Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used ...for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study.
The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of 'definite', 'very likely', 'probable', or 'possible' PD.
A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up.
This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.
A ubiquitously expressed chaperone, heat shock protein 90 (
HSP
90) is of considerable interest as an oncology target because tumor cells and oncogenic proteins are acutely dependent on its activity.
...AT
13387 (2,4‐dihydroxy‐5‐isopropyl‐phenyl)‐5‐(4‐methyl‐piperazin‐1‐ylmethyl)‐1,3‐dihydro‐isoindol‐2‐yl methanone,
l
‐lactic acid salt) a novel, high‐affinity
HSP
90 inhibitor, which is currently being clinically tested, has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. This inhibitor has induced the degradation of specific
HSP
90 client proteins for up to 7 days in tumor cell lines
in vitro
. The primary driver of cell growth (mutant epidermal growth factor receptors) was particularly sensitive to
HSP
90 inhibition. The long duration of client protein knockdown and suppression of phospho‐signaling seen
in vitro
after treatment with
AT
13387 was also apparent
in vivo
, with client proteins and phospho‐signaling suppressed for up to 72 h in xenograft tumors after treatment with a single dose of
AT
13387. Pharmacokinetic analyses indicated that while
AT
13387 was rapidly cleared from blood, its retention in tumor xenografts was markedly extended, and it was efficacious in a range of xenograft models.
AT
13387's long duration of action enabled, in particular, its efficacious once weekly administration in human lung carcinoma xenografts. The use of longer‐acting
HSP
90 inhibitors, such as
AT
13387, on less frequent dosing regimens has the potential to maintain antitumor efficacy as well as minimize systemic exposure and unwanted effects on normal tissues. (
Cancer Sci
, 2012; 103: 522–527)
Co-stimulatory signals are necessary for the full activation of T cells for growth and effector function. As co-stimulatory molecules are normally regulated in their expression, it has been suggested ...that microorganisms enhance their expression on host antigen-presenting cells (APC), thus allowing efficient generation of anti-microbial immunity. We here describe experiments which demonstrate that infection of macrophages, both in vitro and in vivo, by the protozoan parasite Leishmania donovani fails to trigger expression of co-stimulatory molecules B7-1 and heat-stable antigen on these APC. Furthermore, infection with this parasite inhibits the macrophage response to normal regulatory signals, such as bacterial lipopolysaccharide. These changes in the cell surface are mirrored in functional studies of co-stimulation in vitro. Together, these data suggest a further facet of parasite interference in host immunity, but also indicate a potential new target for immunotherapy.
AT9283 is a potent inhibitor of JAK2, JAK3, mutant Abl kinase (T315IAbl) and Aurora kinases A and B all of which have an IC50 <5nM. The compound is currently in early phase clinical development for ...hematological malignancies. Multitargeted kinase inhibitors may be of particular value as anti-proliferative agents as a consequence of their ability to inhibit several signalling pathways simultaneously. Many of the kinases targeted by AT9283 lie in signalling pathways activated by oncogenes and may contribute in a positive way to the anti-tumour action of the compound. Here we describe the characterisation of the anti-tumour effects of AT9283 in models of JAK2-dependent disease The JAK2 V617F mutation has been identified in more than 95% of patients with Polycythemia vera and in 50 to 60% of patients with Essential Thrombocythemia and myelofibrosis. JAK2 is a key modulator of cytokine signalling, transducing signals from cell surface receptors via the JAK/STAT pathway. The point mutation renders the kinase constitutively active and induces cytokine-independent proliferation of cell lines harboring mutated JAK2. AT9283 was profiled against two cell lines harboring JAK2 V617F (HEL, SET-2) as well as two lines with a dependence on cytokine signalling through wild type endogenous JAK2 for survival (BA/F3 wt, TF-1, stimulated with IL3). These lines were compared with two additional leukaemia cell lines not dependent upon JAK signalling for survival, K562 (Ph+CML) and HL60 (N-Ras PML). In each case the dominant effect of the compound is to inhibit cell growth through JAK inhibition where the survival of the cell line depends on signalling through the JAK2 pathway. In contrast the cell lines less dependent on JAK2 for survival show a polyploid phenotype indicative of Aurora kinase inhibition. In HEL cells AT9283 inhibits phosphorylation of JAK2 pathway markers such as phospho-STAT5 (Tyr694) at 100nM, a dose consistent with concentrations required to inhibit the proliferation of these cells. Consequently, the cell cycle profiles generated when either K562 or HL60 cells are treated with AT9283 suggest that endoreduplication derived from Aurora inhibition is the dominant phenotype. In a JAK driven system the dominant phenotype observed is induction of apoptosis via inhibition of JAK. In an in vivo model, administration of a single dose of AT9283 to the JAK-dependent HEL xenograft, inhibited phosphorylation of STAT5 indicating JAK2 inhibition in the tumour tissue and an efficacy study demonstrated growth inhibitory effects of 9283 in this model. Finally the activity of AT9283 was tested in primary assays using cells taken either from healthy volunteers or patients diagnosed with MPD. These data together support further clinical investigation of the compound in patients with a myeloproliferative disorder.
Introduction: This paper provides the results of a year-long evaluation of a large-scale integrated care pilot in North West London. The pilot aimed to integrate care across primary, acute, ...community, mental health and social care for people with diabetes and those over 75 years through: care planning; multidisciplinary case reviews; information sharing; and project management support.
Methods: The evaluation team conducted qualitative studies of change at organisational, clinician, and patient levels (using interviews, focus groups and a survey); and quantitative analysis of change in service use and patient-level clinical outcomes (using patient-level data sets and a matched control study).
Results: The pilot had successfully engaged provider organisations, created a shared strategic vision and established governance structures. However, engagement of clinicians was variable and there was no evidence to date of significant reductions in emergency admissions. There was some evidence of changes in care processes.
Conclusion: Although the pilot has demonstrated the beginnings of large-scale change, it remains in the early stages and faces significant challenges as it seeks to become sustainable for the longer term. It is critical that NHS managers and clinicians have realistic expectations of what can be achieved in a relatively short period of time.
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