronic condition (diabetes or hypertensive disorder) and PNCU. After adjustment for selected maternal characteristics, overall and among those with chronic conditions, foreign-born women reported significantly lower odds of intensive and adequate PNCU and higher odds of intermediate and inadequate PNCU than U.S.-born women. Few differences in report of no care were found by maternal nativity. These findings suggest that foreign-born women may be receiving some form of prenatal care, but adequacy of care is likely to be lower compared to U.S.-born counterparts, even among those with chronic conditions.

Eating disorders are complex and serious psychiatric illnesses whose etiology includes psychological, biological, and social factors. Treatment of eating disorders is challenging as there are few evidence-based treatments and limited understanding of the mechanisms that result in sustained recovery. In the last 20 years, we have begun to identify neural pathways that are altered in eating disorders. Consideration of how these pathways may contribute to an eating disorder can provide an understanding of expected responses to treatments. Eating disorder behaviors include restrictive eating, compulsive overeating, and purging behaviors after eating. Eating disorders are associated with changes in many neural systems. In this targeted review, we focus on three cognitive processes associated with neurocircuitry differences in subjects with eating disorders such as reward, decision-making, and social behavior. We briefly examine how each of these systems function in healthy people, using Neurosynth meta-analysis to identify key regions commonly implicated in these circuits. We review the evidence for disruptions of these regions and systems in eating disorders. Finally, we describe psychiatric and psychological treatments that are likely to function by impacting these regions.

In late spring of 2009 and 2010, there were reports of severe black fly (Simulium spp., shown in Fig. 1) outbreaks in various counties in Mississippi, especially those in and around the Mississippi River Delta. Complaints were of black flies attacking multiple species of backyard poultry and causing high morbidity and mortality in affected flocks. At several affected locations, black flies were readily observed swarming around and feeding on birds. A large number of these parasites were easily trapped on fly strips (Fig. 2). Multifocal to coalescing cutaneous hemorrhagic lesions, consistent with fly bites, were seen on the birds. Upon necropsy examination, a large number of black flies were also observed in the digestive tract (Fig. 3). Although black flies may cause disease directly, such as cardiopulmonary collapse and anaphylactoid reactions, detection of Leucocytozoon in blood smears (Fig. 4) of affected birds prompted further investigations of this protozoan as a cause of disease. Leucocytozoon spp. are known to be transmitted by black flies and may be associated with morbidity and mortality in birds such as poultry. From June 2009 through July 2012, the investigation included a total collection of 1068 individual blood samples, representing 371 individual premises in 89 counties/parishes across Mississippi (59), Alabama (10), Louisiana (4), and Tennessee (16). Of the 371 premises where blood samples were collected, 96 (26%) were either positive or highly suspected to be positive for Leucocytozoon spp. by blood smear analysis, and 5 (1.2%) were positive for Haemoproteus spp. by blood smear analysis. Attempts to diagnose Leucocytozoon spp. by PCR analysis and sequencing were complicated by coinfections with two closely related haemosporidians (Haemoproteus spp. and Plasmodium spp.). A novel technique involving flow cytometry was also explored. This study discusses the black fly field outbreak, the involvement of haemosporidians, molecular methods for detection of both the black flies and blood parasites, and initial attempts at flow cytometry.

Inosine 5'- monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes de novo synthesis of the guanine nucleotide and is overexpressed in both hematologic and solid tumors. FF-10501-01 is a potent new competitive IMPDH inhibitor. We investigated the anti-leukemia effect of FF-10501-01 in a Phase 1 clinical study in advanced AML and MDS, including HMA failures. Previous preclinical studies demonstrated potent anti-proliferative and apoptotic effects of FF-10501-01 on AML cell lines, including HMA-resistant derivatives, through inhibition of de novo guanine nucleotide synthesis. Therefore, we performed a standard 3+3 dose-escalation Phase 1 trial to access the safety and clinical activity of FF-10501-01 in patients with advanced AML, MDS and chronic myelomonocytic leukemia (CMML). Eligibility criteria: age ≥ 18 years, high risk MDS/CMML, AML with documented PD following previous therapy, AML ≥ 60 years of age and not a candidate for other therapy, adequate renal and hepatic function, and no known history of significant cardiac disease. A total of 29 patients, 15M and 14F (23 AML, 6 MDS) have been treated in 7 dose cohorts (50 - 500 mg/m2 PO BID) for 14 days on and 14 days off, and 400 mg/m2 for 21 days on and 7 days off, each 28-day cycle. Median (range) values: age 75 yrs (59 - 88); baseline bone marrow blast counts for AML 34% (12 - 82), for MDS 10% (5 - 16), and overall 30% (5 - 82); and prior treatment regimens 2 (1 - 7). All patients relapsed from, or progressed on, prior HMAs. At baseline, mutations in FLT3, NPM1, GATA2, TET2, ASXL1, DNMT3A, NOTCH1, JAK2, IDH2, PTPN11, KRA, TP53, RUNX1, EZH2 and/or MDM2 were present in 13 of 29 (45%) of patients. Atrial fibrillation (Gr 2) was reported in 2 subjects at a dose of 500 mg/m2 BID. This met the definition of dose-limiting toxicity (DLT) and no further enrollment was made at this dose level. The maximally tolerated dose (MTD) was declared at 1 dose level lower, 400 mg/m2 BID, and this cohort was expanded to 6 subjects. No DLTs have been observed in N=7 total subjects treated at 400 mg/m2 BID x 14 days. FF-10501-01 has been very well tolerated through 24 cycles. The most frequent drug-related AEs have been Gr 1-2 nausea, diarrhea and fatigue. Drug-related thrombocytopenia, neutropenia and bone marrow aplasia (all Gr 4) were reported in 1 patient at 200 mg/m2 BID. The median number of FF-10501-01 cycles received to date is 2 (range 1 - 24). Partial remissions have occurred in 2 AML patients (50 and 100 mg/m2 BID) after 3 cycles, lasting for 5 and 24 cycles, respectively, with the higher dose patient still on study after 24 cycles. A total of 8/23 (34.8%) AML patients, including the 2 PRs, have attained stable disease (SD) control with no disease progression over 3 - 24 cycles. Three AML patients remain on study through 3, 23 and 24 cycles, respectively. A bone marrow complete response was achieved in 1 MDS patient treated at 400 mg/m2 BID after 1 cycle. Although the bone marrow blast counts have increased since, this patient remains stable and is still on therapy through 14 cycles. Three of 6 MDS patients (50%), including the marrow CR, attained SD control with no disease progression over 3, 14 and 14 cycles, and 2 remain on study through 3 and 14 cycles, respectively. FF-10501-01 was rapidly absorbed with mean Tmax of 2.74 hours and mean t1/2 of 4.05 hours. Drug exposure (AUC0-24 and AUCcourse) increased with dose in a near linear manner. Potent suppression of circulating xanthine monophosphate (XMP), a marker of IMPDH activity, has been observed following FF-10501-01 administration on Day 1 of Cycles 1 and 2 at dose levels of 50 mg/m2 BID and above. FF-10501-01 is a promising new agent for the treatment of advanced AML and MDS in patients who have failed or progressed on HMAs and with one or more baseline mutations in pathways known to be affected in AML and MDS. Preclinical activity was seen in multiple leukemia cell lines, including HMA-resistant derivatives. In a Phase 1 trial, clinical activity with a marrow CR, PRs, long-term disease stabilization (≥ 5 cycles) and a highly tolerable safety profile were observed. The Phase 2a expansion phase of the study is soon to begin. Disclosures DiNardo: Agios: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:BMS: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding. Denton:Westat Corporation: Employment. Smith:Westat Corporation: Employment. Tiefenwerth:Westat Corporation: Employment. Iwamura:FUJIFILM Corporation: Employment. Gipson:Strategia Therapeutics, Inc.: Employment. Rosner:Strategia Therapeutics, Inc.: Employment. Myers:Strategia Therapeutics, Inc.: Employment. Paradiso:Strategia Therapeutics, Inc.: Employment.

Inosine 5'- monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes de novo synthesis of the guanine nucleotide and is overexpressed in both hematologic and solid tumors. FF-10501-01 is a potent new competitive IMPDH inhibitor. We investigated the anti-leukemia effect of FF-10501-01 in AML cell lines and in a Phase 1 clinical study in advanced AML and MDS, including HMA failures. Thirteen leukemia cell lines were studied, including 5 parental AML cell lines and their HMA-resistant derivatives (MOLM13, SKM1, HL60, TF1, and U937), and 3 other AML cell lines (KG1, HEL, and OCI-AML3). Cell proliferation was determined using trypan blue analysis. Flow cytometry was performed to detect drug-induced apoptosis and cell cycle analysis. High-performance liquid chromatography (HPLC) was performed to detect the intracellular concentrations of guanine nucleotides. Mycophenolic acid-treated cells were used as positive control. Effect of guanosine supplement on FF-10501-01 treatment was evaluated. Within 72 hours of treatment, FF-10501-01 inhibited proliferation of all 13 AML cell lines. The IC50 of FF-10501-01 ranged between 4.3 and 144.5 µM. MOLM13 was the most sensitive leukemia cell line, whereas the decitabine-resistant TF1 cell line was the most resistant. FF-10501-01-induced apoptosis was observed in all cell lines. Increased numbers of cells in G1 phase and decreased numbers in S phase were observed in MOLM13, SKM1 and TF1 cell lines treated with In summary, FF-10501-01 produced potent anti-proliferative and apoptotic effects on AML cell lines through inhibition of de novo guanine nucleotide synthesis. In view of these pre-clinical findings, we performed a standard 3+3 dose-escalation Phase 1 trial to access the safety and clinical activity of FF-10501-01 in patients with advanced AML, MDS and chronic myelomonocytic leukemia (CMML). Eligibility criteria: age ³ 18 years, high risk MDS/CMML, AML with documented PD following previous therapy, AML ≥ 60 years of age and not a candidate for other therapy, adequate renal and hepatic function, and no known history of significant cardiac disease. Sixteen patients (12 AML, 4 MDS) have been enrolled in 5 dose cohorts (50 - 400 mg/m2 PO BID) for 14 days on/14 days off each 28-day cycle, including 8 M and 8 F. Median (range) values: age 75.3 yrs (59.1 - 88.6); bone marrow blasts for AML patients 40.5% (12 - 71), for MDS patients 10% (6 - 13), or 30% overall (6 - 71); and prior treatment regimens 2.5 (1 - 6). All patients relapsed from, or progressed on, prior HMAs. Mutations in FLT3, NPM1, GATA2, TET2, ASXL1, DNMT3A and/or MDM2 were present in 4/16 (25%) patients. The median number of FF-10501-01 cycles received to date is 1.5 (range 1 - 10). No DLTs or drug-related serious adverse events (AEs) have been observed and FF-10501-01 has been very well tolerated through 5 - 10 cycles. The most frequent drug-related AEs have been Gr 1-2 nausea, diarrhea and fatigue. Drug-related Gr 4 prolonged thrombocytopenia and Gr 4 prolonged neutropenia were reported in one patient at 200 mg/m2 BID. Two partial responses (PRs) have been achieved in 1 patient each at 50 and 100 mg/m2 BID after 3 cycles, 7 (50%) patients demonstrated long-term stable disease over 2 - 10 cycles, and 4 patients have remained on study drug through 5 - 10 cycles and are still ongoing. Updated safety and efficacy data, including PK/PD, will be presented at the meeting. FF-10501-01 is a promising new agent for the treatment of advanced AML and MDS. Preclinical activity was seen in multiple leukemia cell lines. In a Phase 1 trial, clinical activity with PRs, prolonged disease stabilization and a highly tolerable safety profile were observed. The Phase 2 expansion phase will be initiated soon. Disclosures DiNardo: Novartis: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Smith:Westat Corporation: Employment. Iwamura:FUJIFILM Corporation: Employment. Gipson:Strategia Therapeutics, Inc.: Employment. Rosner:Strategia Therapeutic, Inc.: Employment. Madden:Strategia Therapeutics, Inc.: Employment. Myers:Strategia Therapeutics, Inc.: Employment. Paradiso:Strategia Therapeutics, Inc.: Employment.