Screening approaches to generating STAT inhibitors: Allowing the hits to identify the targets

STAT transcription factors are regulators of critical cellular processes such as proliferation, survival, and self-renewal. While the activity of these proteins is tightly regulated under physiological conditions, they can become constitutively activated in a broad range of human cancers. This inappropriate STAT activation leads to enhanced transcription of genes that can directly lead to the malignant phenotype. Since STATs are largely dispensable for normal cell function, this has raised the possibility that STATs might be key targets for cancer therapy. Although a number of structure-based strategies have been used to develop STAT inhibitors, an alternate approach is to use cell-based assays that make use of the transcriptional function of STATs. Employing these systems, one can screen large chemical libraries to identify compounds that specifically block the function of a given STAT. This approach can lead to the identification of compounds that inhibit STATs by a variety of mechanisms, and can suggest novel targets for therapy. This type of functional screening strategy has already identified a drug that potently inhibits STAT3, and which is now being evaluated in a clinical trial for patients with chronic lymphocytic leukemia

Mimicking the effect of prolactin on STAT3/STAT5 activity in breast cancer

Signal transducers and activators of transcription (STAT) 3 and 5 are commonly constitutively activated in breast cancer. STAT5 can outcompete STAT3 and reduce cell proliferation and metastasis. STAT5 activation is stimulated by prolactin, a natural hormone that can be harmful at high levels. The aim of this study is to identify some possible previously developed drugs that mimic the effect of prolactin and STAT5 without the added risk in MDA-MB231 breast cancer cells. Using the CLUE database query app and STAT5 up- and downregulation signatures, three drugs (X, K, and M) were chosen based on their similarity in signatures to those of STAT5. These drugs were then analyzed for cell viability to determine dosage. qPCR was used to compare the expression of STAT5 target genes after drug treatment and the expression after STAT5 activation with prolactin. The drug K was found to show a similar impact on target gene expression to prolactin. Further research is required, but from this study K seems to be a promising option for stimulating STAT5 and improving breast cancer prognosis

STAT3 Activity and Function in Cancer: Modulation by STAT5 and miR-146b

The transcription factor STAT3 regulates genes that control critical cellular processes such as proliferation, survival, pluripotency, and motility. Thus, under physiological conditions, the transcriptional function of STAT3 is tightly regulated as one part of a complex signaling matrix. When these processes are subverted through mutation or epigenetic events, STAT3 becomes highly active and drives elevated expression of genes underlying these phenotypes, leading to malignant cellular behavior. However, even in the presence of activated STAT3, other cellular modulators can have a major impact on the biological properties of a cancer cell, which is reflected in the clinical behavior of a tumor. Recent evidence has suggested that two such key modulators are the activation status of other STAT family members, particularly STAT5, and the expression of STAT3-regulated genes that are part of negative feedback circuits, including microRNAs such as miR-146b. With attention to these newly emerging areas, we will gain greater insight into the consequence of STAT3 activation in the biology of human cancers. In addition, understanding these subtleties of STAT3 signaling in cancer pathogenesis will allow the development of more rational molecular approaches to cancer therapy

Extension rates across the northern Shanxi Grabens, China, from Quaternary geology, seismicity and geodesy

Discrepancies between geological, seismic and geodetic rates of strain can indicate that rates of crustal deformation, and hence seismic hazard, are varying through time. Previous studies in the northern Shanxi Grabens, at the northeastern corner of the Ordos Plateau in northern China, have found extension rates of anywhere between 0 and 6 mm a−1 at an azimuth of between 95° and 180°. In this paper we determine extension rates across the northern Shanxi Grabens from offset geomorphological features and a variety of Quaternary dating techniques (including new IRSL and Ar-Ar ages), a Kostrov summation using a 700 yr catalogue of historical earthquakes, and recent campaign GPS measurements. We observe good agreement between Quaternary, seismic and geodetic rates of strain, and we find that the northern Shanxi Grabens are extending at around 1–2 mm a−1 at an azimuth of ≈151°. The azimuth of extension is particularly well constrained and can be reliably inferred from catalogues of small earthquakes. We do not find evidence for any substantial variations in extension rate through time, though there is a notable seismic moment rate deficit since 1750. This deficit could indicate complex fault interactions across large regions, aseismic accommodation of deformation, or that we are quite late in the earthquake cycle with the potential for larger earthquakes in the relatively near future

Return to Sport and Athletic Function in an Active Population After Primary Arthroscopic Labral Reconstruction of the Hip

Background: Labral reconstruction has been advocated as an alternative to debridement for the treatment of irreparable labral tears, showing favorable short-term results. However, literature is scarce regarding outcomes and return to sport in the nonelite athletic population. Purpose: To report minimum 1-year clinical outcomes and the rate of return to sport in athletic patients who underwent primary hip arthroscopy with labral reconstruction in the setting of femoroacetabular impingement syndrome and irreparable labral tears. Study Design: Case series; Level of evidence, 4. Methods: Data were prospectively collected and retrospectively analyzed for patients who underwent an arthroscopic labral reconstruction between August 2012 and December 2017. Patients were included if they identified as an athlete (high school, college, recreational, or amateur); had follow-up on the following patient-reported outcomes (PROs): modified Harris Hip Score (mHHS), Nonarthritic Hip Score (NAHS), Hip Outcome Score–Sport Specific Subscale (HOS-SSS), and visual analog scale (VAS); and completed a return-to-sport survey at 1 year postoperatively. Patients were excluded if they underwent any previous ipsilateral hip surgery, had dysplasia, or had prior hip conditions. The proportions of patients who achieved the minimal clinically important difference (MCID) and patient acceptable symptomatic state (PASS) for mHHS and HOS-SSS were calculated. Statistical significance was set at P =.05. Results: There were 32 (14 females) athletes who underwent primary arthroscopic labral reconstruction during the study period. The mean age and body mass index of the group were 40.3 years (range, 15.5-58.7 years) and 27.9 kg/m2 (range, 19.6-40.1 kg/m2), respectively. The mean follow-up was 26.4 months (range, 12-64.2 months). All patients demonstrated significant improvement in mHHS, NAHS, HOS-SSS, and VAS (P \u3c.001) at latest follow-up. Additionally, 84.4% achieved MCID and 81.3% achieved PASS for mHHS, and 87.5% achieved MCID and 75% achieved PASS for HOS-SSS. VAS pain scores decreased from 4.4 to 1.8, and the satisfaction with surgery was 7.9 out of 10. The rate of return to sport was 78%. Conclusion: At minimum 1-year follow-up, primary arthroscopic labral reconstruction, in the setting of femoroacetabular impingement syndrome and irreparable labral tears, was associated with significant improvement in PROs in athletic populations. Return to sport within 1 year of surgery was 78%

Planning a method for covariate adjustment in individually randomised trials: a practical guide

Background: It has long been advised to account for baseline covariates in the analysis of confirmatory randomised trials, with the main statistical justifications being that this increases power and, when a randomisation scheme balanced covariates, permits a valid estimate of experimental error. There are various methods available to account for covariates but it is not clear how to choose among them. // Methods: Taking the perspective of writing a statistical analysis plan, we consider how to choose between the three most promising broad approaches: direct adjustment, standardisation and inverse-probability-of-treatment weighting. // Results: The three approaches are similar in being asymptotically efficient, in losing efficiency with mis-specified covariate functions and in handling designed balance. If a marginal estimand is targeted (for example, a risk difference or survival difference), then direct adjustment should be avoided because it involves fitting non-standard models that are subject to convergence issues. Convergence is most likely with IPTW. Robust standard errors used by IPTW are anti-conservative at small sample sizes. All approaches can use similar methods to handle missing covariate data. With missing outcome data, each method has its own way to estimate a treatment effect in the all-randomised population. We illustrate some issues in a reanalysis of GetTested, a randomised trial designed to assess the effectiveness of an electonic sexually transmitted infection testing and results service. // Conclusions: No single approach is always best: the choice will depend on the trial context. We encourage trialists to consider all three methods more routinely

Report on the Texas Legislature, 85th Session: An Urban Perspective-Criminal Justice Edition

In Texas, the legislature meets every 2 years and at the end of a regular legislative session, hundreds of passed bills will have been sent to the governor for approval. The large number of bills and the wide range of topics they cover can make it difficult to gain an understanding of all the new laws that were passed. At the close of each legislative session the Earl Carl Institute publishes, for the benefit of its constituents, highlights from the session in a bi-annual legislative report. In this year’s publication entitled Report on the Texas Legislature, 85th Session: An Urban Perspective the Institute attempted to cover matters that it believes to be of concern to the urban community, however, many of the highlights cover issues of particular concern to other traditionally disenfranchised communities as well. The legislation covered in these reports generally falls under such issues as Election, Criminal Justice (Human Trafficking, Criminal Procedure, Wrongful Convictions, Domestic Violence), Juvenile Justice, Family Law, Property, Education, Healthcare, Wills, Estate and Probate, Wealth and Litigation. We are pleased to present, via The Bridge: Interdisciplinary Perspectives on Legal & Social Policy, an excerpt this year’s legislative report that highlights legislative actions in the area of criminal justice reform in the State of Texas. The full report, published in August 2017, can be accessed via the Institute’s website www.tsulaw.edu/centers/ECI/publications.html

Rethinking non-inferiority: a practical trial design for optimising treatment duration.

Background Trials to identify the minimal effective treatment duration are needed in different therapeutic areas, including bacterial infections, tuberculosis and hepatitis C. However, standard non-inferiority designs have several limitations, including arbitrariness of non-inferiority margins, choice of research arms and very large sample sizes. Methods We recast the problem of finding an appropriate non-inferior treatment duration in terms of modelling the entire duration-response curve within a pre-specified range. We propose a multi-arm randomised trial design, allocating patients to different treatment durations. We use fractional polynomials and spline-based methods to flexibly model the duration-response curve. We call this a 'Durations design'. We compare different methods in terms of a scaled version of the area between true and estimated prediction curves. We evaluate sensitivity to key design parameters, including sample size, number and position of arms. Results A total sample size of ~ 500 patients divided into a moderate number of equidistant arms (5-7) is sufficient to estimate the duration-response curve within a 5% error margin in 95% of the simulations. Fractional polynomials provide similar or better results than spline-based methods in most scenarios. Conclusion Our proposed practical randomised trial 'Durations design' shows promising performance in the estimation of the duration-response curve; subject to a pending careful investigation of its inferential properties, it provides a potential alternative to standard non-inferiority designs, avoiding many of their limitations, and yet being fairly robust to different possible duration-response curves. The trial outcome is the whole duration-response curve, which may be used by clinicians and policymakers to make informed decisions, facilitating a move away from a forced binary hypothesis testing paradigm