A High Throughput Screen Identifies Nefopam as Targeting Cell Proliferation in β-Catenin Driven Neoplastic and Reactive Fibroproliferative Disorders

Fibroproliferative disorders include neoplastic and reactive processes (e.g. desmoid tumor and hypertrophic scars). They are characterized by activation of β-catenin signaling, and effective pharmacologic approaches are lacking. Here we undertook a high throughput screen using human desmoid tumor cell cultures to identify agents that would inhibit cell viability in tumor cells but not normal fibroblasts. Agents were then tested in additional cell cultures for an effect on cell proliferation, apoptosis, and β-catenin protein level. Ultimately they were tested in Apc1638N mice, which develop desmoid tumors, as well as in wild type mice subjected to full thickness skin wounds. The screen identified Neofopam, as an agent that inhibited cell numbers to 42% of baseline in cell cultures from β-catenin driven fibroproliferative disorders. Nefopam decreased cell proliferation and β-catenin protein level to 50% of baseline in these same cell cultures. The half maximal effective concentration in-vitro was 0.5 uM and there was a plateau in the effect after 48 hours of treatment. Nefopam caused a 45% decline in tumor number, 33% decline in tumor volume, and a 40% decline in scar size when tested in mice. There was also a 50% decline in β-catenin level in-vivo. Nefopam targets β-catenin protein level in mesenchymal cells in-vitro and in-vivo, and may be an effective therapy for neoplastic and reactive processes driven by β-catenin mediated signaling

F-Theorem without Supersymmetry

The conjectured F-theorem for three-dimensional field theories states that the finite part of the free energy on S^3 decreases along RG trajectories and is stationary at the fixed points. In previous work various successful tests of this proposal were carried out for theories with {\cal N}=2 supersymmetry. In this paper we perform more general tests that do not rely on supersymmetry. We study perturbatively the RG flows produced by weakly relevant operators and show that the free energy decreases monotonically. We also consider large N field theories perturbed by relevant double trace operators, free massive field theories, and some Chern-Simons gauge theories. In all cases the free energy in the IR is smaller than in the UV, consistent with the F-theorem. We discuss other odd-dimensional Euclidean theories on S^d and provide evidence that (-1)^{(d-1)/2} \log |Z| decreases along RG flow; in the particular case d=1 this is the well-known g-theorem.Comment: 34 pages, 2 figures; v2 refs added, minor improvements; v3 refs added, improved section 4.3; v4 minor improvement

Towards the F-Theorem: N=2 Field Theories on the Three-Sphere

For 3-dimensional field theories with {\cal N}=2 supersymmetry the Euclidean path integrals on the three-sphere can be calculated using the method of localization; they reduce to certain matrix integrals that depend on the R-charges of the matter fields. We solve a number of such large N matrix models and calculate the free energy F as a function of the trial R-charges consistent with the marginality of the superpotential. In all our {\cal N}=2 superconformal examples, the local maximization of F yields answers that scale as N^{3/2} and agree with the dual M-theory backgrounds AdS_4 x Y, where Y are 7-dimensional Sasaki-Einstein spaces. We also find in toric examples that local F-maximization is equivalent to the minimization of the volume of Y over the space of Sasakian metrics, a procedure also referred to as Z-minimization. Moreover, we find that the functions F and Z are related for any trial R-charges. In the models we study F is positive and decreases along RG flows. We therefore propose the "F-theorem" that we hope applies to all 3-d field theories: the finite part of the free energy on the three-sphere decreases along RG trajectories and is stationary at RG fixed points. We also show that in an infinite class of Chern-Simons-matter gauge theories where the Chern-Simons levels do not sum to zero, the free energy grows as N^{5/3} at large N. This non-trivial scaling matches that of the free energy of the gravity duals in type IIA string theory with Romans mass.Comment: 66 pages, 10 figures; v2: refs. added, minor improvement

From Necklace Quivers to the F-theorem, Operator Counting, and T(U(N))

The matrix model of Kapustin, Willett, and Yaakov is a powerful tool for exploring the properties of strongly interacting superconformal Chern-Simons theories in 2+1 dimensions. In this paper, we use this matrix model to study necklace quiver gauge theories with {\cal N}=3 supersymmetry and U(N)^d gauge groups in the limit of large N. In its simplest application, the matrix model computes the free energy of the gauge theory on S^3. The conjectured F-theorem states that this quantity should decrease under renormalization group flow. We show that for a simple class of such flows, the F-theorem holds for our necklace theories. We also provide a relationship between matrix model eigenvalue distributions and numbers of chiral operators that we conjecture holds more generally. Through the AdS/CFT correspondence, there is therefore a natural dual geometric interpretation of the matrix model saddle point in terms of volumes of 7-d tri-Sasaki Einstein spaces and some of their 5-d submanifolds. As a final bonus, our analysis gives us the partition function of the T(U(N)) theory on S^3.Comment: 3 figures, 41 pages; v2 minor improvements, refs adde

Tightly Secure Ring-LWE Based Key Encapsulation with Short Ciphertexts

We provide a tight security proof for an IND-CCA Ring-LWE based Key Encapsulation Mechanism that is derived from a generic construction of Dent (IMA Cryptography and Coding, 2003). Such a tight reduction is not known for the generic construction. The resulting scheme has shorter ciphertexts than can be achieved with other generic constructions of Dent or by using the well-known Fujisaki-Okamoto constructions (PKC 1999, Crypto 1999). Our tight security proof is obtained by reducing to the security of the underlying Ring-LWE problem, avoiding an intermediate reduction to a CPA-secure encryption scheme. The proof technique maybe of interest for other schemes based on LWE and Ring-LWE

Detection and characterisation of multi-drug resistance protein 1 (MRP-1) in human mitochondria

BACKGROUND: Overexpression of plasma membrane multi-drug resistance protein 1 (MRP-1) can lead to multidrug resistance. In this study, we describe for the first time the expression of mitochondrial MRP-1 in untreated human normal and cancer cells and tissues. METHODS: MRP-1 expression and subcellular localisation in normal and cancer cells and tissues was examined by differential centrifugation and western blotting, and immunofluorescence microscopy. Viable mitochondria were isolated and MRP-1 efflux activity measured using the calcein-AM functional assay. MRP-1 expression was increased using retroviral infection and specific overexpression confirmed by RNA array. Cell viability was determined by trypan blue exclusion and annexin V-propidium iodide labelling of cells. RESULTS: MRP-1 was detected in the mitochondria of cancer and normal cells and tissues. The efflux activity of mitochondrial MRP-1 was more efficient (55-64%) than that of plasma membrane MRP-1 (11-22%; P<0.001). Induced MRP-1 expression resulted in a preferential increase in mitochondrial MRP-1, suggesting selective targeting to this organelle. Treatment with a non-lethal concentration of doxorubicin (0.85 nM, 8 h) increased mitochondrial and plasma membrane MRP-1, increasing resistance to MRP-1 substrates. For the first time, we have identified MRP-1 with efflux activity in human mitochondria. CONCLUSION: Mitochondrial MRP-1 may be an exciting new therapeutic target where historically MRP-1 inhibitor strategies have limited clinical success

Type-1 Collagen differentially alters β-catenin accumulation in primary Dupuytren's Disease cord and adjacent palmar fascia cells

<p>Abstract</p> <p>Background</p> <p>Dupuytren's Disease (DD) is a debilitating contractile fibrosis of the palmar fascia characterised by excess collagen deposition, contractile myofibroblast development, increased Transforming Growth Factor-β levels and β-catenin accumulation. The aim of this study was to determine if a collagen-enriched environment, similar to <it>in vivo </it>conditions, altered β-catenin accumulation by primary DD cells in the presence or absence of Transforming Growth Factor-β.</p> <p>Methods</p> <p>Primary DD and patient matched, phenotypically normal palmar fascia (PF) cells were cultured in the presence or absence of type-1 collagen and Transforming Growth Factor-β1. β-catenin and α-smooth muscle actin levels were assessed by western immunoblotting and immunofluorescence microscopy.</p> <p>Results</p> <p>DD cells display a rapid depletion of cellular β-catenin not evident in patient-matched PF cells. This effect was not evident in either cell type when cultured in the absence of type-1 collagen. Exogenous addition of Transforming Growth Factor-β1 to DD cells in collagen culture negates the loss of β-catenin accumulation. Transforming Growth Factor-β1-induced α-smooth muscle actin, a marker of myofibroblast differentiation, is attenuated by the inclusion of type-1 collagen in cultures of DD and PF cells.</p> <p>Conclusion</p> <p>Our findings implicate type-1 collagen as a previously unrecognized regulator of β-catenin accumulation and a modifier of TGF-β1 signaling specifically in primary DD cells. These data have implications for current treatment modalities as well as the design of <it>in vitro </it>models for research into the molecular mechanisms of DD.</p

The impact of radiotherapy in the treatment of desmoid tumours. An international survey of 110 patients. A study of the Rare Cancer Network

PURPOSE: A multi-centre study to assess the value of combined surgical resection and radiotherapy for the treatment of desmoid tumours. PATIENTS AND METHODS: One hundred and ten patients from several European countries qualified for this study. Pathology slides of all patients were reviewed by an independent pathologist. Sixty-eight patients received post-operative radiotherapy and 42 surgery only. Median follow-up was 6 years (1 to 44). The progression-free survival time (PFS) and prognostic factors were analysed. RESULTS: The combined treatment with radiotherapy showed a significantly longer progression-free survival than surgical resection alone (p smaller than 0.001). Extremities could be preserved in all patients treated with combined surgery and radiotherapy for tumours located in the limb, whereas amputation was necessary for 23% of patients treated with surgery alone. A comparison of PFS for tumour locations proved the abdominal wall to be a positive prognostic factor and a localization in the extremities to be a negative prognostic factor. Additional irradiation, a fraction size larger than or equal to 2 Gy and a total dose larger than 50 Gy to the tumour were found to be positive prognostic factors with a significantly lower risk for a recurrence in the univariate analysis. This analysis revealed radiotherapy at recurrence as a significantly worse prognostic factor compared with adjuvant radiotherapy. The addition of radiotherapy to the treatment concept was a positive prognostic factor in the multivariate analysis. CONCLUSION: Postoperative radiotherapy significantly improved the PFS compared to surgery alone. Therefore it should always be considered after a non-radical tumour resection and should be given preferably in an adjuvant setting. It is effective in limb preservation and for preserving the function of joints in situations where surgery alone would result in deficits, which is especially important in young patients