Interleukin-18, neutrophils, and ANCA

Hewins et al. show that IL-18 is expressed in the kidneys of patients with ANCA-associated glomerulonephritis, and that IL-18 primes neutrophils via p38 MAPK. These findings suggest a role for IL-18, including IL-18-induced TH1 polarization and IFN-γ production, in the progression of ANCA disease

ρ\rho Polarization and `Model Independent' Extraction of ∣Vub∣/∣Vcd∣|V_{ub}|/|V_{cd}| from D→ρℓνD\to\rho\ell\nu and B→ρℓνB\to\rho\ell\nu

We briefly discuss the predictions of the heavy quark effective theory for the semileptonic decays of a heavy pseudoscalar to a light one, or to a light vector meson. We point out that measurement of combinations of differential helicity decay rates at Cleo-c and the $B$ factories can provide a model independent means of extracting the ratio $|V_{ub}|/|V_{cd}|$. We briefly discuss the corrections to this prediction.Comment: 8 pages, LaTeX, 1 figur

Subleading Shape Functions in Inclusive B Decays

The contributions of subleading shape functions to inclusive decay distributions of B mesons are derived from a systematic two-step matching of QCD current correlators onto soft-collinear and heavy-quark effective theory. At tree-level, the results can be expressed in terms of forward matrix elements of bi-local light-cone operators. Four-quark operators, which arise at O(g^2), are included. Their effects can be absorbed entirely into a redefinition of other shape functions. Our results are in disagreement with some previous studies of subleading shape-function effects in the literature. A numerical analysis of B->X_u+l+nu decay distributions suggests that power corrections are small, with the possible exception of the endpoint region of the charged-lepton energy spectrum.Comment: 22 pages, 2 figures; several typos corrected; version published in JHE

External Operators and Anomalous Dimensions in Soft-Collinear Effective Theory

It has recently been argued that soft-collinear effective theory for processes involving both soft and collinear partons contains a new soft-collinear mode, which can communicate between the soft and collinear sectors of the theory. The formalism incorporating the corresponding fields into the effective Lagrangian is extended to include external current and four-quark operators relevant to weak interactions. An explicit calculation of the anomalous dimensions of these operators reveals that soft-collinear modes are needed for correctly describing the ultraviolet behavior of the effective theory.Comment: 15 pages, 2 figure

Probing CP Violation with the Deuteron Electric Dipole Moment

We present an analysis of the electric dipole moment (EDM) of the deuteron as induced by CP-violating operators of dimension 4, 5 and 6 including theta QCD, the EDMs and color EDMs of quarks, four-quark interactions and the Weinberg operator. We demonstrate that the precision goal of the EDM Collaboration's proposal to search for the deuteron EDM, (1-3)\times 10^{-27} e cm, will provide an improvement in sensitivity to these sources of one-two orders of magnitude relative to the existing bounds. We consider in detail the level to which CP-odd phases can be probed within the MSSM.Comment: 5 pages, 4 figures; precision estimates clarified, to appear in Phys. Rev.

Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants

Histologic variants of idiopathic focal segmental glomerulosclerosis (FSGS) may have prognostic value. A recent working classification system has distinguished five FSGS variants. We evaluated a cohort of adult patients with biopsy-proven FSGS diagnosed between March 1982 and July 2001 to determine if subtypes were associated with renal outcome. Renal biopsies were reviewed by two pathologists. Demographic and clinical data were obtained from charts. Outcomes were partial and complete remission of the nephrotic syndrome, and renal failure. The frequency of FSGS variants was: 3% cellular (=6), 11% collapsing (=22), 17% tip lesion (=34), 26% perihilar (=52), and 42% not otherwise specified (NOS) (=83). Collapsing FSGS affected younger and more often black patients. Black race was uncommon in tip variant. Collapsing and tip variants had higher proteinuria and lower serum albumin than perihilar and NOS variants. Better renal function and less severe tubulointerstitial injury were observed in patients with tip variant. These patients were more likely to receive steroids and more often achieved complete remission (50%). After a median follow-up of 1.8 years, 23% of patients were on dialysis and 28% had renal failure. Collapsing FSGS had worse 1-year (74%) and 3-year (33%) renal survival compared to other variants (overall cohort renal survival at 1 and 3 years: 86 and 67%). Different histologic variants of FSGS have substantial differences in clinical features at the time of biopsy diagnosis and substantial differences in renal outcomes

Hadronic EDMs, the Weinberg Operator, and Light Gluinos

We re-examine questions concerning the contribution of the three-gluon Weinberg operator to the electric dipole moment of the neutron, and provide several QCD sum rule-based arguments that the result is smaller than - but nevertheless consistent with - estimates which invoke naive dimensional analysis. We also point out a regime of the MSSM parameter space with light gluinos for which this operator provides the dominant contribution to the neutron electric dipole moment due to enhancement via the dimension five color electric dipole moment of the gluino.Comment: 6 pages, RevTeX, 3 figures; v2: references added; v3: typos corrected, to appear in Phys. Rev.

CP Violation in Supersymmetric U(1)' Models

The supersymmetric CP problem is studied within superstring-motivated extensions of the MSSM with an additional U(1)' gauge symmetry broken at the TeV scale. This class of models offers an attractive solution to the mu problem of the MSSM, in which U(1)' gauge invariance forbids the bare mu term, but an effective mu parameter is generated by the vacuum expectation value of a Standard Model singlet S which has superpotential coupling of the form SH_uH_d to the electroweak Higgs doublets. The effective mu parameter is thus dynamically determined as a function of the soft supersymmetry breaking parameters, and can be complex if the soft parameters have nontrivial CP-violating phases. We examine the phenomenological constraints on the reparameterization invariant phase combinations within this framework, and find that the supersymmetric CP problem can be greatly alleviated in models in which the phase of the SU(2) gaugino mass parameter is aligned with the soft trilinear scalar mass parameter associated with the SH_uH_d coupling. We also study how the phases filter into the Higgs sector, and find that while the Higgs sector conserves CP at the renormalizable level to all orders of perturbation theory, CP violation can enter at the nonrenormalizable level at one-loop order. In the majority of the parameter space, the lightest Higgs boson remains essentially CP even but the heavier Higgs bosons can exhibit large CP-violating mixings, similar to the CP-violating MSSM with large mu parameter.Comment: 29 pp, 3 figs, 2 table

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours

Background: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours. Methods: We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2. Results: Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease. Conclusions: Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs. Clinical trial identifier: NCT02157792

Leukocyte gene expression signatures in antineutrophil cytoplasmic autoantibody and lupus glomerulonephritis

Leukocytes play a major role in the development and progression of autoimmune diseases. We measured gene expression differences in leukocytes from patients that were antineutrophil cytoplasmic autoantibody (ANCA) positive, patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), and healthy donors to explore potential pathways for clinical intervention. Leukocyte gene expression profiles were determined on Affymetrix U133A/B chips in 88 autoimmune patients, 28 healthy donors, and healthy donor leukocyte cell subtypes that were activated . Comparison of gene expression in leukocytes identified differentially expressed signature genes that distinguish each donor source. The microarray expression levels for many signature genes correlated with the clinical activity of small vessel vasculitis in the ANCA patients; a result confirmed by quantitative real time-polymerase chain reaction for 16 relevant genes. Comparison with -activated leukocyte subtypes from healthy donors revealed that the ANCA signature genes were expressed by neutrophils while the SLE signature genes were expressed in activated monocytes and T cells. We have found that leukocyte gene expression data can differentiate patients with RA, SLE, and ANCA-related small vessel vasculitis. Monitoring changes in the expression of specific genes may be a tool to help quantify disease activity during treatment