Field localization in warped gauge theories

We present four-dimensional gauge theories that describe physics on five-dimensional curved (warped) backgrounds, which includes bulk fields with various spins (vectors, spinors, and scalars). Field theory on the AdS$_5$ geometry is examined as a simple example of our formulation. Various properties of bulk fields on this background, e.g., the mass spectrum and field localization behavior, can be achieved within a fully four-dimensional framework. Moreover, that gives a localization mechanism for massless vector fields. We also consider supersymmetric cases, and show in particular that the conditions on bulk masses imposed by supersymmetry on warped backgrounds are derived from a four-dimensional supersymmetric theory on the flat background. As a phenomenological application, models are shown to generate hierarchical Yukawa couplings. Finally, we discuss possible underlying mechanisms which dynamically realize the required couplings to generate curved geometries.Comment: 24 pages, 12 figures; more explanation of nonuniversal gauge couplings added, typos corrected, references update

Population pharmacokinetic analysis of pexidartinib in healthy subjects and patients with tenosynovial giant cell tumor or other solid tumors

Pexidartinib is a kinase inhibitor that induces tumor response and improvements in symptoms and functional outcomes in adult patients with symptomatic tenosynovial giant cell tumor (TGCT). A population pharmacokinetic (PK) model for pexidartinib and its metabolite, ZAAD, was developed, and effects of demographic and clinical factors on the PK of pexidartinib and ZAAD were estimated. The analysis included pooled data from 7 studies in healthy volunteers (N = 159) and 2 studies in patients with TGCT or other solid tumors (N = 216). A structural 2-compartment model with sequential zero- and first-order absorption and lag time, and linear elimination from the central compartment adequately described pexidartinib and ZAAD PKs. Clearance of pexidartinib was estimated at 5.83 L/h in a typical patient with reference covariates (male, non-Asian, weight = 80 kg, creatinine clearance >= 90 mL/min, aspartate aminotransferase <= 80 U/L, and total bilirubin <= 20.5 mu mol/L). In the covariate analysis, Asians and healthy subjects had modestly lower pexidartinib exposure (21% decrease each) in terms of steady-state area under the curve values from 0 to 24 hours (AUC(0-24,ss)). Effects of body weight, sex, and hepatic function parameters on pexidartinib AUC(0-24,ss)were generally <20%. Patients with TGCT with mild renal impairment were predicted to have approximately 23% higher AUC(0-24,ss)than those with normal renal function. The effects of covariates on ZAAD exposure were similar to those on pexidartinib. These results indicate small and generally clinically nonmeaningful effects of patient demographic and clinical characteristics on pexidartinib and ZAAD PK profiles.Experimentele farmacotherapi

Exposure-response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor

This analysis was conducted to assess exposure-response relationships for efficacy and safety of pexidartinib in patients with tenosynovial giant cell tumor. Efficacy was assessed categorically by overall response rate (ORR) with Response Evaluation Criteria in Solid Tumors version 1.1 and longitudinally (changes in tumor size and volume). Safety included hepatic parameters (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], and total bilirubin). Average pexidartinib concentration (C-avg) was identified as the primary exposure parameter correlated with response. In categorical and longitudinal analyses, higher C-avg coincided with greater ORR and tumor size reduction, respectively, with smaller joint size having a greater impact. For safety, a significant relationship was observed between C-avg and incidence of ALT-related and AST-related adverse events (AEs). With increased exposure, an increase in efficacy was predicted with near maximum effect at 800 mg/day. Higher initial dose (1000 mg/day) during the first 2 weeks did not improve efficacy. Higher doses were associated with an increased risk of ALT-related and AST-related AEs. These results support the US Food and Drug Administration-approved dose (400 mg two times/day without initial loading dose).Experimentele farmacotherapi

Residential demolition and its impact on vacant lot hydrology: Implications for the management of stormwater and sewer system overflows

AbstractIncreased residential demolitions have made vacant lots a ubiquitous feature of the contemporary urban landscape. Vacant lots may provide ecosystem services such as stormwater runoff capture, but the extent of these functions will be regulated by soil hydrology. We evaluated soil physical and hydrologic characteristics at each of low- (backyard, fenceline) and high-disturbance (within the demolition footprint) positions in 52 vacant lots in Cleveland, OH, which were the result of different eras of demolition process and quality (i.e., pre-1996, post-1996). Penetrometer refusal averaged 56% (range: 15–100%) and was attributed to high concentration of remnant buried debris in anthropogenic backfill soils. Both disturbance level and demolition type significantly regulated infiltration rate to an average of 1.8cmh−1 (range: 0.03–10.6cmh−1). Sub-surface saturated hydraulic conductivity (Ksat) averaged higher at 4.0cmh−1 (range: 0–68.2cmh−1), was influenced by a significant interaction between both disturbance and demolition factors, and controlled by subsurface soil texture and presence/absence of unconsolidated buried debris. Our observations were synthesized in rainfall-runoff models that simulated average, high- and low-hydrologic functioning, turf-dominated, and a prospective green infrastructure simulation, which indicated that although the typical Cleveland vacant lot is a net producer of runoff volume, straightforward change in demolition policy and process, coupled with reutilization as properly designed and managed infiltration-type green infrastructure may result in a vacant lot that has sufficient capacity for detention of the average annual rainfall volume for a major Midwestern US city

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors

Altres ajuts: National Institutes of Health/National Cancer Institute (P30 CA008748); Daiichi Sankyo, Co., Ltd.Background: Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib. Materials, and Methods: Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288. Results: In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases. Conclusion: This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury. Implications for Practice: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors

Background Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib.Materials, and Methods Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288.Results In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases.Conclusion This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury.Implications for Practice This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.Orthopaedics, Trauma Surgery and Rehabilitatio