Project Safe Neighborhoods in Chicago: Looking Back a Decade Later

Project Safe Neighborhoods (PSN) is a federally funded initiative that brings together federal, state, and local law enforcement to reduce gun violence in urban centers. In Chicago, PSN implemented supply-side gun policing tactics, enhanced federal prosecution of gun crimes, and notification forums warning offenders of PSN’s heightened criminal sanctions. Prior evaluations provide evidence that PSN initiatives have reduced crime in the first few years of their operation. But over a decade after the program was established, we still know little about whether these effects are sustained over an extended period of time. This Article examines PSN Chicago, an anti-violence program in operation since 2002. Consistent with a previous evaluation, we find that several program components were associated with reductions in violence in the initial target areas. These associations, however, are concentrated in the first few years of the intervention. We also examine the effect of PSN in several subsequent expansion areas and find no detectable effects. We suggest that the effects of PSN were diluted as the program expanded to larger areas of the city without an increase in funding or resources. Still, we recommend that future research consider PSN’s strategies in Chicago that appeared effective in the early years and leverage those insights for future programs

Functional renormalization group for non-Hermitian and PT-symmetric systems

We generalize the vertex expansion approach of the functional renormalization group to non-Hermitian systems. As certain anomalous expectation values might not vanish, additional terms as compared to the Hermitian case can appear in the flow equations. We investigate the merits and shortcomings of the vertex expansion for non-Hermitian systems by considering an exactly solvable PT-symmetric non-linear toy-model and reveal, that in this model, the fidelity of the vertex expansion in a perturbatively motivated truncation schema is comparable with that of the Hermitian case. The vertex expansion appears to be a viable method for studying correlation effects in non-Hermitian systems

The Current and Evolving Landscape of First-Line Treatments for Advanced Renal Cell Carcinoma

Agents targeting the vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), as well as the mammalian target of rapamycin (mTOR) and immune checkpoint receptor programmed death 1 (PD-1) signaling pathway have improved clinical outcomes for patients with advanced renal cell carcinoma (RCC). The VEGFR tyrosine kinase inhibitors (TKIs) pazopanib and sunitinib are FDA-approved first-line treatment options for advanced RCC; however, other treatment options in this setting are available, including the recently approved combination of nivolumab (anti-PD-1) and ipilimumab (anti-cytotoxic T-lymphocyte-associated protein-4 [CTLA-4]) for patients with intermediate or poor risk. Unfortunately, treatment guideline recommendations provide little guidance to aid first-line treatment choice. In addition, several ongoing randomized phase III trials of investigational first-line regimens may complicate the RCC treatment paradigm if these agents gain approval. This article reviews clinical trial and real-world evidence for currently approved and investigational first-line treatment regimens for advanced RCC and provides clinical evidence to aid first-line treatment selection. Implications for Practice: Vascular endothelial growth factor receptor tyrosine kinase inhibitors are approved by the U.S. Food and Drug Administration as first-line treatment options for advanced renal cell carcinoma; however, the treatment paradigm is rapidly evolving. The combination of nivolumab plus ipilimumab was recently approved for intermediate- and poor-risk patients, and other combination strategies and novel first-line agents will likely be introduced soon

A molecular signature of myalgia in myotonic dystrophy 2

Background: Chronic muscle pain affects close to 20% of the population and is a major health burden. The underlying mechanisms of muscle pain are difficult to investigate as pain presents in patients with very diverse histories. Treatment options are therefore limited and not tailored to underlying mechanisms. To gain insight into the pathophysiology of myalgia we investigated a homogeneous group of patients suffering from myotonic dystrophy type 2 (DM2), a monogenic disorder presenting with myalgia in at least 50% of affected patients. Methods: After IRB approval we performed an observational cross-sectional cohort study and recruited 42 patients with genetically confirmed DM2 plus 20 healthy age and gender matched control subjects. All participants were subjected to an extensive sensory-testing protocol. In addition, RNA sequencing was performed from 12 muscle biopsy specimens obtained from DM2 patients. Findings: Clinical sensory testing as well as RNA sequencing clearly separated DM2 myalgic from non-myalgia patients and also from healthy controls. In particular pressure pain thresholds were significantly lowered for all muscles tested in myalgic DM2 patients but were not significantly different between non-myalgic patients and healthy controls. The expression of fourteen muscle expressed genes in myalgic patients was significantly up or down-regulated in myalgic compared to non-myalgic DM2 patients. Interpretation: Our data support the idea that molecular changes in the muscles of DM2 patients are associated with muscle pain. Further studies should address whether muscle-specific molecular pathways play a significant role in myalgia in order to facilitate the development of mechanism-based therapeutic strategies to treat musculoskeletal pain

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

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Smooth Muscle Stiffness Sensitivity is Driven by Soluble and Insoluble ECM Chemistry

Smooth muscle cell (SMC) invasion into plaques and subsequent proliferation is a major factor in the progression of atherosclerosis. During disease progression, SMCs experience major changes in their microenvironment, such as what integrin-binding sites are exposed, the portfolio of soluble factors available, and the elasticity and modulus of the surrounding vessel wall. We have developed a hydrogel biomaterial platform to examine the combined effect of these changes on SMC phenotype. We were particularly interested in how the chemical microenvironment affected the ability of SMCs to sense and respond to modulus. To our surprise, we observed that integrin binding and soluble factors are major drivers of several critical SMC behaviors, such as motility, proliferation, invasion, and differentiation marker expres- sion, and these factors modulated the effect of stiffness on proliferation and migration. Overall, modulus only modestly affected behaviors other than proliferation, relative to integrin binding and soluble factors. Surprisingly, patho- logical behaviors (proliferation, motility) are not inversely related to SMC marker expression, in direct conflict with previous studies on substrates coupled with single extracel- lular matrix (ECM) proteins. A high-throughput bead-based ELISA approach and inhibitor studies revealed that differ- entiation marker expression is mediated chiefly via focal adhesion kinase (FAK) signaling, and we propose that integrin binding and FAK drive the transition from a migratory to a proliferative phenotype. We emphasize the importance of increasing the complexity of in vitro testing platforms to capture these subtleties in cell phenotypes and signaling, in order to better recapitulate important features of in vivo disease and elucidate potential context-dependent therapeutic targets

Conversion of red fluorescent protein into a bright blue probe

We used a red chromophore formation pathway, in which the anionic red chromophore is formed from the neutral blue intermediate, to suggest a rational design strategy to develop blue fluorescent proteins with a tyrosine-based chromophore. The strategy was applied to red fluorescent proteins of the different genetic backgrounds, such as TagRFP, mCherry, HcRed1, M355NA, and mKeima, which all were converted into blue probes. Further improvement of the blue variant of TagRFP by random mutagenesis resulted in an enhanced monomeric protein, mTagBFP, characterized by the substantially higher brightness, the faster chromophore maturation, and the higher pH stability than blue fluorescent proteins with a histidine in the chromophore. The detailed biochemical and photochemical analysis indicates that mTagBFP is the true monomeric protein tag for multicolor and lifetime imaging, as well as the outstanding donor for green fluorescent proteins in Forster resonance energy transfer applications

ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma

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Thermoelectric Response of an Interacting Two-Dimensional Electron Gas in Quantizing Magnetic Field

We present a discussion of the linear thermoelectric response of an interacting electron gas in a quantizing magnetic field. Boundary currents can carry a significant fraction of the net current passing through the system. We derive general expressions for the bulk and boundary components of the number and energy currents. We show that the local current density may be described in terms of ``transport'' and ``internal magnetization'' contributions. The latter carry no net current and are not observable in standard transport experiments. We show that although Onsager relations cannot be applied to the local current, they are valid for the transport currents and hence for the currents observed in standard transport experiments. We relate three of the four thermoelectric response coefficients of a disorder-free interacting two-dimensional electron gas to equilibrium thermodynamic quantities. In particular, we show that the diffusion thermopower is proportional to the entropy per particle, and we compare this result with recent experimental observations.Comment: 18 pages, 2 postscript figures included. Revtex with epsf.tex and multicol.sty. In the revised version, the comparison with experimental observations at $\nu=1/2, 3/2$ is extended to include the possibility of corrections due to weak impurity scattering. The conclusions that we reach regarding the applicability of the composite fermion model at these filling fractions are not affecte