Doctoral students' intention to use assessments in their career: The incremental role of self-reported competence.

OBJECTIVE: Attaining competence in assessment is a necessary step in graduate training and has been defined to include multiple domains of training relevant to this attainment. While important to ensure trainees meet these standards of training, it is critical to understand how and if competence shapes a trainees' professional identity, therein promoting lifelong competency. METHODS: The current study assessed currently enrolled graduate trainees' knowledge and perception of their capabilities related to assessment to determine if self-reported and performance-based competence would incrementally predict their intention to use assessment in their future above basic training characteristics and intended career interests. RESULTS: Self-reported competence, but not performance-based competence, played an incremental role in trainees' intention to use assessments in their careers. Multiple graduate training characteristics and practice experiences were insignificant predictors after accounting for other relative predictors (i.e., intended career settings, integrated reports). CONCLUSION: Findings are discussed about the critical importance of incorporating a hybrid competency-capability assessment training framework to further emphasize the role of trainee self-efficacy in hopes of promoting lifelong competence in their continued use of assessments.

Screening Utility of the PHQ-2 and PHQ-9 for Depression in College Students: Relationships with Substantive Scales of the MMPI-3.

We investigated the validity and screening effectiveness of the PHQ-2 and PHQ-9 scores in 229 college students in a cross-sectional design. PHQ associations with Minnesota Multiphasic Personality Inventory-3 internalizing scales suggest PHQ scores are effective screening tools for college students and may aid in effective triage and service needs.

Relationship of Personality Assessment Inventory (PAI) over-reporting scales to performance validity testing in a military neuropsychological sample.

This study evaluated the Personality Assessment Inventory's (PAI) symptom validity-based over-reporting scales with concurrently administered performance validity testing in a sample of active-duty military personnel seen within a neuropsychology clinic. We utilize two measures of performance validity to identify problematic performance validity (pass all/fail any) in 468 participants. Scale means, sensitivity, specificity, predictive value, and risk ratios were contrasted across symptom validity-based over-reporting scales. Results indicate that the Negative Impression Management (NIM), Malingering Index (MAL), and Multiscale Feigning Index (MFI) scales are the best at classifying failed performance validity testing with medium to large effects (d = .61-.73). In general, these scales demonstrated high specificity and low sensitivity. Roger's Discriminant Function (RDF) had negligible group differences and poor classification. The Feigned Adult ADHD index (FAA) performed inconsistently. This study provides support for the use of several PAI over-reporting scales at detecting probable patterns of performance-based invalid responses within a military sample. Military clinicians using NIM, MAL, or MFI are confident that those who elevate these scales at recommended cut scores are likely to fail concurrent performance validity testing. Use of the Feigned Adult FAA and RDF scales is discouraged due to their poor or mixed performance.

Preliminary indications that recombinant human IL-16 attracts and stimulates lymphocytes of the amphibian, Xenopus laevis implying an ancestral role for CD4 as a cytokine receptor.

The D1 domain of the CD4 co-receptor interacts with MHC class II during Helper CD4+ Th-cell activation and effector function in all gnathostomes but the sequence and structure of this region are not well conserved through phylogeny. Conversely, the proximal D4 domain of CD4 is the binding site of the cytokine IL-16 and is highly conserved, allowing for promiscuous binding of IL-16 to CD4 between disparate gnathostomes. We report here that recombinant human IL-16 (rhIL-16) bound to Xenopus lymphocytes to allow separation on a magnetic column. Incubation with rhIL-16 resulted in an increased expression of MHC class II mRNA by Xenopus CD8- cells more than by CD8+ cells. An in vivo assay demonstrated that rhIL-16 can recruit lymphocytes of Xenopus frogs. Our data suggest that a subset of Xenopus laevis lymphocytes express a CD4 homolog on their surface that is capable of binding IL-16. These results imply that CD4 most likely arose from a primordial cytokine receptor.

Resveratrol prevents tumorigenesis in mouse model of Kras activated sporadic colorectal cancer by suppressing oncogenic Kras expression.

Sporadic and non-hereditary mutations account for the majority of colorectal cancers (CRC). After the loss of adenomatous polyposis coli (APC) function and activation of the ß-catenin/LEF signaling pathway, activating mutations in Kras are major drivers of sporadic CRC. Preventing the outgrowth of cells that develop sporadic mutations will decrease CRC. Resveratrol, a naturally occurring polyphenolic compound has anti-inflammatory, anti-oxidant and anti-cancer activities. We used a genetically engineered mouse model for sporadic CRC where the APC locus is knocked out and Kras is activated specifically in the distal colon to determine the effects of resveratrol on preventing and treating CRC. Feeding mice a diet supplemented with 150 or 300 ppm resveratrol (105 and 210mg daily human equivalent dose, respectively) before tumors were visible by colonoscopy resulted in a 60% inhibition of tumor production. In the 40% of mice that did develop tumors Kras expression was lost in the tumors. In a therapeutic assay where tumors were allowed to develop prior to treatment, feeding tumor bearing mice with resveratrol resulted in a complete remission in 33% of the mice and a 97% decrease in tumor size in the remaining mice. Analysis of miRNA expression in non-tumoral and tumoral colonic tissue of resveratrol treated mice showed an increased expression of miR-96, a miRNA previously shown to regulate Kras translation. These data indicate that resveratrol can prevent the formation and growth of colorectal tumors by downregulating Kras expression.

An electronic tool for systematic reporting of fractures on skeletal surveys in suspected child abuse: prototype development and physician feedback.

OBJECTIVE: To describe a skeletal survey data entry and compilation tool and assess physician attitudes toward this reporting approach. BACKGROUND: Narrative skeletal survey reports are highly variable and prone to inconsistencies with potential adverse impact on patients. MATERIALS AND METHODS: The prototype skeletal survey data entry and compilation tool was developed and introduced into clinical practice at a large urban children's hospital. Pediatric radiologists and child protection team (CPT) pediatricians completed a survey of reporting preferences. Skeletal survey reports between March 1, 2013, and March 1, 2014, were reviewed to assess use of the tool. RESULTS: The survey response rate was 70% (14/20) for radiologists and 100% (4/4) for CPT pediatricians. Among responding radiologists, 54.5% (6/11) indicated that a skeletal survey data entry and compilation tool was helpful for skeletal surveys with >3 fractures; 80% (8/10) of responding radiologists indicated that tabulated data from prior skeletal survey was helpful when interpreting a follow-up skeletal survey with >3 fractures; 90.9% (10/11) of radiologists thought the tool improved report organization; 72.7% (8/11) thought it improved accuracy. Most radiologists (11/12, 91.7%) and 100% (4/4) of CPT clinicians preferred reports with both free text and a tabulated fracture list for testifying in court when >3 fractures were present. The tool was used in the reporting of 14/23 (61%) skeletal surveys with >3 fractures during a 1-year period. A case example using the application is presented. CONCLUSION: Most radiologists and CPT physicians at our center prefer skeletal survey reports with tabulated data and narrative description; 91.7% (11/12) of radiologists and all CPT clinicians prefer this approach for testifying in court when >3 fractures are present.

Yield of radiographic skeletal surveys for detection of hand, foot, and spine fractures in suspected child abuse.

OBJECTIVE: Previous studies have found that fractures involving the spine, hands, and feet are rare on skeletal surveys in cases of suspected child abuse, leading some authors to suggest eliminating these regions from the initial skeletal survey protocol. We assessed this recommendation by performing a historical review of these injuries in a pediatric population undergoing film screen-based radiographic skeletal surveys for suspected child abuse. MATERIALS AND METHODS: This cross-sectional retrospective study reviewed reports of initial skeletal surveys of all children younger than 2 years with suspected abuse imaged between April 1988 and December 2001. Radiographic skeletal survey imaging was performed according to American College of Radiology standards. Sixty-two percent (225/365) of all skeletal surveys had positive findings, and 44% (98/225) showed more than one fracture. Surveys with fractures involving the spine, hands, or feet were identified, and the data were tabulated and analyzed. RESULTS: Twenty of 365 studies (5.5%) yielded fractures involving the spine, hands, or feet. Of all positive skeletal surveys, 8.9% (20/225) had fractures involving the spine, hands, or feet. Of all patients with more than one fracture on skeletal survey, 20.4% (20/98) had fractures involving these regions. CONCLUSION: These data, acquired during the film-screen era, suggest that fractures of the spine, hands, and feet may not be rare in infants and toddlers in cases of suspected child abuse. The benefits of eliminating views of these regions from the initial skeletal survey should be carefully weighed against the cost of missing these potentially important injuries in at-risk pediatric populations.

Detecting feigned ADHD in college students using the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF).

Objective: To investigate the utility of the validity scales of the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) for detecting feigned Attention-Deficit Hyperreactivity Disorder (ADHD), we utilized a simulation design. Method: We examined group differences across the Restructured Clinical (RC) and validity scales as well as the classification ability of the validity scales across three cut scores. Analyses were conducted across five simulation groups (N = 177) and a standard instruction group (N = 32). Results: Across most of the RC and validity scales, those feigning ADHD produced significantly higher scores than the standard instruction group, but generally no significant differences between the feigning groups were demonstrated. The most promising scales for detecting feigned ADHD were F-r, Fp-r, and Fs at cut scores in the 70 T to 80 T range, respectively. Conclusions: Results support the use of the MMPI-2-RF in ADHD evaluations with scores on F-r, Fs, and Fp-r being particularly useful in detecting feigned ADHD in college students. However, there was no evidence to support the feigning of distinct ADHD symptoms presentations.

Anti-tumor efficacy of naked siRNAs for ERBB3 or AKT2 against lung adenocarcinoma cell xenografts.

The use of siRNAs against specific molecular targets has potential for cancer therapy but has been thought to be limited by the need for formulation to improve cellular uptake. Lung adenocarcinoma cells are markedly suppressed in culture by siRNAs to the receptor ERBB3 or its downstream signaling partner AKT2. We now demonstrate that naked, unformulated siRNAs to ERBB3 or AKT2, administered i.v. as saline solutions, 2 µg/g five times per week for 3 weeks (total dose 30 µg/g), were effective suppressors of growth of A549 human lung adenocarcinoma cell xenografts in athymic mice, 12 mice per group, in four different experiments. ERBB3 and AKT2 siRNAs each inhibited growth by 70-90% on average, compared to saline-treated or untreated controls; a nonsilencing siRNA was without significant effect. Lesser but significant effects were noted with a total dose of 12 µg/g. With the higher dose, effects persisted for several weeks after the end of treatment. Expected reductions of ERBB3 and AKT2 mRNAs and proteins occurred and correlated with decrease in tumor volume. There were no significant changes in serum cytokines. These results show that naked siRNAs to ERBB3 or AKT2 may have potential for lung cancer therapy.

Evaluating the performance of the MMPI-3 over-reporting scales: Sophisticated simulators and the effects of comorbid conditions.

OBJECTIVE: We examined the utility of the Minnesota Multiphasic Personality Inventory-3 (MMPI-3) to detect feigned over-reporting using a symptom-based coaching simulation design across a control group and three diagnostic conditions: posttraumatic stress disorder (PTSD), minor traumatic brain injury (mTBI), and comorbid PTSD and mTBI. METHOD: Participants were310 college students who wererandomly assigned to one of the four conditions. For participants in the feigning conditions, they were provided with a descriptionof their respective disorder condition throughout the duration of the session and asked to feign according to their condition while completing the MMPI-3. RESULTS: MMPI-3 over-reporting scales perform well at classifying feigning. There is low sensitivity, high specificity, and effect magnitudes are medium to large range (1.12 - 2.47). There are no differences in scales assessing over-reporting between diagnostic conditions with dissimilar symptoms. CONCLUSIONS: Findings provide initial support for the use of the MMPI-3 overreporting scales for detecting feigned PTSD, mTBI, and comorbid PTSD and mTBI. Further, individuals feigning different disorders, namely PTSD, mTBI, and comorbid PTSD and mTBI, feign predominantly general psychopathological symptoms, making Fp the strongest scale in terms of detecting these feigned disorders. Future research will benefit from establishing relevant diagnostic comparison groups to contrast with this study and utilizing known-group designs withboth PVT and SVT administration.

The nitric oxide prodrug JS-K is effective against non-small-cell lung cancer cells in vitro and in vivo: involvement of reactive oxygen species.

Non-small-cell lung cancer is among the most common and deadly forms of human malignancies. Early detection is unusual, and there are no curative therapies in most cases. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Here, we show that O(2)-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) is a potent cytotoxic agent against a subset of human non-small-cell lung cancer cell lines both in vitro and as xenografts in mice. JS-K treatment led to 75% reduction in the growth of H1703 lung adenocarcinoma cells in vivo. Differences in sensitivity to JS-K in different lung cancer cell lines seem to be related to their endogenous levels of reactive oxygen species (ROS)/reactive nitrogen species (RNS). Other related factors, levels of peroxiredoxin 1 (PRX1) and 8-oxo-deoxyguanosine glycosylase (OGG1), also correlated with drug sensitivity. Treatment of the lung adenocarcinoma cells with JS-K resulted in oxidative/nitrosative stress in cells with high basal levels of ROS/RNS, which, combined with the arylating properties of the compound, was reflected in glutathione depletion and alteration in cellular redox potential, mitochondrial membrane permeabilization, and cytochrome c release. Inactivation of manganese superoxide dismutase by nitration was associated with increased superoxide and significant DNA damage. Apoptosis followed these events. Taken together, the data suggest that diazeniumdiolate-based NO-releasing prodrugs may have application as a personalized therapy for lung cancers characterized by high levels of ROS/RNS. PRX1 and OGG1 proteins, which can be easily measured, could function as biomarkers for identifying tumors sensitive to the therapy.

Causal inference in suicide research: When you should (and should not!) control for extraneous variables.

OBJECTIVE: Although causal inference is often straightforward in experimental contexts, few research questions in suicide are amenable to experimental manipulation and randomized control. Instead, suicide prevention specialists must rely on observational data and statistical control of confounding variables to make effective causal inferences. We provide a brief summary of recent covariate practice and a tutorial on casual inference tools for covariate selection in suicide research. METHOD: We provide an introduction to modern causal inference tools, suggestions for statistical control selection, and demonstrations using simulated data. RESULTS: Statistical controls are often mistakenly selected due to their significant correlation with other study variables, their consistency with previous research, or no explicit reason at all. We clarify what it means to control for a variable and when controlling for the wrong covariates systematically distorts results. We describe directed acyclic graphs (DAGs) and tools for identifying the right choice of covariates. Finally, we provide four best practices for integrating causal inference tools in future studies. CONCLUSION: The use of causal model tools, such as DAGs, allows researchers to carefully and thoughtfully select statistical controls and avoid presenting distorted findings; however, limitations of this approach are discussed.

TFE3 Xp11.2 Translocation Renal Cell Carcinoma Mouse Model Reveals Novel Therapeutic Targets and Identifies GPNMB as a Diagnostic Marker for Human Disease.

Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix-loop-helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC. IMPLICATIONS: Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.

Nitric oxide (NO) releasing poly ADP-ribose polymerase 1 (PARP-1) inhibitors targeted to glutathione S-transferase P1-overexpressing cancer cells.

We report the antitumor effects of nitric oxide (NO) releasing derivatives of the PARP-1 inhibitor olaparib (1). Compound 5b was prepared by coupling the carboxyl group of 3b and the free amino group of arylated diazeniumdiolated piperazine 4. Analogue 5a has the same structure except that the F is replaced by H. Compound 13 is the same as 5b except that a Me2N-N(O)═NO- group was added para and ortho to the nitro groups of the dinitrophenyl ring. The resulting prodrugs are activated by glutathione in a reaction accelerated by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancers. This metabolism generates NO plus a PARP-1 inhibitor simultaneously, consuming reducing equivalents, leading to DNA damage concomitant with inhibition of DNA repair, and in the case of 13 inducing cross-linking glutathionylation of proteins. Compounds 5b and 13 reduced the growth rates of A549 human lung adenocarcinoma xenografts with no evidence of systemic toxicity.

Western Database of Lipid Variants (WDLV): a catalogue of genetic variants in monogenic dyslipidemias.

BACKGROUND: Next-generation sequencing (NGS) is nearing routine clinical application, especially for diagnosis of rare monogenic cardiovascular diseases. But NGS uncovers so much variation in an individual genome that filtering steps are required to streamline data management. The first step is to determine whether a potential disease-causing variant has been observed previously in affected patients. METHODS: To facilitate this step for lipid disorders, we developed the Western Database of Lipid Variants (WDLV) of 2776 variants in 24 genes that cause monogenic dyslipoproteinemias, including conditions characterized primarily by either high or low low-density lipoprotein cholesterol, high or low high-density lipoprotein cholesterol, high triglyceride, and some miscellaneous disorders. We incorporated quality-control steps to maximize the likelihood that a listed mutation was disease causing. RESULTS: The details of each mutation found in a dyslipidemia, together with a mutation map of the causative genes, are shown in graphical display items. CONCLUSIONS: WDLV will help clinicians and researchers determine the potential pathogenicity of mutations discovered by DNA sequencing of patients or research participants with lipid disorders.

Activation of the c-Jun N-terminal kinase/activating transcription factor 3 (ATF3) pathway characterizes effective arylated diazeniumdiolate-based nitric oxide-releasing anticancer prodrugs.

Improved therapies are needed for nonsmall cell lung cancer. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Recently, we have shown that O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, 1) is effective against nonsmall cell lung cancer (NSCLC) cells in culture and in vivo. Here we report mechanistic studies with compound 1 and its homopiperazine analogue and structural modification of these into more stable prodrugs. Compound 1 and its homopiperazine analogue were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector ATF3. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have antitumor activity. The data suggest that rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs.

Smad ubiquitination regulatory factor 2 promotes metastasis of breast cancer cells by enhancing migration and invasiveness.

Controlled protein degradation mediated by ubiquitin/proteasome system (UPS) plays a crucial role in modulating a broad range of cellular responses. Dysregulation of the UPS often accompanies tumorigenesis and progression. Here, we report that Smad ubiquitination regulatory factor 2 (Smurf2), a HECT-domain containing E3 ubiquitin ligase, is up-regulated in certain breast cancer tissues and cells. We show that reduction of Smurf2 expression with specific short interfering RNA in metastatic breast cancer cells induces cell rounding and reorganization of the actin cytoskeleton, which are associated with a less motile and invasive phenotype. Overexpression of Smurf2 promotes metastasis in a nude mouse model and increases migration and invasion of breast cancer cells. Moreover, expression of Smurf2CG, an E3 ligase-defective mutant of Smurf2, suppresses the above metastatic behaviors. These results establish an important role for Smurf2 in breast cancer progression and indicate that Smurf2 is a novel regulator of breast cancer cell migration and invasion.

Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene.

CACNA2D2 is a putative tumor suppressor gene located in the human chromosome 3p21.3 region that shows frequent allelic imbalances in lung, breast, and other cancers. The alpha2delta-2 protein encoded by the gene is a regulatory subunit of voltage-dependent calcium channels and is expressed in brain, heart, and other tissues. Here we report that mice homozygous for targeted disruption of the Cacna2d2 gene exhibit growth retardation, reduced life span, ataxic gait with apoptosis of cerebellar granule cells followed by Purkinje cell depletion, enhanced susceptibility to seizures, and cardiac abnormalities. The Cacna2d2(tm1NCIF) null phenotype has much in common with that of Cacna1a mutants, such as cerebellar neuro-degeneration associated with ataxia, seizures, and premature death. A tendency to bradycardia and limited response of null mutants to isoflurane implicate alpha2delta-2 in sympathetic regulation of cardiac function. In summary, our findings provide genetic evidence that the alpha2delta-2 subunit serves in vivo as a component of P/Q-type calcium channels, is indispensable for the central nervous system function, and may be involved in hereditary cerebellar ataxias and epileptic disorders in humans.