Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.

Background-Recent magnetic resonance imaging (MRI) studies suggest increased transverse relaxation rate (R2*) and reduced diffusion tensor imaging (DTI) fractional anisotropy (FA) values in the SN in PD. The R2* and FA changes may reflect different aspects of PD-related

Background The pattern of dopamine cell loss in Parkinson's disease is known to be prominent in the ventrolateral and caudal substantia nigra, but less severe in the dorsal and rostral region. Both diffusion tensor imaging and R2* relaxometry of the substantia nigra have been reported as potential markers for Parkinson's disease, but their relative ability to mark disease progression and differences in pathophysiological bases remains unclear. Methods High resolution T2-weigthed, R2*, and diffusion tensor imaging were obtained from 28 controls and 40 Parkinson's disease subjects [15 early-stage (disease duration≤1 year), 14 mid-stage (duration 2-5 years), and 11 late-stage (duration>5 years)]. Fractional anisotropy and R2* values in both rostral and caudal substantia nigra were obtained for all subjects, and clinical measures (disease duration; levodopa-equivalent daily dosage; “off”-drug Unified Parkinson's Disease Rating Scale motor score) were obtained for Parkinson's subjects. Results There was no correlation between fractional anisotropy and clinical measures, whereas R2* was strongly associated with disease progression. Compared to controls, fractional anisotropy in caudal substantia nigra was significantly decreased in Parkinson's disease patients of all stages, whereas in rostral substantia nigra it was decreased significantly only in the late-stage group. R2* in both substantia nigra regions was significantly increased in the mid-stage and late-stage, but not early-stage, of Parkinson's disease subjects. Conclusions These findings suggest that fractional anisotropy changes may mark early pathological changes in caudal substantia nigra, whereas the changes in R2* may more closely track Parkinson's disease's clinical progression after symptom onset.

Parkinson's disease (PD) presents clinically with varying degrees of resting tremor, rigidity, and bradykinesia. For decades, striatal-thalamo-cortical (STC) dysfunction has been implied in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure:The authors have reported no conflicts of interest. Specific Contributions of AuthorsMechelle M. Lewis: Data acquisition, analysis, and interpretation; obtaining funding for the study, administrative support for the study; primary drafting and critical revision of the manuscript. Guangwei Du: Data analysis and interpretation, drafting and critical revision of the manuscript, Suman Sen: Data acquisition, critical revision of the manuscript. Atsushi Kawaguchi: Statistical analysis of the data and data interpretation. Young Truong: Statistical analysis of the data, data interpretation, critical revision of the manuscript. Seonjoo Lee: Statistical analysis of the data and critical revision of the manuscript. Richard Mailman: Data interpretation and critical revision of the manuscript. Xuemei Huang: Conception and design of the study; data acquisition, analysis, and interpretation; drafting and critical revision of the manuscript; obtaining funding for the study; administration and supervision of the project. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2012 March 17. Zetusky et al., 1985), is less reliably responsive to dopaminergic modulation (Marjama-Lyons and Koller, 2000), and does not worsen at the same rate as bradykinesia and rigidity (Zetusky et al., 1985;Louis et al., 1999;Jankovic and Kapadia, 2001). Recent PD imaging studies suggest dopamine transporter levels and myocardial sympathetic degeneration correlate with hypokinesia/rigidity but not tremor (Spiegel et al., 2007). Finally, there is no correlation between rest tremor and striatal 18 Ffluorodopa uptake in PD patients (Vingerhoets et al., 1997).The pathological hallmark of PD is dopamine neuron loss in the substantia nigra pars compacta (SNc) of the basal ganglia (BG). For decades, a classic model emphasized the role of the BG in modulating cortical function through striatal-thalamo-cortical (STC) circuits (DeLong et al., 1984;Alexander et al., 1986;Albin et al., 1989), the dysfunction of which may lead to bradykinesia and rigidity. This model does not, however, explain PD resting tremor. Emerging evidence suggests the necessity of incorpating cerebello-thalamo-cortical (CTC) circuitry into discussions of motor function in both normal (Kelly et al., 2009) and dysfunctional (Deiber et al., 1993;Neychev et al., 2008;A...

Polyimides are proved to be an important class of polymers due to their outstanding set of physical and chemical properties. However, this class of polymers suffers from poor processability, which limits their scope of application. This review article deals with approaches that have been undertaken by different researchers to improve the processability of this class of polymers. Mostly, these are synthetic approaches using new diamine and dianhydride monomers that reduce the interchain interaction of the final poyimide by flexibilizing the polymer chain or increasing the fraction free volume. Accordingly, the structural factors that are responsible for better processability are discussed and representative diamine and diahydride structures are tabulated under different categories. Major efforts towards development of soluble polyimides but maintaining excellent mechanical and thermal properties have been done by our group and are also covered in this article.

Both the basal ganglia and cerebellum are known to influence cortical motor and motor-associated areas via the thalamus. Whereas striato-thalamo-cortical (STC) motor circuit dysfunction has been implicated clearly in Parkinson's disease (PD), the role of the cerebello-thalamo-cortical (CTC) motor circuit has not been well defined. Functional magnetic resonance imaging (fMRI) is a convenient tool for studying the role of the CTC in vivo in PD patients, but large inter-individual differences in fMRI activation patterns require very large numbers of subjects in order to interpret data from cross-sectional, case control studies. To understand the role of the CTC during PD progression, we obtained longitudinal fMRI two years apart from five PD (57 ± 8 yr) and five Controls (57 ± 9 yr) performing either externally-(EG) or internally-guided (IG) sequential finger movements. All PD subjects had unilateral motor symptoms at baseline, but developed bilateral symptoms at follow-up. Within-group analyses were performed by comparing fMRI activation patterns between baseline and follow-up scans. Between-group comparisons were made by contrasting fMRI activation patterns generated by the more-affected and less-affected hands of PD subjects with the dominant and non-dominant hands of Controls, respectively. Compared to baseline, Controls showed changes in CTC circuits, but PD subjects had increased recruitment of both cortical motor-associated and cerebellar areas. Compared to Controls, PD subjects demonstrated augmented recruitment of CTC circuits over time that was statistically significant when the IG task was performed by the hand that transitioned from non-symptomatic to symptomatic. This longitudinal fMRI study demonstrates increased recruitment of the CTC motor circuit concomitant with PD progression, suggesting a role of the CTC circuit in accommodation to, or pathophysiology of, PD. KeywordsParkinson's disease; Longitudinal; FMRI; Cerebellum; Neurocircuits; Motor Control Corresponding Author: Xuemei Huang, MD, PhD, Department of Neurology, Penn State University -Milton S. Hershey Medical Center, H037, 500 University Drive, Hershey, PA 17033-0850, Office phone: 717-531-1803; Fax: 717-531-0465, Xuemei@psu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 March 17. Parkinson's disease (PD) is a progressive, neurodegenerative disorder characterized by asymmetrical onset of motor symptoms such as bradykinesia, rigidity, and tremor. The principal pathology in PD is the loss of dopamine...

SummaryDickkopf-1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti-DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose-limiting toxicity (DLT) of escalating doses in combination with anti-myeloma therapy and zoledronic acid. Twenty-eight patients were enrolled and received BHQ880 at doses of 3-40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal-related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.

Background Parkinson's disease (PD) traditionally is characterized by tremor, rigidity, and bradykinesia, although cognitive impairment also is a common symptom. The clinical presentation of PD is heterogeneous and associated with different risk factors for developing cognitive impairment. PD patients with primary akinetic/rigidity (PDAR) are more likely to develop cognitive deficits compared to those with tremor-predominant symptoms (PDT). Because cognitive impairment in PD appears to be related to changes in the default mode network (DMN), this study tested the hypothesis that DMN integrity is different between PDAR and PDT subtypes. Method Resting state fMRI (rs-fMRI) and whole brain volumetric data were obtained from 17 PDAR, 15 PDT and 24 healthy controls (HCs) using a 3T scanner. PD patients were matched closely to HCs for demographic and cognitive variables, and showed no symptoms of dementia. Voxel-based morphometry (VBM) was used to examine brain gray matter (GM) volume changes between groups. Independent component analysis (ICA) interrogated differences in the DMN among PDAR, PDT, and HC. Results There was decreased activity in the left inferior parietal cortex (IPC) and the left posterior cingulate cortex (PCC) within the DMN between PDAR and both HC and PDT subjects, even after controlling for multiple comparisons, but not between PDT and HC. GM volume differences between groups were detected at a lower threshold (p < 0.001, uncorrected). Resting state activity in IPC and PCC were correlated with some measures of cognitive performance in PD but not in HC. Conclusion This is the first study to demonstrate DMN differences between cognitively comparable PDAR and PDT subtypes. The DMN differences between PD and HC appear to be driven by the PDAR subtype. Further studies are warranted to understand the underlying neural mechanisms and their relevance to clinical and cognitive outcomes in PDAR and PDT subtypes.