Understanding the characteristics of nonspecific binding of drug-like compounds to canonical stem-loop RNAs and their implications for functional cellular assays.

Identifying small molecules that selectively bind an RNA target while discriminating against all other cellular RNAs is an important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like small molecules that minimize electrostatic and stacking interactions that lead to nonspecific binding of aminoglycosides and intercalators to many stem-loop RNAs. Many such compounds have been reported to bind RNAs and inhibit their cellular activities. However, target engagement and cellular selectivity assays are not routinely performed, and it is often unclear whether functional activity directly results from specific binding to the target RNA. Here, we examined the propensities of three drug-like compounds, previously shown to bind and inhibit the cellular activities of distinct stem-loop RNAs, to bind and inhibit the cellular activities of two unrelated HIV-1 stem-loop RNAs: the transactivation response element (TAR) and the rev response element stem IIB (RREIIB). All compounds bound TAR and RREIIB in vitro, and two inhibited TAR-dependent transactivation and RRE-dependent viral export in cell-based assays while also exhibiting off-target interactions consistent with nonspecific activity. A survey of X-ray and NMR structures of RNA-small molecule complexes revealed that aminoglycosides and drug-like molecules form hydrogen bonds with functional groups commonly accessible in canonical stem-loop RNA motifs, in contrast to ligands that specifically bind riboswitches. Our results demonstrate that drug-like molecules can nonspecifically bind stem-loop RNAs most likely through hydrogen bonding and electrostatic interactions and reinforce the importance of assaying for off-target interactions and RNA selectivity in vitro and in cells when assessing novel RNA-binders.

Fractionated Bilirubin Among 252 892 Utah Newborns with and Without Biliary Atresia: A 15-year Historical Birth Cohort Study.

OBJECTIVES: To determine whether neonatal conjugated or direct bilirubin levels were elevated in infants with biliary atresia (BA) and to estimate the number of newborns who would have positive screens in the nursery necessitating repeat testing after discharge. STUDY DESIGN: We used administrative data from a large integrated healthcare network in Utah to identify newborns who had a fractionated bilirubin recorded during birth admission from 2005 through 2019. Elevated conjugated bilirubin was defined as greater than 0.2 mg/dL and direct bilirubin was defined as greater than 0.5 mg/dL (>97.5th percentile for the assays). We performed simulations to estimate the anticipated number of false-positive screens. RESULTS: There were 32 cases of BA and 468 161 live births during the study period (1/14 700). There were 252 892 newborns with fractionated bilirubin assessed, including 26 of those subsequently confirmed to have BA. Conjugated or direct bilirubin was elevated in all 26 infants with BA and an additional 3246 newborns (1.3%) without BA. Simulated data suggest 9-21 per 1000 screened newborns will have an elevated conjugated or direct bilirubin using laboratory-based thresholds for a positive screen. Screening characteristics improved with higher thresholds without increasing false-negative tests. CONCLUSIONS: This study validates the previous findings that conjugated or direct bilirubin are elevated in the newborn period in patients with BA. A higher threshold for conjugated bilirubin improved screening performance. Future studies are warranted to determine the optimal screening test for BA and to assess the effectiveness and cost-effectiveness of implementing such a program.

A Formative Evaluation of a Diabetes Prevention Program Using the RE-AIM Framework in a Learning Health Care System, Utah, 2013-2015.

INTRODUCTION: Evaluation of interventions can help to close the gap between research and practice but seldom takes place during implementation. Using the RE-AIM framework, we conducted a formative evaluation of the first year of the Intermountain Healthcare Diabetes Prevention Program (DPP). METHODS: Adult patients who met the criteria for prediabetes (HbA1c of 5.70%-6.49% or fasting plasma glucose of 100-125 mg/dL) were attributed to a primary care provider from August 1, 2013, through July 31, 2014. Physicians invited eligible patients to participate in the program during an office visit. We evaluated 1) reach, with data on patient eligibility, participation, and representativeness; 2) effectiveness, with data on attaining a 5% weight loss; 3) adoption, with data on providers and clinics that referred patients to the program; and 4) implementation, with data on patient encounters. We did not measure maintenance. RESULTS: Of the 6,862 prediabetes patients who had an in-person office visit with their provider, 8.4% of eligible patients enrolled. Likelihood of participation was higher among patients who were female, aged 70 years or older, or overweight; had depression and higher weight at study enrollment; or were prescribed metformin. DPP participants were more likely than nonparticipants to achieve a 5% weight loss (odds ratio, 1.70; 95% confidence interval, 1.29-2.25; P < .001). Providers from 7 of 8 regions referred patients to the DPP; 174 providers at 53 clinics enrolled patients. The mean number of DPP counseling encounters per patient was 2.3 (range, 1-16). CONCLUSION: The RE-AIM framework was useful for estimating the formative impact (ie, reach, effectiveness, adoption, and implementation fidelity) of a DPP-based lifestyle intervention deployed in a learning health care system.

Predictors and Survival Impact of False-Negative Sentinel Nodes in Melanoma.

BACKGROUND: The status of the sentinel lymph node in melanoma is an important prognostic factor. The clinical predictors and implications of false-negative (FN) biopsy remain debatable. METHODS: We compared patients with positive sentinel lymph node biopsy (SNB) [true positive (TP)] and negative SNB with and without regional recurrence [FN, true negative (TN)] from our prospective institutional database. RESULTS: Among 2986 patients (84 FN, 494 TP, and 2408 TN; median follow-up 93 months), the incidence of FN-SNB was 2.8%. While calculated FN rate was 14.5% [84 FN/(494 TP + 84 FN) × 100], when we accounted for local/in-transit recurrence (LITR) this rate was 8.5% [46 FN/(494 TP + 46 FN) × 100 %]. On multivariate analysis, male gender (OR 2.0, 95% CI 1.1-3.6, p = 0.018), head/neck primaries (OR 2.5, 95% CI 1.3-4.8, p < 0.006), and LITR (OR 3.5, 95% CI 2.1-5.8, p < 0.001) were associated with FN-SNB. Melanoma-specific survival (MSS) for the FN group was similar to the TP group at 5 years (68 vs. 73%, p = 0.539). However, MSS declined more for the FN group with a longer follow up and was significantly worse at 10 years (44 vs. 64%, p < 0.001). On multivariate analysis, FN-SNB was a significant predictor of worse MSS in melanomas <4 mm in Breslow thickness (HR 1.6; 95% CI 1.1-2.5, p = 0.021). CONCLUSIONS: Male gender, LITR, and head and neck tumors were associated with FN-SNB. FN-SNB was an independent predictor of worse MSS in melanomas <4 mm in thickness, but this survival difference did not become apparent until after 5 years of follow-up.

Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis.

Efforts to improve the clinical outcome of highly aggressive triple-negative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Thus, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that ubiquitin-associated and SH3 domain-containing B (UBASH3B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion, and metastasis largely through modulating epidermal growth factor receptor (EGFR). We also show that UBASH3B is a functional target of anti-invasive microRNA200a (miR200a) that is down-regulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR up-regulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thereby providing a potential therapeutic target for TNBC.

Attitudes and Perceptions of Surgical Oncology Fellows on ACGME Accreditation and the Complex General Surgical Oncology Certification.

BACKGROUND: With the first qualifying examination administered September 15, 2014, complex general surgical oncology (CGSO) is now a board-certified specialty. We aimed to assess the attitudes and perceptions of current and future surgical oncology fellows regarding the recently instituted Accreditation Council for Graduate Medical Education (ACGME) accreditation. METHODS: A 29-question anonymous survey was distributed to fellows in surgical oncology fellowship programs and applicants interviewing at our fellowship program. RESULTS: There were 110 responses (79 fellows and 31 candidates). The response rate for the first- and second-year fellows was 66 %. Ninety-percent of the respondents were aware that completing an ACGME-accredited fellowship leads to board eligibility in CGSO. However, the majority (80 %) of the respondents stated that their decision to specialize in surgical oncology was not influenced by the ACGME accreditation. The fellows in training were concerned about the cost of the exam (90 %) and expressed anxiety in preparing for another board exam (83 %). However, the majority of the respondents believed that CGSO board certification will be helpful (79 %) in obtaining their future career goals. Interestingly, candidate fellows appeared more focused on a career in general complex surgical oncology (p = 0.004), highlighting the impact that fellowship training may have on organ-specific subspecialization. CONCLUSIONS: The majority of the surveyed surgical oncology fellows and candidates believe that obtaining board certification in CGSO is important and will help them pursue their career goals. However, the decision to specialize in surgical oncology does not appear to be motivated by ACGME accreditation or the new board certification.

Epigenetic regulation of cancer stem cell genes in triple-negative breast cancer.

Expression of specific breast cancer stem cells (BCSCs) is seen in aggressive tumors, but their regulation is unclear. Epigenetic changes influence gene expression and are implicated in breast cancer progression. We hypothesized that promoter methylation regulates specific BCSC-related genes [CD44, CD133, CD24, MSH1 (alias, Musashi-1), and ALDH1] and that this epigenetic profile can identify aggressive subtypes, such as triple-negative breast cancer (TNBC). Methylation analysis was performed using MassARRAY EpiTYPER sequencing; CpG-rich sites were identified in the promoter regions of BCSC genes, except ALDH1. These sites were screened by treatment with 5-aza-2'-deoxycytidine in four TN and five non-TNBC cell lines. The specific regulatory CpG site demonstrating the most significant inverse correlation between CpG site methylation and mRNA expression was identified for CD44, CD133, and Musashi-1, but not for CD24. Methylation of CD44, CD133, and Musashi-1 was evaluated in 91 American Joint Committee on Cancer stage I to III primary breast cancer tumors, and these sites were significantly hypomethylated in TNBC versus non-TNBC. The IHC staining of primary tumors with the highest and lowest methylation levels revealed the strongest staining in hypomethylated specimens, suggesting that hypomethylation leads to gene activation. We demonstrate that methylation is a significant mechanism regulating CD44, CD133, and Musashi-1, and that gene hypomethylation correlates with TNBC. Assessment of epigenetic changes in BCSC genes may provide a more accurate classification of TNBC and could be developed as potential therapeutic targets.

Management of papillary lesions of the breast: can larger core needle biopsy samples identify patients who may avoid surgical excision?

BACKGROUND: The ability to distinguish benign from atypical/malignant papillary lesions on core needle biopsy is limited by the representative nature of the biopsy method, thus follow-up excision is usually recommended. We aimed to determine if larger samples of tissue obtained by core needle biopsy can more reliably predict the true benign nature of a papilloma. METHODS: We reviewed the pathology slides and medical records of 51 patients who were diagnosed with benign papillomas on core needle biopsy from 2000 to 2010, who subsequently underwent surgical excision. The characteristics of the core needle biopsy that were associated with retention of benign histology on excision were determined and analyzed. RESULTS: Atypical ductal hyperplasia and carcinoma were identified in 5.8 % (3/51) and 5.8 % (3/51) of papillary lesions, respectively, when excised. Patients whose lesions were diagnosed as benign on excision were significantly distinguished by the area (mm(2)) of tissue sampled by core needle biopsy (mean ± standard deviation (SD): 101.5 ± 106.5) compared with those with atypia or carcinoma on excision (mean ± SD: 41.7 ± 24.0, P = 0.003). All biopsies performed with 12-gauge or larger needles retained benign features on excision. Core needle biopsy tissue samples consisting of ≥7 cores, or measuring >96 mm(2) in aggregate, had a negative predictive value for atypia/malignancy of 100 %. CONCLUSIONS: Larger tissue samples significantly improved the predictive value of benign histology on core needle biopsy. A papilloma sampled by a 12-gauge or larger needle, ≥7 cores, or >96 mm(2) retained its benign features upon excision.

Discovery, characterization, and redesign of potent antimicrobial thanatin orthologs from Chinavia ubica and Murgantia histrionica targeting E. coli LptA.

Podisus maculiventris thanatin has been reported as a potent antimicrobial peptide with antibacterial and antifungal activity. Its antibiotic activity has been most thoroughly characterized against E. coli and shown to interfere with multiple pathways, such as the lipopolysaccharide transport (LPT) pathway comprised of seven different Lpt proteins. Thanatin binds to E. coli LptA and LptD, thus disrupting the LPT complex formation and inhibiting cell wall synthesis and microbial growth. Here, we performed a genomic database search to uncover novel thanatin orthologs, characterized their binding to E. coli LptA using bio-layer interferometry, and assessed their antimicrobial activity against E. coli. We found that thanatins from Chinavia ubica and Murgantia histrionica bound tighter (by 3.6- and 2.2-fold respectively) to LptA and exhibited more potent antibiotic activity (by 2.1- and 2.8-fold respectively) than the canonical thanatin from P. maculiventris. We crystallized and determined the LptA-bound complex structures of thanatins from C. ubica (1.90 Å resolution), M. histrionica (1.80 Å resolution), and P. maculiventris (2.43 Å resolution) to better understand their mechanism of action. Our structural analysis revealed that residues A10 and I21 in C. ubica and M. histrionica thanatin are important for improving the binding interface with LptA, thus overall improving the potency of thanatin against E. coli. We also designed a stapled variant of thanatin that removes the need for a disulfide bond but retains the ability to bind LptA and antibiotic activity. Our discovery presents a library of novel thanatin sequences to serve as starting scaffolds for designing more potent antimicrobial therapeutics.

Comparison of patient characteristics and outcomes of contralateral prophylactic mastectomy and unilateral total mastectomy in breast cancer patients.

BACKGROUND: There has been an increasing trend toward contralateral prophylactic mastectomy (CPM) in the management of breast cancer (BCa). This study's objective was to compare clinicopathologic characteristics of BCa patients who elected CPM to those who elected unilateral total mastectomy (UTM) and to determine whether CPM improved survival. METHODS: Comparison was performed on 355 patients with stage 0-III BCa matched by age and stage who underwent mastectomy from 1995 to 2008: 177 patients had CPM; 178 patients had UTM. Clinicopathological characteristics and survival outcomes were analyzed. RESULTS: Women who underwent preoperative MRI were twice as likely to have CPM (40.9 vs. 19.7%, P < 0.001). MRI identified additional suspicious foci in 45% CPM and 19% UTM. Patients with history of previous breast biopsies, family history, or BRCA mutation were more likely to choose CPM than UTM (40.1 vs. 24%, P = 0.001; 64.3 vs. 41.4%, P < 0.001; 20.3 vs. 6.5%, P = 0.04, respectively). CPM patients elected nipple preservation (26 vs. 5.2%, P < 0.001) and immediate reconstruction more often (92.2 vs. 73.5%, P < 0.001); UTM patients were more likely to have attempted breast conservation prior to mastectomy (52.8 vs. 39.5%, P = 0.01). CPM identified occult BCa in 11 patients (6.6%), and three UTM patients (1.7%) developed contralateral BCa. With median follow-up of 61 months, by univariable/multivariable analyses, CPM did not improve overall, disease-free, or distant metastases-free survival. CONCLUSION: Factors that may influence choice of CPM included preoperative MRI, history of prior breast biopsies, immediate reconstruction, nipple preservation, family history, and BRCA status. Those who chose CPM did not have improved survival.

Reducing Admission for Anaphylaxis in a Pediatric Emergency Department Using a Clinical Decision Support Tool.

Introduction: Anaphylaxis is a life-threatening condition necessitating emergent management. However, the benefits of prolonged observation and indications for hospitalization are not well established. Through the implementation of a disposition-focused clinical decision support tool (CDST), this quality improvement initiative aimed to reduce hospitalization for low-risk patients presenting to the pediatric emergency department (PED) with anaphylaxis from 49% to ≤12% within 12 months of implementation. Methods: The intervention included patients 18 years and younger of age presenting with anaphylaxis to the PED. A multidisciplinary team identified a 2006 evidence-based guideline as a significant contributor to hospitalization. The updated guideline incorporated a disposition-focused CDST that stratified patients as low-risk or high-risk and recommended discharge of low-risk patients after a 4-hour observation period. The primary outcome measure was the percentage of low-risk patients hospitalized. Balancing measures included low-risk patient 72-hour return rate and PED length of stay for all comers. Secondary outcomes included a focused cost analysis. Results: Fifty-three children preintervention and 43 children postintervention presenting with anaphylaxis met low-risk criteria. Postimplementation, hospitalization of low-risk patients decreased from 49% to 7% (P < 0.0001). No low-risk patients returned in 72 hours for an anaphylaxis-related concern (P = 0.83). The median PED length of stay increased from 189 to 193 minutes (P < 0.0001). The median cost per low-risk encounter decreased by $377 (P = 0.013). Conclusions: After implementing an evidence-based disposition-focused CDST, hospitalization of low-risk patients presenting to the PED with anaphylaxis significantly decreased without an increase in 72-hour returns. In addition, patient encounters demonstrated cost savings.

A novel transition clinic structure for adolescent and young adult patients with childhood onset rheumatic disease improves transition outcomes.

BACKGROUND: The transition of health care from Pediatric to Adult providers for adolescents and young adults with chronic disease is associated with poor outcomes. Despite the importance of this transition, over 80% of these patients do not receive the services necessary to transition to Adult health care. In 2018, we initiated a transition clinic structure, integrating an Internal Medicine - Pediatrics trained Adult Rheumatologist in a Pediatric Rheumatology clinic to guide this transition. Our goal was to improve transition outcomes. We report the methods of this clinic and its preliminary outcomes. METHODS: For patients referred to the transition clinic, the Adult Rheumatologist assumed medical management and implemented a six-part modular transition curriculum. This curriculum included a Transition Policy, Transition Readiness Assessment, medication review and education, diagnosis review and education, and counseling on differences between Pediatric and Adult-oriented care. Eligible patients and their families were enrolled in a prospective observational outcomes research registry. Initial data from this transition clinic is reported including adherence with certain aspects of the transition curriculum and clinic utilization. RESULTS: The transition clinic Adult Rheumatologist saw 177 patients in 2 years, and 57 patients were eligible for, approached, and successfully enrolled in the registry. From this registry, all patients reviewed the Transition Policy with the Adult Rheumatologist and 45 (78.9%) completed at least one Transition Readiness Assessment. Of the 22 patients for whom transition was indicated, all were successfully transitioned to an Adult Rheumatologist. 17 (77.3%) continued care post-transition with the transition clinic Adult Rheumatologist, and 5 (22.7%) continued care post-transition with a different Adult Rheumatologist. The median time between the last transition clinic visit and first Adult clinic visit was 5.1 months. CONCLUSIONS: Our experience demonstrated the success of our clinic model regarding participation in the transition curriculum and improved clinic utilization data. Our results are an improvement over transition rates reported elsewhere that did not implement our model. We believe that this structure could be applied to other primary care and subspecialty clinics. TRIAL REGISTRATION: This research was approved by the University of Utah Institutional Review Board (IRB) in January 2019 (IRB_00115964). Patients were retrospectively registered if involved prior to this date.

Generation of a humanized Aß expressing mouse demonstrating aspects of Alzheimer's disease-like pathology.

The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aß under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aß sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aß sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAß expression, rescues cognition and reduces the formation of PAS granules.

Primary Care Autism Screening and Later Autism Diagnosis.

OBJECTIVES: To describe the proportion of children screened by the Modified Checklist for Autism in Toddlers (M-CHAT), identify characteristics associated with screen completion, and examine associations between autism spectrum disorder (ASD) screening and later ASD diagnosis. METHODS: We examined data from children attending 18- and 24-month visits between 2013 and 2016 from 20 clinics within a health care system for evidence of screening with the M-CHAT and subsequent coding of ASD diagnosis at age >4.75 years. We interviewed providers for information about usual methods of M-CHAT scoring and ASD referral. RESULTS: Of 36 233 toddlers, 73% were screened and 1.4% were later diagnosed with ASD. Hispanic children were less likely to be screened (adjusted prevalence ratio [APR]: 0.95, 95% confidence interval [CI]: 0.92-0.98), and family physicians were less likely to screen (APR: 0.12, 95% CI: 0.09-0.15). Compared with unscreened children, screen-positive children were more likely to be diagnosed with ASD (APR: 10.3, 95% CI: 7.6-14.1) and were diagnosed younger (38.5 vs 48.5 months, P < .001). The M-CHAT's sensitivity for ASD diagnosis was 33.1%, and the positive predictive value was 17.8%. Providers routinely omitted the M-CHAT follow-up interview and had uneven referral patterns. CONCLUSIONS: A majority of children were screened for ASD, but disparities exist among those screened. Benefits for screen-positive children are improved detection and younger age of diagnosis. Performance of the M-CHAT can be improved in real-world health care settings by administering screens with fidelity and facilitating timely ASD evaluations for screen-positive children. Providers should continue to monitor for signs of ASD in screen-negative children.

Multiplex Gene Profiling of Cell-Free DNA in Patients With Metastatic Melanoma for Monitoring Disease.

PURPOSE: Hotspot blood cell-free DNA (cfDNA) biomarker assays have limited utility in profiling tumor heterogeneity and burden and in capturing regional metastasis with low disease burden in patients with melanoma. We investigated the utility of a sensitive 54-cancer gene digital next-generation sequencing approach targeting blood cfDNA single nucleotide variants (SNVs) and copy number amplification for monitoring disease in patients with melanoma with regional or distant organ metastasis (DOM). PATIENTS AND METHODS: A total of 142 blood samples were evaluated by digital next-generation sequencing across two patient cohorts. Cohort 1 contained 44 patients with stage II, III, or IV disease with matched tumor DNA at the time of surgery or DOM. Cohort 2 consisted of 12 overlapping patients who were longitudinally monitored after complete lymph node dissection to DOM. RESULTS: In cohort 1, cfDNA SNVs were detected in 75% of patients. Tumor-cfDNA somatic SNV concordance was 85% at a variant allele fraction of ≥ 0.5%. An SNV load (number of unique SNVs detected) of greater than two SNVs and an SNV burden (total cumulative SNV VAF) of > 0.5% were significantly associated with worse overall survival (P < .05) in stage IV patients. In cohort 2, 98 longitudinal blood samples along with matched regional and distant metastases from 12 stage III patients were analyzed before complete lymph node dissection and throughout disease progression. cfDNA SNV levels correlated with tumor burden (P = .019), enabled earlier detection of recurrence compared with radiologic imaging (P < .01), captured tumor heterogeneity, and identified increasing SNVs levels before recurrence. CONCLUSION: This study demonstrates significant utility for cfDNA profiling in patients with melanoma with regional and/or distant metastasis for earlier detection of recurrence and progression and in capturing tumor evolution and heterogeneity, thus impacting how patients with melanoma are monitored.

PPARγ regulates meibocyte differentiation and lipid synthesis of cultured human meibomian gland epithelial cells (hMGEC).

PURPOSE: To evaluate the role of PPARγ in regulating meibocyte differentiation and lipid synthesis in a human meibomian gland epithelial cell line (hMGEC). METHODS: HMGEC were exposed to the PPARγ agonist, Rosiglitazone, from 10-50 µM. Cultures were also exposed to specific PPARγ antagonist, T0070907, to block PPARγ receptor signaling. Cells were then stained with Ki-67 and LipidTox to determine the effects on cell cycling and lipid synthesis, respectively. Expression of meibocyte differentiation related proteins, ADFP, PPARγ, ELOVL4, and FABP4, were evaluated by quantitative PCR and western blotting. A human corneal epithelial cell line (hTCEpi) was used as a control. RESULT: Rosiglitazone significantly decreased Ki-67 staining within 2 days in a dose-dependent manner (P = 0.003) and increased lipid accumulation in hMGEC in a dose dependent manner. T0070907 suppressed both lipid droplet synthesis and cell cycle exit. Rosiglitazone significantly upregulated expression of ADFP, PPARγ, ELOVL4, and FABP4 by 9.6, 2.7, 2.6, and 3.3 fold on average (all P < 0.05 except for FABP4, P = 0.057) in hMGEC. T0070907 significantly abrogated rosiglitazone-induced upregulation of these genes when treated prior to rosiglitazone treatment (all P < 0.05). The observed lipogenic differentiation response was not duplicated in hTCEpi after exposure to rosiglitazone. CONCLUSION: Rosiglitazone induced cell cycle exit and upregulation of lipogenic gene expression leading to lipid accumulation in hMGEC. These effects were suppressed by PPARγ antagonist indicating that PPARγ signaling specifically directs lipogenesis in hMGEC. These findings suggest that PPARγ plays a critical role in meibocyte differentiation.

Stepping Back to Move Forward: Evaluating the Effectiveness of a Diabetes Prevention Program Within a Large Integrated Healthcare Delivery System.

OBJECTIVE: To evaluate the short-term effectiveness of the Intermountain Healthcare (IH) Diabetes Prevention Program (DPP) for patients with prediabetes (preDM) deployed within primary care clinics. STUDY DESIGN: A quasi-experimental study design was used to deploy the DPP within the IH system to identify patients with preDM and target a primary goal of a 5% weight loss within 6-12 months of enrollment. STUDY POPULATION: Adults (aged 18-75 years) who met the American Diabetes Association criteria for preDM were included for study. Patients who attended DPP counseling between August 2013 and July 2014 were considered as the intervention (or DPP) group. The DPP group was matched using propensity scores at a 1:4 ratio with a control group of patients with preDM who did not participate in DPP. RESULTS: Of the 17,142 patients who met the inclusion criteria for preDM, 40% had an in-person office visit with their provider. On average, patients were 58 years old, and greater than 60% were women. Based on multivariate logistic regression, the DPP group was more likely to achieve a 5% weight loss within 6-12 months after enrollment (OR = 1.70; 95% CI = 1.29-2.25; p < .001) when compared with the no-DPP group. CONCLUSIONS: Diabetes Prevention Program-based lifestyle interventions demonstrated significant reduction in body weight and incident Type 2 diabetes mellitus when compared with nonenrollees.

Liquid Biopsies for Assessing Metastatic Melanoma Progression.

The field of genomic biomarkers in melanoma has evolved dramatically in the past few decades. Whereas much of the prior focus was on molecular assessment of tumor tissue, circulating tumor cells (CTCs), and cell-free circulating tumor DNA (ctDNA) as sources of a "liquid biopsy" in cancer patients provide promising potential as a method to assess tumor progression, identify targets for therapy, and evaluate clinical response to treatment. Blood biomarker assays have the advantage of being noninvasive, allow for dynamic evaluation of disease over a serial time frame, and help to address the issue of tissue sampling bias and tumor heterogeneity. However, there remains an assortment of technologies and techniques to isolate and detect CTCs and ctDNA and a standardized method has yet to be established. Despite these challenges, multiple studies have already demonstrated the clinical prognostic utility of blood-based genomic biomarker assays. With the advent of next-generation sequencing and genome-wide ctDNA analysis, this will undoubtedly lead to an improved understanding of tumor progression, help to identify new targets for treatment, and improve monitoring of treatment response and development of resistance.

Using Electronic Health Record Data to Identify Prostate Cancer Patients That May Qualify for Active Surveillance.

INTRODUCTION: The introduction of the protein-specific antigen (PSA) test in care means that prostate cancer (PCa) is being detected earlier and more frequently. The result of increased screening using PSA, digital rectal examination and awareness of prostate was an increase in the number of men with low risk cancers. Active surveillance has become a viable alternative to immediate treatment with surgery, radiation and other forms of localized treatment. Evidence suggests that there is no significant difference in mortality rates between AS and surgery. In addition, patients may potentially delay other complications associated with surgery, radiation or deprivation therapy. METHODS: This quality improvement study using a delivery system science framework describes the electronic identification of AS candidates given an evidence-based identification criteria based upon national guidelines and clinical judgement. The study population (n=649) was drawn from health records of all patients who received a prostate biopsy (n=1731) at Intermountain Healthcare from 1/1/2013 to 12/31/2014. Automated and manual abstraction was performed. Receiver operating characteristic (ROC) analysis was used to compare AS-eligible patients to the actual treatment received to identify potential care improvement opportunities. Among those with complete data, 24.7% of this population (n=160) met "AS-eligible" criteria. 39.1% of the population had not received surgery, radiation or androgen deprivation therapy and were considered as being treated using an AS approach. 9% of AS-eligible patients did not receive AS; 27% of patients who did not meet AS-eligible criteria received AS. Estimated guideline adherence measured using area under the curve was 0.70 (95% CI: 0.66-0.73). Modest variation in criteria parameters for identifying AS-eligible patients did not significantly change estimated adherence levels. CONCLUSION: Implementation of evidence-based criteria for detection of AS candidates is feasible using electronic health record data and provides a reasonable basis for delivery system evaluation of practice patterns and for quality improvement.

Impact of Laparoscopic Adrenalectomy on Overall Survival in Patients with Nonmetastatic Adrenocortical Carcinoma.

BACKGROUND: Appropriate use of laparoscopic adrenalectomy (LA) for adrenocortical carcinoma (ACC) remains controversial because complete resection with negative margins is the best chance for potential cure. This study compared the oncologic outcomes and overall survival (OS) of LA and open adrenalectomy (OA) for ACC. STUDY DESIGN: A retrospective analysis of the National Cancer Data Base (NCDB) between 2010 and 2014 identified 423 European Network for the Study of Adrenal Tumors (ENSAT) stage I to III ACC patients who had LA (n = 137) or OA (n = 286). Outcomes and OS were compared between the 2 groups. RESULTS: Patients who underwent OA had more advanced stage disease (p = 0.0001), larger (≥5 cm) tumors (p < 0.0001), and were younger (age less than 55 years, p = 0.05). Nodal assessment was rare in LA (n = 4) compared with OA (n = 88) (p < 0.0001). Margin positivity was affected only by surgical approach in patients with T3 tumors (LA 54.6% vs OA 21.7%; p = 0.0009). Neither surgical procedure nor any socio-demographic factor(s) affected OS for the entire cohort. Only positive margins (p = 0.007), positive nodes (p = 0.02), tumor extension (p = 0.01), and more advanced ENSAT stage (p = 0.004) increased mortality. When stratified by disease stage, LA decreased OS for patients with stage II disease (p = 0.04), and remained an independent risk factor for death on multivariate analysis (hazard ratio [HR] 1.86, 95% CI 1.02 to 3.38; p = 0.04). Only positive margins decreased OS in the entire cohort (HR 2.17, 95% CI 1.32 to 3.57; p = 0.002). CONCLUSIONS: Use of LA may decrease OS in select patients with ACC. Because margin status remains the strongest predictor of mortality, caution should be used in selecting LA for patients with ACC.