Necdin, a Negative Growth Regulator, Is a Novel STAT3 Target Gene Down-Regulated in Human Cancer

Cytokine and growth factor signaling pathways involving STAT3 are frequently constitutively activated in many human primary tumors, and are known for the transcriptional role they play in controlling cell growth and cell cycle progression. However, the extent of STAT3's reach on transcriptional control of the genome as a whole remains an important question. We predicted that this persistent STAT3 signaling affects a wide variety of cellular functions, many of which still remain to be characterized. We took a broad approach to identify novel STAT3 regulated genes by examining changes in the genome-wide gene expression profile by microarray, using cells expressing constitutively-activated STAT3. Using computational analysis, we were able to define the gene expression profiles of cells containing activated STAT3 and identify candidate target genes with a wide range of biological functions. Among these genes we identified Necdin, a negative growth regulator, as a novel STAT3 target gene, whose expression is down-regulated at the mRNA and protein levels when STAT3 is constitutively active. This repression is STAT3 dependent, since inhibition of STAT3 using siRNA restores Necdin expression. A STAT3 DNA-binding site was identified in the Necdin promoter and both EMSA and chromatin immunoprecipitation confirm binding of STAT3 to this region. Necdin expression has previously been shown to be down-regulated in a melanoma and a drug-resistant ovarian cancer cell line. Further analysis of Necdin expression demonstrated repression in a STAT3-dependent manner in human melanoma, prostate and breast cancer cell lines. These results suggest that STAT3 coordinates expression of genes involved in multiple metabolic and biosynthetic pathways, integrating signals that lead to global transcriptional changes and oncogenesis. STAT3 may exert its oncogenic effect by up-regulating transcription of genes involved in promoting growth and proliferation, but also by down-regulating expression of negative regulators of the same cellular processes, such as Necdin

The potential role of three-dimensional surface imaging as a tool to evaluate aesthetic outcome after Breast Conserving Therapy (BCT)

To establish whether objective measurements of symmetry of volume and shape using three-dimensional surface imaging (3D-SI) can be used as surrogate markers of aesthetic outcome in patients who have undergone breast conserving therapy (BCT). Women who had undergone unilateral BCT in the preceding 1-6 years were invited to participate. Participants completed a satisfaction questionnaire (BREAST-Q) and underwent 3D-SI. Volume and surface symmetry were measured on the images. Assessment of aesthetic outcome was undertaken by a panel of clinicians. The Kruskal-Wallis test was used to assess the relationship between volume and shape symmetry measurements with the panel score. Spearman's rho correlations were used to assess the relationship between the measurements and patient satisfaction. 200 women participated. Median volume symmetry was 87% (IQR 78-93) and shape symmetry was 5.9 mm (IQR 4.2-8.0). The participants were grouped according to panel assessment of aesthetic outcome (poor, fair, good, excellent) and the median volume and shape symmetry was calculated for each group. Volume symmetry significantly differed between the groups. Post hoc pairwise comparisons demonstrated that these differences existed between panel scores of fair versus good and good versus excellent. Median shape symmetry also differed according to patient panel groups with four significant pairwise comparisons between poor versus good, poor versus excellent, fair versus good and fair versus excellent. There was a significant but weak correlation of both volume symmetry and surface asymmetry with BREAST-Q scores (correlation coefficients 0.187 and -0.229, respectively). Breast volume and shape symmetry are both associated with panel assessment scores and patient satisfaction. The objective volume and shape symmetry measures were strongly associated with panel assessment scores, such that a 3D-SI tool could replace panel assessment as a faster and more objective method of evaluating aesthetic outcomes

Identification of Novel STAT3 Target Genes Associated with Oncogenesis

Cytokine and growth factor signaling pathways involving STAT3 are frequently constitutively activated in many human primary tumors, and are known for the transcriptional role they play in controlling cell growth and cell cycle progression. However, the extent of STAT3\u27s reach on transcriptional control of the genome as a whole remains an important question. We predicted that this persistent STAT3 signaling affects a wide variety of cellular functions, many of which still remain to be characterized. We took a broad approach to identify novel STAT3 regulated genes by examining changes in the genome-wide gene expression profile by microarray, using cells expressing constitutively-activated STAT3. Using computational analysis, we were able to define the gene expression profiles of cells containing activated STAT3 and identify candidate target genes with a wide range of biological functions. Among these genes we identified Necdin, a negative growth regulator, as a novel STAT3 target gene, whose expression is down-regulated at the mRNA and protein levels when STAT3 is constitutively active. This repression is STAT3 dependent, since inhibition of STAT3 using siRNA restores Necdin expression. A STAT3 DNA-binding site was identified in the Necdin promoter and both EMSA and chromatin immunoprecipitation confirm binding of STAT3 to this region. Necdin expression has previously been shown to be down-regulated in a melanoma and a drug-resistant ovarian cancer cell line. Further analysis of Necdin expression demonstrated repression in a STAT3-dependent manner in human melanoma, prostate and breast cancer cell lines. These results suggest that STAT3 coordinates expression of genes involved in multiple metabolic and biosynthetic pathways, integrating signals that lead to global transcriptional changes and oncogenesis. STAT3 may exert its oncogenic effect by up-regulating transcription of genes involved in promoting growth and proliferation, but also by down-regulating expression of negative regulators of the same cellular processes, such as Necdin

Cohort Study of Downgraded Misdemeanor Convictions and Subsequent Violent Crime: Differences by Defendant Race and Ethnicity.

INTRODUCTION: Criminal convictions may be imperfect markers of criminalized behavior, in part because of criminal legal system processes (e.g., plea bargaining). In this retrospective cohort study of individuals convicted of misdemeanors, authors compared the risk of subsequent criminal charges for a violent crime among those initially charged with a felony with that among those initially charged with only misdemeanors, overall and by defendant race and ethnicity. METHODS: The study population included individuals aged ≥18 years who were convicted of a misdemeanor in Washington Superior Courts from January 1, 2015 to December 31, 2019. Those with and without initial felony charges were age/gender matched in a 4:1 ratio. The primary outcome was the first subsequent violent crime charge in Washington Superior Courts through December 31, 2020. Data were analyzed with Fine-Gray hazard models from June 2022 to November 2023. RESULTS: There were 3,841 individuals with initial felony charges and 956 with initial misdemeanor charges only. Median follow-up was 2.4 years for both groups. During follow-up, there were 166 new violent crime charges. In multivariable models, White defendants with initial felony charges had a greater risk of subsequent violent crime charges (subdistribution hazard ratio=2.58; 95% CI=1.24, 5.36) than White defendants with initial misdemeanor charges only. Among Black and Hispanic/Latinx defendants, initial felony versus misdemeanor charges were not associated with subsequent violent crime charges (subdistribution hazard ratio=0.93; 95% CI=0.44, 1.97 among Black defendants; subdistribution hazard ratio=0.49; 95% CI=0.15, 1.57 among Hispanic/Latinx defendants). CONCLUSIONS: Findings suggest differential associations between downgrading of felony charges to misdemeanor convictions and future violent crime charges by defendant race and ethnicity, with implications for inequitable collateral consequences of criminal convictions

Surveys of 12 California crops for phytoseiid predatory mites show changes compared to earlier studies

Phytoseiid mites are key predators in agricultural crops. However, not all species regulate pest populations below economic thresholds, and therefore knowledge of which species are associated with particular crops aids pest control recommendations. Surveys of 12 crops across six geographical regions of California demonstrated that phytoseiid species varied by crop and geographical location, with subtropical crops exhibiting the lowest species diversity and grape the greatest. The western predatory mite, Galendromus occidentalis, long cited as a dominant species in California crops, was not found to be the major species in most situations. Euseius stipulatus, a species introduced in the 1970s, was found in the surveyed crops in many areas of the state and appears to be displacing E. hibisci along the south coast

Trajectory Analysis of Serum Biomarker Concentrations Facilitates Outcome Prediction after Pediatric Traumatic and Hypoxemic Brain Injury

Traumatic brain injury (TBI) and hypoxic ischemic encephalopathy (HIE) are leading causes of morbidity and mortality in children. Several studies over the past several years have evaluated the use of serum biomarkers to predict outcome after pediatric brain injury. These studies have all used simple point estimates such as initial and peak biomarker concentrations to predict outcome. However, this approach does not recognize patterns of change over time. Trajectory analysis is a type of analysis which can capture variance in biomarker concentrations over time and has been used with success in the social sciences. We used trajectory analysis to evaluate the ability of the serum concentrations of 3 brain-specific biomarkers – S100B, neuron-specific enolase (NSE) and myelin basic protein (MBP) – to predict poor outcome (Glasgow Outcome Scale scores 3–5) after pediatric TBI and HIE. Clinical and biomarker data from 100 children with TBI or HIE were evaluated. For each biomarker, we validated 2-, 3- and 4-group models for outcome prediction, using sensitivity and specificity. For S100B, the 3-group model predicted poor outcome with a sensitivity of 59% and specificity of 100%. For NSE, the 3-group model predicted poor outcome with a sensitivity of 48% and specificity of 98%. For MBP, the 3-group model predicted poor outcome with a sensitivity of 73% and specificity of 61%. Thus, when the models predicted a poor outcome, there was a very high probability of a poor outcome. In contrast, 17% of subjects with a poor outcome were predicted to have a good outcome by all 3 biomarker trajectories. These data suggest that trajectory analysis of biomarker data may provide a useful approach for predicting outcome after pediatric brain injury