MET inhibition in tumor cells by PHA665752 impairs homologous recombination repair of DNA double strand breaks

Abnormal activation of cellular DNA repair pathways by deregulated signaling of receptor tyrosine kinase systems has broad implications for both cancer biology and treatment. Recent studies suggest a potential link between DNA repair and aberrant activation of the hepatocyte growth factor receptor Mesenchymal-Epithelial Transition (MET), an oncogene that is overexpressed in numerous types of human tumors and considered a prime target in clinical oncology. Using the homologous recombination (HR) direct-repeat direct-repeat green fluorescent protein ((DR)-GFP) system, we show that MET inhibition in tumor cells with deregulated MET activity by the small molecule PHA665752 significantly impairs in a dose-dependent manner HR. Using cells that express MET-mutated variants that respond differentially to PHA665752, we confirm that the observed HR inhibition is indeed MET-dependent. Furthermore, our data also suggest that decline in HR-dependent DNA repair activity is not a secondary effect due to cell cycle alterations caused by PHA665752. Mechanistically, we show that MET inhibition affects the formation of the RAD51-BRCA2 complex, which is crucial for error-free HR repair of double strand DNA lesions, presumably via downregulation and impaired translocation of RAD51 into the nucleus. Taken together, these findings assist to further support the role of MET in the cellular DNA damage response and highlight the potential future benefit of MET inhibitors for the sensitization of tumor cells to DNA damaging agents.

The \bar{B} \to X_s γγdecay: NLL QCD contribution of the Electromagnetic Dipole operator O_7

We calculate the set of O(\alpha_s) corrections to the double differential decay width d\Gamma_{77}/(ds_1 \, ds_2) for the process \bar{B} \to X_s \gamma \gamma originating from diagrams involving the electromagnetic dipole operator O_7. The kinematical variables s_1 and s_2 are defined as s_i=(p_b - q_i)^2/m_b^2, where p_b, q_1, q_2 are the momenta of b-quark and two photons. While the (renormalized) virtual corrections are worked out exactly for a certain range of s_1 and s_2, we retain in the gluon bremsstrahlung process only the leading power w.r.t. the (normalized) hadronic mass s_3=(p_b-q_1-q_2)^2/m_b^2 in the underlying triple differential decay width d\Gamma_{77}/(ds_1 ds_2 ds_3). The double differential decay width, based on this approximation, is free of infrared- and collinear singularities when combining virtual- and bremsstrahlung corrections. The corresponding results are obtained analytically. When retaining all powers in s_3, the sum of virtual- and bremstrahlung corrections contains uncanceled 1/\epsilon singularities (which are due to collinear photon emission from the s-quark) and other concepts, which go beyond perturbation theory, like parton fragmentation functions of a quark or a gluon into a photon, are needed which is beyond the scope of our paper.

Single center experience with provisional abciximab therapy in complex lower limb interventions

BACKGROUND: Abciximab, a glycoprotein IIb/IIIa antagonist has been shown to improve patency and clinical outcome in patients undergoing endovascular recanalization of femoro-popliteal occlusions. However, data on abciximab therapy in complex peripheral catheter interventions of lower limbs are quite limited. The objective of this retrospective study was to evaluate the clinical and hemodynamic outcomes of patients treated with provisional abciximab during complex peripheral catheter interventions. PATIENTS AND METHODS: Analysis of a consecutive series of 44 patients with provisional abciximab therapy in complex peripheral catheter interventions with imminent risk of early rethrombosis defined as revascularization of arterial occlusions associated with one or more of the following additional circumstances named as time-consuming intervention > 3 hours, compromised contrast flow not solved by stenting, distal embolization not solved by mechanical thromboembolectomy, and peri-interventional notice of thrombus evolution despite adequate heparin adjustment of lower limbs. Adjunctive abciximab therapy was started in accordance to percutaneous coronary bailout situations. The decision to add abciximab was based on the decision of the operator and went along with the judgement that there is a rising risk of reocclusion due to the progressive complexity of an individual intervention. A bolus of 0.25 mg per kilogram of body weight, followed by a maintenance infusion of 0.125 microg/kg/min (up to a maximum dosage of 10 microg/min) for 12 hours was administered. Clinical and hemodynamic outcome was prospectively assessed at discharge, three and six months after the index procedure. RESULTS: The occluded artery of 44 limbs was in the iliac (2%), in the femoro-popliteal (73%) or below the knee segment (25%). Overall, occlusion length was 11.5 +/- 6.5 cm. Technical success rate was 95%. Mean ABI increased from 0.5 +/- 0.16 to 0.88 +/- 0.19 (p < 0.001) with immediate hemodynamic improvement of 91%. Overall, sustained clinical improvement was 84% and 66% at three and six months follow-up, with best results in iliac (100%), followed by below the knee (73%) and by femoro-popliteal segment (63%) at six months, respectively. Overall, secondary clinical improvement was 86% at six months. Minor and major bleeding complications were 16% and 9%, respectively. CONCLUSION: Abciximab should be noticed as medical adjunct in the interventional armamentarium to prevent imminent rethrombosis in complex peripheral catheter interventions.

Early loading of sandblasted and acid-etched implants: a randomized-controlled double-blind split-mouth study. Five-year results

OBJECTIVES: The aim of the present split-mouth study is to assess the peri-implant conditions around early-loaded sandblasted and acid-etched (SLA) implants, 5 years after abutment connection and to compare, in the same patients, the results obtained with a standard protocol using identical implants with a TPS surface. MATERIAL AND METHODS: Surgical procedure was performed by the same operator and was identical at test (SLA) and control (TPS) sites, in 32 healthy patients. Abutment connection was carried out at 35 N cm 6 weeks postsurgery for test sites and 12 weeks for the controls. Patients were seen regularly, for control and professional cleaning. At 60 months, clinical measures and radiographic bone changes were recorded by the same operator, blind to the type of surface of the implant, on 27 patients, as five patients were lost to follow-up. RESULTS: A total number of 106 implants were examined. No implant was lost. No significant differences were found with respect to the presence of plaque [modified plaque index (mPI) 0.27+/-0.56 vs. 0.32+/-0.54], bleeding on probing (29% vs. 32%), mean pocket depth (3.2+/-1 vs. 3.2+/-1 mm) or mean marginal bone loss (0.32+/-1.04 vs. 0.44+/-1.12 mm) between test and control. Four implants that presented 'spinning' at the time of abutment connection presented no significant differences from the rest of the test sites. CONCLUSION: The results of this prospective study confirm that SLA implants, under defined conditions, are suitable for early loading at 6 weeks in both the mandible and the maxilla. Limited implant spinning, occasionally found at abutment connection, produces no detrimental effect on the clinical outcome when properly handled.

A rare anomaly of the anterior communicating artery complex hidden by a large broad-neck aneurysm and disclosed by three-dimensional rotational angiography

Double fenestration of the anterior communicating artery (ACoA) complex associated with an aneurysm is a very rare finding and is usually caused by ACoA duplication and the presence of a median artery of the corpus callosum (MACC). We present a patient in whom double fenestration was not associated with ACoA duplication or even with MACC, representing therefore, a previously unreported anatomic variation. A 43 year old woman experienced sudden headache and the CT scans showed subarachnoid haemorrhage (SAH). On admission, her clinical condition was consistent with Hunt and Hess grade II. Conventional digital subtraction angiography (DSA) was performed and revealed multiple intracranial aneurysms arising from both middle cerebral arteries (MCA) and from the ACoA. Three-dimensional rotational angiography (3D-RA) disclosed a double fenestration of the ACoA complex which was missed by DSA. The patient underwent a classic pterional approach in order to achieve occlusion of both left MCA and ACoA aneurysms by surgical clipping. The post-operative period was uneventful. A rare anatomical variation characterised by a double fenestration not associated with ACoA duplication or MACC is described. The DSA images missed the double fenestration which was disclosed by 3D-RA, indicating the importance of 3D-RA in the diagnosis and surgical planning of intracranial aneurysms.

Ctp1 and the MRN-complex are required for endonucleolytic Rec12 removal with release of a single class of oligonucleotides in fission yeast

DNA double-strand breaks (DSBs) are formed during meiosis by the action of the topoisomerase-like Spo11/Rec12 protein, which remains covalently bound to the 5' ends of the broken DNA. Spo11/Rec12 removal is required for resection and initiation of strand invasion for DSB repair. It was previously shown that budding yeast Spo11, the homolog of fission yeast Rec12, is removed from DNA by endonucleolytic cleavage. The release of two Spo11 bound oligonucleotide classes, heterogeneous in length, led to the conjecture of asymmetric cleavage. In fission yeast, we found only one class of oligonucleotides bound to Rec12 ranging in length from 17 to 27 nucleotides. Ctp1, Rad50, and the nuclease activity of Rad32, the fission yeast homolog of Mre11, are required for endonucleolytic Rec12 removal. Further, we detected no Rec12 removal in a rad50S mutant. However, strains with additional loss of components localizing to the linear elements, Hop1 or Mek1, showed some Rec12 removal, a restoration depending on Ctp1 and Rad32 nuclease activity. But, deletion of hop1 or mek1 did not suppress the phenotypes of ctp1Delta and the nuclease dead mutant (rad32-D65N). We discuss what consequences for subsequent repair a single class of Rec12-oligonucleotides may have during meiotic recombination in fission yeast in comparison to two classes of Spo11-oligonucleotides in budding yeast. Furthermore, we hypothesize on the participation of Hop1 and Mek1 in Rec12 removal.

NLL QCD contribution of the electromagnetic dipole operator to B -> Xs gamma gamma with a massive strange quark

We calculate the O(αs) corrections to the double differential decay width dΓ77/(ds1ds2) for the process B¯→Xsγγ, originating from diagrams involving the electromagnetic dipole operator O7. The kinematical variables s1 and s2 are defined as si=(pb−qi)2/m2b, where pb, q1, q2 are the momenta of the b quark and two photons. We introduce a nonzero mass ms for the strange quark to regulate configurations where the gluon or one of the photons become collinear with the strange quark and retain terms which are logarithmic in ms, while discarding terms which go to zero in the limit ms→0. When combining virtual and bremsstrahlung corrections, the infrared and collinear singularities induced by soft and/or collinear gluons drop out. By our cuts the photons do not become soft, but one of them can become collinear with the strange quark. This implies that in the final result a single logarithm of ms survives. In principle, the configurations with collinear photon emission could be treated using fragmentation functions. In a related work we find that similar results can be obtained when simply interpreting ms appearing in the final result as a constituent mass. We do so in the present paper and vary ms between 400 and 600 MeV in the numerics. This work extends a previous paper by us, where only the leading power terms with respect to the (normalized) hadronic mass s3=(pb−q1−q2)2/m2b were taken into account in the underlying triple differential decay width dΓ77/(ds1ds2ds3).

Out-of-Body Experiences and Other Complex Dissociation Experiences in a Patient with Unilateral Peripheral Vestibular Damage and Deficient Multisensory Integration

Out-of-body experiences (OBEs) are illusory perceptions of one's body from an elevated disembodied perspective. Recent theories postulate a double disintegration process in the personal (visual, proprioceptive and tactile disintegration) and extrapersonal (visual and vestibular disintegration) space as the basis of OBEs. Here we describe a case which corroborates and extends this hypothesis. The patient suffered from peripheral vestibular damage and presented with OBEs and lucid dreams. Analysis of the patient's behaviour revealed a failure of visuo-vestibular integration and abnormal sensitivity to visuo-tactile conflicts that have previously been shown to experimentally induce out-of-body illusions (in healthy subjects). In light of these experimental findings and the patient's symptomatology we extend an earlier model of the role of vestibular signals in OBEs. Our results advocate the involvement of subcortical bodily mechanisms in the occurrence of OBEs.