A first-in-class, humanized antibody targeting alternatively spliced tissue factor: preclinical evaluation in an orthotopic model of pancreatic ductal adenocarcinoma

In 2021, pancreatic ductal adenocarcinoma (PDAC) is the 3(rd) leading cause of cancer deaths in the United States. This is largely due to a lack of symptoms and limited treatment options, which extend survival by only a few weeks. There is thus an urgent need to develop new therapies effective against PDAC. Previously, we have shown that the growth of PDAC cells is suppressed when they are co-implanted with RabMab1, a rabbit monoclonal antibody specific for human alternatively spliced tissue factor (asTF). Here, we report on humanization of RabMab1, evaluation of its binding characteristics, and assessment of its in vivo properties. hRabMab1 binds asTF with a K-D in the picomolar range; suppresses the migration of high-grade Pt45.P1 cells in Boyden chamber assays; has a long half-life in circulation (similar to 5 weeks); and significantly slows the growth of pre-formed orthotopic Pt45.P1 tumors in athymic nude mice when administered intravenously. Immunohistochemical analysis of tumor tissue demonstrates the suppression of i) PDAC cell proliferation, ii) macrophage infiltration, and iii) neovascularization, whereas RNAseq analysis of tumor tissue reveals the suppression of pathways that promote cell division and focal adhesion. This is the first proof-of-concept study whereby a novel biologic targeting asTF has been investigated as a systemically administered single agent, with encouraging results. Given that hRabMab1 has a favorable PK profile and is able to suppress the growth of human PDAC cells in vivo, it comprises a promising candidate for further clinical development.Thrombosis and Hemostasi

Three-dimensional force microscope: A nanometric optical tracking and magnetic manipulation system for the biomedical sciences

We report here the development of a three-dimensional (3D) magnetic force microscope for applying forces to and measuring responses of biological systems and materials. This instrument combines a conventional optical microscope with a free-floating or specifically bound magnetic bead used as a mechanical probe. Forces can be applied by the bead to microscopic structures of interest (specimens), while the reaction displacement of the bead is measured. This enables 3D mechanical manipulations and measurements to be performed on specimens in fluids. Force is generated by the magnetically permeable bead in reaction to fields produced by external electromagnets. The displacement is measured by interferometry using forward light scattered by the bead from a focused laser beam. The far-field interference pattern is imaged on a quadrant photodetector from which the 3D displacement can be computed over a limited range about the focal point. The bead and specimen are mounted on a 3D translation stage and feedback techniques are used to keep the bead within this limited range. We demonstrate the system with application to beads attached to cilia in human lung cell cultures

Search for Higgs bosons decaying to tautau pairs in ppbar collisions at sqrt(s) = 1.96 TeV

We present a search for the production of neutral Higgs bosons decaying into tautau pairs in ppbar collisions at a center-of-mass energy of 1.96 TeV. The data, corresponding to an integrated luminosity of 5.4 fb-1, were collected by the D0 experiment at the Fermilab Tevatron Collider. We set upper limits at the 95% C.L. on the product of production cross section and branching ratio for a scalar resonance decaying into tautau pairs, and we then interpret these limits as limits on the production of Higgs bosons in the minimal supersymmetric standard model (MSSM) and as constraints in the MSSM parameter space.Comment: 7 pages, 5 figures, submitted to PL

Measurement of the photon+b+b-jet production differential cross section in ppˉp\bar{p} collisions at \sqrt{s}=1.96~\TeV

We present measurements of the differential cross section dsigma/dpT_gamma for the inclusive production of a photon in association with a b-quark jet for photons with rapidities |y_gamma|< 1.0 and 30<pT_gamma <300 GeV, as well as for photons with 1.5<|y_gamma|< 2.5 and 30< pT_gamma <200 GeV, where pT_gamma is the photon transverse momentum. The b-quark jets are required to have pT>15 GeV and rapidity |y_jet| < 1.5. The results are based on data corresponding to an integrated luminosity of 8.7 fb^-1, recorded with the D0 detector at the Fermilab Tevatron $p\bar{p}$ Collider at sqrt(s)=1.96 TeV. The measured cross sections are compared with next-to-leading order perturbative QCD calculations using different sets of parton distribution functions as well as to predictions based on the kT-factorization QCD approach, and those from the Sherpa and Pythia Monte Carlo event generators.Comment: 10 pages, 9 figures, submitted to Phys. Lett.

Limits on anomalous trilinear gauge boson couplings from WW, WZ and Wgamma production in pp-bar collisions at sqrt{s}=1.96 TeV

We present final searches of the anomalous gammaWW and ZWW trilinear gauge boson couplings from WW and WZ production using lepton plus dijet final states and a combination with results from Wgamma, WW, and WZ production with leptonic final states. The analyzed data correspond to up to 8.6/fb of integrated luminosity collected by the D0 detector in pp-bar collisions at sqrt{s}=1.96 TeV. We set the most stringent limits at a hadron collider to date assuming two different relations between the anomalous coupling parameters Delta\kappa_\gamma, lambda, and Delta g_1^Z for a cutoff energy scale Lambda=2 TeV. The combined 68% C.L. limits are -0.057<Delta\kappa_\gamma<0.154, -0.015<lambda<0.028, and -0.008<Delta g_1^Z<0.054 for the LEP parameterization, and -0.007<Delta\kappa<0.081 and -0.017<lambda<0.028 for the equal couplings parameterization. We also present the most stringent limits of the W boson magnetic dipole and electric quadrupole moments.Comment: 10 pages, 5 figures, submitted to PL

Measurement of three-jet differential cross sections d sigma-3jet / d M-3jet in p anti-p collisions at sqrt(s)=1.96 TeV

We present the first measurement of the inclusive three-jet differential cross section as a function of the invariant mass of the three jets with the largest transverse momenta in an event in p anti-p collisions at sqrt(s) = 1.96 TeV. The measurement is made in different rapidity regions and for different jet transverse momentum requirements and is based on a data set corresponding to an integrated luminosity of 0.7 fb^{-1} collected with the D0 detector at the Fermilab Tevatron Collider. The results are used to test the three-jet matrix elements in perturbative QCD calculations at next-to-leading order in the strong coupling constant. The data allow discrimination between parametrizations of the parton distribution functions of the proton.Comment: 10 pages, 4 figures, 2 tables, submitted to Phys. Lett. B, corrected chi2 values for NNPD

Search for pair production of the scalar top quark in muon+tau final states

We present a search for the pair production of scalar top quarks ($\tilde{t}_{1}$), the lightest supersymmetric partners of the top quarks, in $p\bar{p}$ collisions at a center-of-mass energy of 1.96 TeV, using data corresponding to an integrated luminosity of {7.3 $fb^{-1}$} collected with the \dzero experiment at the Fermilab Tevatron Collider. Each scalar top quark is assumed to decay into a $b$ quark, a charged lepton, and a scalar neutrino ($\tilde{\nu}$). We investigate final states arising from $\tilde{t}_{1} \bar{\tilde{t}_{1}} \rightarrow b\bar{b}\mu\tau \tilde{\nu} \tilde{\nu}$ and $\tilde{t}_{1} \bar{\tilde{t}_{1}} \rightarrow b\bar{b}\tau\tau \tilde{\nu} \tilde{\nu}$. With no significant excess of events observed above the background expected from the standard model, we set exclusion limits on this production process in the ($m_{\tilde{t}_{1}}$,$m_{\tilde{\nu}}$) plane.Comment: Submitted to Phys. Lett.

Measurements of inclusive W+jets production rates as a function of jet transverse momentum in ppbar collisions at sqrt{s}=1.96 TeV

This Letter describes measurements of inclusive W (--> e nu) + n jet cross sections (n = 1-4), presented as total inclusive cross sections and differentially in the nth jet transverse momentum. The measurements are made using data corresponding to an integrated luminosity of 4.2 fb-1 collected by the D0 detector at the Fermilab Tevatron Collider, and achieve considerably smaller uncertainties on W +jets production cross sections than previous measurements. The measurements are compared to next-to-leading order perturbative QCD (pQCD) calculations in the n =1-3 jet multiplicity bins and to leading order pQCD calculations in the 4-jet bin. The measurements are generally in agreement with pQCD predictions, although certain regions of phase space are identified where the calculations could be improved