Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists. <br></br> EXPERIMENTAL DESIGN: In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing. <br></br> RESULTS: Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients.<br></br> CONCLUSION: Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors.<br></br&gt

A proteomic approach to identify endosomal cargoes controlling cancer invasiveness

We have previously shown that Rab17 - a small GTPase associated with epithelial polarity - is specifically suppressed by ERK2 signalling to promote an invasive phenotype. However, the mechanisms through which Rab17 loss permits invasiveness, and the endosomal cargoes that are responsible for mediating this are not known. Using quantitative mass spectrometry-based proteomics, we have found that knockdown of Rab17 leads to highly selective reduction in the cellular levels of a v-SNARE (Vamp8). Moreover, proteomics and immunofluorescence indicate that Vamp-8 is associated with Rab17 at late endosomes. Reduced levels of Vamp8 promote transition between ductal carcinoma in situ (DCIS) and a more invasive phenotype. We developed an unbiased proteomic approach to elucidate the complement of receptors that redistributes between endosomes and the plasma membrane, and have pin-pointed neuropilin-2 (NRP2) as a key pro-invasive cargo of Rab17/Vamp8-regulated trafficking. Indeed, reduced Rab17 or Vamp8 levels lead to increased mobilisation of NRP2-containing late endosomes and upregulated cell surface expression of NRP2. Finally, we show that NRP2 is required for the basement membrane disruption which accompanies transition between DCIS and a more invasive phenotype

The long term implications for the future of Dental Anaesthetic Practice following the General Dental Council's Guidelines of November 1998

"The long term implicationsfor thefuture ofDental Anaesthetic Practice in Lincolnshirefollowing the General Dental Council's Guidelines ofNovember 1998."The subject of this thesis is based on the continuing requirements of patients for dental anaesthesia following the revised General Dental Council (GDC) Guidelines of November 1998.The factors to be considered in particular are issues which directly apply to referred patients for a dental general anaesthetic (DGA) namely - social class, gender, ethnicity, occupation, background education, attitude towards dental treatment and pre-operative medical history. In addition to considering the issues involved in assessing the suitability of patients for a general anaesthetic (GA) attention will be paid to the General Dental Practitioners (GDP) rationale for referring a patient for GA and whether the choice of such treatment was in any way influenced by the mindset of the patient. Issues relating to case selection will be taken into account along with the steps taken to avoid a repeat anaesthetic. The factors which motivate a GDP to offer GA, sedation or LA will be examined along with the possible reasons which guided the patient to make that decision. A look to the future will be undertaken with regard to GA and sedation services in the UK subsequent to the November 1998 guidelines with some emphasis placed on the adult use of such services.In order to assess the implications and effects of the GDC guidelines on GA services, a study of the attitudes and opinions of both referring and treating dentists was undertaken. This study also took into account the views and attitudes of patients both pre- and post-assessment.The methodology used was both qualitative and quantitative in nature involving the use of questionnaires; two questionnaires were sent to the referring and clinical dentist. The purpose of the questionnaire to the clinical dentists was to determine referral patterns post-guidelines and to monitor compliance with these, whilst the questionnaire to the treating dentists was designed to monitor attitudes regarding referrals for treatment. Likewise patients were given two questionnaires to determine whether patients referred for GA, sedation or LA were satisfied with the treatment plan and subsequent outcome.Since the Poswillo Report of 1990 there have been general recommendations to move from the position of GA towards sedation. Correspondingly part of the referring dentists questionnaire contained a section on this aspect of patient care.The results of the study are considered in detail and inferences drawn relating to the present and future provision of both GA and sedation in the UK

Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

A CFD investigation of synthetic jets

On current helicopter designs, the rotor blades are commonly articulated at their root. This system is employed to ensure that the resultant force of the rotor disc acts through its hub, preventing a rolling moment from being produced in forward flight. The movement which the blades are allowed however, restricts control of the blade angle of attack and allows potential lifting capability to be lost. To address this problem, on-blade flow control using synthetic jets is suggested. Miniature synthetic jets show promise for the alleviation of a number of flow control problems. These may be especially suitable for helicopter application since proposed actuator designs are remotely activated and do not require a secondary jet fluid. These features mean that actuators may be located at large spanwise distances from the rotor hub. An investigation of the operation of synthetic jets and their ability to effect flow control is begun with a CFD study of a single synthetic jet actuator issuing into an otherwise still atmosphere. A jet flow is developed from a rapidly deforming cavity. Velocity profiles are compared with previously published data. Simulations are next extended to crossflow conditions. An alternative synthetic jet model is developed to improve computational efficiency. For this, the deforming cavity is removed and the flow to and from the actuator is simulated by means of an imposed sinusoidally varying velocity. Both approaches for the production of a synthetic jet flow are compared and the same essential features are found. Depending on conditions, different flow behaviours are observed. The actuator produces vortices on its blowing schedule which are either convected with the freestream, or become part of a recirculating system which becomes permanently established a short distance downstream of the actuator exit. When varying freestream and jet operating conditions, optimal mean reduction of surface pressures is found to coincide with the first occurrence of the latter flow behaviour. Using the simpler actuator model, a parameter study is performed to determine optimum jet operation across a range of conditions. The operation of a single synthetic jet on an aerofoil section is finally considered. The same flow behaviours are once again produced. On the aerofoil, the large velocity variation means that achieving the maximum pressure reduction requires operation at high values of reduced frequency. A single actuator makes only a small difference to the overall lift, but the improvement is encouraging and suggests that a number of actuators may make a more significant difference

A study of p120-catenin and its tyrosine phopshorylation in cancer cell adhesion and invasion

Abstract available p i

Cohesion policy after Brexit: the economic, social and institutional challenges

Since 1988, when the current EU Cohesion Policy was introduced, it has played an influential role in setting priorities for policies aimed at dealing with the effects of European economic integration on regional and social disparities. Although, latterly, the amount of money spent in the UK through the European Structural and Investment Funds (ESIF) has declined, EUprogrammes have had a disproportionate effect on the design and implementation of UK policies shaping regional and local economic and social development. This paper starts by recalling how EU Cohesion Policy has functioned in the UK, then considers how Brexit may affect regional and social development and the need for a corresponding policy response, focusing on the sorts of policies currently supported by the European Regional Development Fund (ERDF) and the European Social Fund (ESF). The paper shows that filling the policy vacuum will be far from straightforward because complementary national policies and institutional frameworks have lacked consistency or coherence. It concludes by examining the wider policy issues arising from rethinking domestic policy outside the ESIF framework.The sub-national level, in particular, will need a fresh approach following Brexit

A study of p120-catenin and its tyrosine phosphorylation in cancer cell adhesion and invasion

Abstract available p i.EThOS - Electronic Theses Online ServiceGBUnited Kingdo