Synergistic combination of cytotoxic chemotherapy and cyclin-dependent kinase 4/6 inhibitors in biliary tract cancers

Background and aims: Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin-dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive.Approach and results: Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity, and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy attributable to autophagy-induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine.Conclusions: As such, these data provide robust preclinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.</p

Measurement of the CP-Violating Asymmetry Amplitude sin2β\beta

We present results on time-dependent CP-violating asymmetries in neutral B decays to several CP eigenstates. The measurements use a data sample of about 88 million Y(4S) --> B Bbar decays collected between 1999 and 2002 with the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC. We study events in which one neutral B meson is fully reconstructed in a final state containing a charmonium meson and the other B meson is determined to be either a B0 or B0bar from its decay products. The amplitude of the CP-violating asymmetry, which in the Standard Model is proportional to sin2beta, is derived from the decay-time distributions in such events. We measure sin2beta = 0.741 +/- 0.067 (stat) +/- 0.033 (syst) and |lambda| = 0.948 +/- 0.051 (stat) +/- 0.017 (syst). The magnitude of lambda is consistent with unity, in agreement with the Standard Model expectation of no direct CP violation in these modes

Diagnostic laboratory standardization and validation of platelet transmission electron microscopy

<p>Platelet transmission electron microscopy (PTEM) is considered the gold standard test for assessing distinct ultrastructural abnormalities in inherited platelet disorders (IPDs). Nevertheless, PTEM remains mainly a research tool due to the lack of standardized procedures, a validated dense granule (DG) count reference range, and standardized image interpretation criteria. The aim of this study was to standardize and validate PTEM as a clinical laboratory test. Based on previously established methods, we optimized and standardized preanalytical, analytical, and postanalytical procedures for both whole mount (WM) and thin section (TS) PTEM. Mean number of DG/platelet (plt), percentage of plts without DG, platelet count (PC), mean platelet volume (MPV), immature platelet fraction (IPF), and plt light transmission aggregometry analyses were measured on blood samples from 113 healthy donors. Quantile regression was used to estimate the reference range for DG/plt, and linear regression was used to assess the association of DG/plt with other plt measurements. All PTEM procedures were standardized using commercially available materials and reagents. DG interpretation criteria were established based on previous publications and expert consensus, and resulted in improved operator agreement. Mean DG/plt was stable for 2 days after blood sample collection. The median within patient coefficient of variation for mean DG/plt was 22.2%; the mean DG/plt reference range (mid-95th %) was 1.2–4.0. Mean DG/plt was associated with IPF (<i>p </i>= .01, R² = 0.06) but not age, sex, PC, MPV, or plt maximum aggregation or primary slope of aggregation (<i>p </i>> .17, R² < 0.02). Baseline ultrastructural features were established for TS-PTEM. PTEM was validated using samples from patients with previously established diagnoses of IPDs. Standardization and validation of PTEM procedures and interpretation, and establishment of the normal mean DG/plt reference range and PTEM baseline ultrastructural features, will facilitate implementation of PTEM as a valid clinical laboratory test for evaluating ultrastructural abnormalities in IPDs.</p

Penguin Mediated B Decays at BABAR

We report on preliminary results of searches for penguin mediated B decays based on 20.7 fb^{-1} of data collected at the Y(4S) peak with the BABAR detector at PEP-II. The following branching fractions have been measured: BR(B+ --> phi K+) = (7.7^{+1.6}_{-1.4} +- 0.8)*10^{-6}, BR(B0 --> phi K0) = (8.1^{+3.1}_{-2.5} +- 0.8)*10^{-6}, BR(B+ --> phi K*+) = (9.7^{+4.2}_{-3.4} +- 1.7)*10^{-6}, BR(B0 --> phi K*0) = (8.7^{+2.5}_{-2.1} +- 1.1)*10^{-6}, BR(B+--> omega pi+) = (6.6^{+2.1}_{-1.8} +- 0.7)*10^{-6}, BR(B --> eta K^*0) = (19.8^{+6.5}_{-5.6} +-1.7)*10^{-6}, where the first error is statistical and the second systematic. For several other modes we report upper limits on their branching fractions; for example for the following flavor-changing neutral current decays, BR(B--> K l+ l-) 0.6*10^{-6}, BR(B--> K* l+ l-) 2.5*10^{-6}, at 90% Confidence Level (C.L.)

Search for the Exclusive Radiative Decays B→ργB \rightarrow \rho\gamma and B0→ωγB^0 \rightarrow \omega\gamma

A search for the exclusive radiative decays B->rho(770) gamma and B^0->omega(782) gamma is performed on a sample of 84 million BB-bar events collected by the BABAR detector at the PEP-II asymmetric e^+e^- collider. No significant signal is seen in any of the channels. We set preliminary upper limits of BR[B^0->rho^0 gamma] rho^+ gamma] omega gamma] rho gamma, we find the preliminary limit BR[B -> rho gamma] rho gamma]/BR[B-> K* gamma] < 0.047 at 90% Confidence Level

A Study of Time-Dependent CPCP Asymmetry in B0→J/ψπ0B^0 \rightarrow J/\psi\pi^0 Decays

We present our first study of the time-dependent CP-violating asymmetry in B0 --> J/psi pi0 decays using e^+e^- annihilation data collected with the BABAR detector at the Y(4S) resonance during the years 1999--2002 at the PEP-II asymmetric-energy B Factory at SLAC. With about 88 million B Bbar pairs, our preliminary results for the coefficients of the cosine and sine terms of the CP asymmetry are C_{J/psi pi0} = 0.38 +/- 0.41 (stat) +/- 0.09 (syst) and S_{J/psi pi0} = 0.05 +/- 0.49 (stat) +/- 0.16 (syst)

Determination of the Branching Fraction for Inclusive Decays B→XsγB \rightarrow X_{s}\gamma

We present a preliminary determination of the inclusive branching fraction for the rare radiative penguin transition B -> X_{s} gamma. The measurement is based on a data sample of 60 million BB pairs collected between 1999 and 2001 with the BaBar detector at the PEPII asymmetric-energy e+e- B Factory at SLAC. We study events containing a high-energy photon from one B (or Bbar) decay and a tagging primary lepton from the decay of the other B meson. By this means, we are able to reduce a significant component of the background without introduction of model dependent uncertainties in the event selection efficiency. We determine the branching fraction BR(B->X_{s} gamma)=3.88 +-0.36(stat.)+-0.37(sys.) +0.43-0.23(model.)x10^{-4}, which is consistent with Standard Model predictions and provides a constraint on possible new physics contributions to the electromagnetic penguin amplitude in B decays

Dalitz Plot Analysis of D0D^0 Hadronic Decays D0→K0K−π+D^0 \rightarrow K^0K^-\pi^+, D0→Kˉ0K+π−D^0 \rightarrow \bar K^0K^+\pi^- and D0→Kˉ0K+K−D^0 \rightarrow \bar K^0K^+K^-

A Dalitz plot analysis of the D0 hadronic decays D0 -> K0 K- pi+, D0 -> K0bar K+ pi- and D0 -> K0bar K+ K- is presented. This analysis is based on a data sample of 22 fb-1 collected with the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC running on or near the Y(4S) resonance. The events are selected from continuum e+ e- annihilations using the decay D*+ -> D0 pi+. Preliminary measurements of the branching fractions of the above hadronic decays are obtained. Preliminary estimates of fractions and phases for resonant and nonresonant contributions to the Dalitz plot are also presented