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1.  A System Calibration and Fast Iterative Reconstruction Method for Next-Generation SPECT Imagers 
IEEE transactions on nuclear science  2012;59(5):1990-1996.
Recently, high-resolution gamma cameras have been developed with detectors containing > 105–106 elements. Single-photon emission computed tomography (SPECT) imagers based on these detectors usually also have a large number of voxel bins and therefore face memory storage issues for the system matrix when performing fast tomographic reconstructions using iterative algorithms. To address these issues, we have developed a method that parameterizes the detector response to a point source and generates the system matrix on the fly during MLEM or OSEM on graphics hardware. The calibration method, interpolation of coefficient data, and reconstruction results are presented in the context of a recently commissioned small-animal SPECT imager, called FastSPECT III.
PMCID: PMC4520546
Calibration; graphics processing units (GPUs); high-performance computing; image reconstruction; ordered-subset expectation maximization (OSEM); single-photon emission computed tomography (SPECT); system matrix
2.  Functional MRI during Hippocampal Deep Brain Stimulation in the Healthy Rat Brain 
PLoS ONE  2015;10(7):e0133245.
Deep Brain Stimulation (DBS) is a promising treatment for neurological and psychiatric disorders. The mechanism of action and the effects of electrical fields administered to the brain by means of an electrode remain to be elucidated. The effects of DBS have been investigated primarily by electrophysiological and neurochemical studies, which lack the ability to investigate DBS-related responses on a whole-brain scale. Visualization of whole-brain effects of DBS requires functional imaging techniques such as functional Magnetic Resonance Imaging (fMRI), which reflects changes in blood oxygen level dependent (BOLD) responses throughout the entire brain volume. In order to visualize BOLD responses induced by DBS, we have developed an MRI-compatible electrode and an acquisition protocol to perform DBS during BOLD fMRI. In this study, we investigate whether DBS during fMRI is valuable to study local and whole-brain effects of hippocampal DBS and to investigate the changes induced by different stimulation intensities. Seven rats were stereotactically implanted with a custom-made MRI-compatible DBS-electrode in the right hippocampus. High frequency Poisson distributed stimulation was applied using a block-design paradigm. Data were processed by means of Independent Component Analysis. Clusters were considered significant when p-values were <0.05 after correction for multiple comparisons. Our data indicate that real-time hippocampal DBS evokes a bilateral BOLD response in hippocampal and other mesolimbic structures, depending on the applied stimulation intensity. We conclude that simultaneous DBS and fMRI can be used to detect local and whole-brain responses to circuit activation with different stimulation intensities, making this technique potentially powerful for exploration of cerebral changes in response to DBS for both preclinical and clinical DBS.
PMCID: PMC4508110  PMID: 26193653
3.  Medical students' preferences for problem-based learning in relation to culture and personality: a multicultural study 
The aim of this study was to explore positive and negative preferences towards problem-based learning in relation to personality traits and socio-cultural context.
The study was an anonymous and voluntary cross-sectional survey of medical students (N=449) in hybrid problem-based curricula in Nepal, Norway and North Dakota. Data was collected on gender, age, year of study, cohabitation and medical school. The PBL Preference Inventory identified students' positive and negative preferences in relation to problem-based learning; the personality traits were detected by the NEO Five-Factor Inventory. The determinants of the two kinds of preferences were analyzed by hierarchical multiple linear regressions.
Positive preferences were mostly determined by personality; associations were found with the traits Extraversion, Openness to experience, Conscientiousness and Neuroticism; the first three are related to sociability, curiosity and orderliness, the last, to mental health. The learning environments of such curricula may be supportive for some and unnerving for others who score high on Neuroticism. Negative preferences were rather determined by culture, but also, they correlated with Neuroticism and Conscientiousness. Negative preferences were lower among females and students living in symmetrical relationships. Some high on Conscientiousness disliked group work, and the negative correlation with Agreeableness indicated that less sociable students were not predisposed to this kind of learning activity.
Preferences related to problem-based learning were significantly and independently determined both by personality traits and culture. More insights into the nature of students' preferences may guide aspects of curriculum modifications and the daily facilitation of groups.
PMCID: PMC4515359  PMID: 26188962
Small group teaching; interactive skills; student satisfac-tion; learning styles; PBL
4.  A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas 
Investigational new drugs  2008;26(4):369-379.
3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) is a novel small molecule inhibitor of ribonucleotide reductase (RR) with clinical signs of activity in pancreatic cancer. Therefore, the Phase 2 Consortium (P2C) initiated a trial (two single stage studies with planned interim analysis) of 3-AP at 96 mg/m2 intravenously days 1–4 and 15–18 of a 28-day cycle in both chemotherapy-naive and gemcitabine-refractory (GR) patients with advanced pancreatic cancer. The primary endpoint was survival at six months (chemotherapy-naive) and four months (GR). Secondary endpoints were toxicity, response, overall survival, time to progression and mechanistic studies. Fifteen patients were enrolled including one chemotherapy-naïve and 14 GR. The chemotherapy-naïve patient progressed during cycle 1 with grade 3 and 4 toxicities. Of 14 GR patients, seven received two cycles, six received one cycle and one received eight cycles. Progression precluded further treatment in 11 GR patients. Additionally, one died of an ileus in cycle 1 considered related to treatment and two stopped treatment due to toxicity. Five GR patients had grade 4 toxicities possibly related to 3-AP and six GR patients had grade 3 fatigue. Toxicities and lack of meaningful clinical benefit prompted early study closure. Four-month survival in GR patients was 21% (95% CI: 8–58%). Correlative studies confirmed that 3-AP increased the percentage of S-phase buccal mucosal cells, the presence of multidrug resistance gene polymorphisms appeared to predict leukopenia, and baseline pancreatic tumor RR M2 expression was low relative to other tumors treated with 3-AP. In conclusion, this regimen appears inactive against predominantly GR pancreatic cancer. RR M2 protein may not have a critical role in the malignant potential of pancreatic cancer.
PMCID: PMC4461052  PMID: 18278438
Pancreatic cancer; Triapine; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP; Ribonucleotide reductase
5.  The role of biotic forces in driving macroevolution: beyond the Red Queen 
A multitude of hypotheses claim that abiotic factors are the main drivers of macroevolutionary change. By contrast, Van Valen's Red Queen hypothesis is often put forward as the sole representative of the view that biotic forcing is the main evolutionary driver. This imbalance of hypotheses does not reflect our current knowledge: theoretical work demonstrates the plausibility of biotically driven long-term evolution, whereas empirical work suggests a central role for biotic forcing in macroevolution. We call for a more pluralistic view of how biotic forces may drive long-term evolution that is compatible with both phenotypic stasis in the fossil record and with non-constant extinction rates. Promising avenues of research include contrasting predictions from relevant theories within ecology and macroevolution, as well as embracing both abiotic and biotic proxies while modelling long-term evolutionary data. By fitting models describing hypotheses of biotically driven macroevolution to data, we could dissect their predictions and transcend beyond pattern description, possibly narrowing the divide between our current understanding of micro- and macroevolution.
PMCID: PMC4455800  PMID: 25948685
microevolution; macroevolution; Court Jester; theoretical ecology; food-web models; biotic interactions
6.  Targeting RANKL in metastasis 
BoneKEy Reports  2014;3:519.
Acting through its cognate receptor, receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) is an essential mediator of osteoclast function and survival. Preclinical data have now firmly established that blockade of tumor-induced osteoclastogenesis by RANKL inhibition will not only protect against bone destruction but will also inhibit the progression of established bone metastases and delay the formation of de novo bone metastases in cancer models. In patients with bone metastases, skeletal complications are driven by increased osteoclastic activity and may result in pathological fractures, spinal cord compression and the need for radiotherapy to the bone or orthopedic surgery (collectively known as skeletal-related events (SREs)). Denosumab, a fully human monoclonal antibody against RANKL, has been demonstrated to prevent or delay SREs in patients with solid tumors that have metastasized to bone. In addition to its central role in tumor-induced osteolysis, bone destruction and skeletal tumor progression, there is emerging evidence for direct pro-metastatic effects of RANKL, independent of osteoclasts. For example, RANKL also stimulates metastasis via activity on RANK-expressing cancer cells, resulting in increased invasion and migration. Pharmacological inhibition of RANKL may also reduce bone and lung metastasis through blockade of the direct action of RANKL on metastatic cells. This review describes these distinct but potentially overlapping mechanisms by which RANKL may promote metastases.
PMCID: PMC4007167  PMID: 24795813
7.  Irisin – a myth rather than an exercise-inducible myokine 
Scientific Reports  2015;5:8889.
The myokine irisin is supposed to be cleaved from a transmembrane precursor, FNDC5 (fibronectin type III domain containing 5), and to mediate beneficial effects of exercise on human metabolism. However, evidence for irisin circulating in blood is largely based on commercial ELISA kits which are based on polyclonal antibodies (pAbs) not previously tested for cross-reacting serum proteins. We have analyzed four commercial pAbs by Western blotting, which revealed prominent cross-reactivity with non-specific proteins in human and animal sera. Using recombinant glycosylated and non-glycosylated irisin as positive controls, we found no immune-reactive bands of the expected size in any biological samples. A FNDC5 signature was identified at ~20 kDa by mass spectrometry in human serum but was not detected by the commercial pAbs tested. Our results call into question all previous data obtained with commercial ELISA kits for irisin, and provide evidence against a physiological role for irisin in humans and other species.
PMCID: PMC4352853  PMID: 25749243
8.  The differential anti-tumour effects of zoledronic acid in breast cancer – evidence for a role of the activin signaling pathway 
BMC Cancer  2015;15:55.
Neo-adjuvant breast cancer clinical trials of zoledronic acid (ZOL) have shown that patients with oestrogen negative (ER-ve) tumours have improved disease outcomes. We investigated the molecular mechanism behind this differential anti-tumour effect according to ER status, hypothesising it may in part be mediated via the activin signaling pathway.
The effects of activin A, its inhibitor follistatin and zoledronic acid on proliferation of breast cancer cells was evaluated using either an MTS proliferation assay or trypan blue. Secretion of activin A and follistatin in conditioned medium (CM) from MDA-MB-231, MDA-MB-436, MCF7 and T47D cell lines were measured using specific ELISAs. The effects of ZOL on phosphorylation domains of Smad2 (pSmad2c + pSmad2L) were evaluated using immunofluorescence. Changes seen in vitro were confirmed in a ZOL treated subcutaneous ER-ve MDA-MB-436 xenograft model.
Activin A inhibits proliferation of both ER-ve and oestrogen positive (ER + ve) breast cancer cells, an effect impaired by follistatin. ZOL significantly inhibits proliferation and the secretion of follistatin from ER-ve cells only, which increases the biological activity of the canonical activin A pathway by significantly increasing intracellular pSmad2c and decreasing nuclear accumulation of pSmad2L. In vivo, ZOL significantly decreases follistatin and pSmad2L expression in ER-ve subcutaneous xenografts compared to saline treated control animals.
This is the first report showing a differential effect of ZOL, according to ER status, on the activin pathway and its inhibitors in vitro and in vivo. These data suggest a potential molecular mechanism contributing to the differential anti-tumour effects reported from clinical trials and requires further evaluation in clinical samples.
PMCID: PMC4329195  PMID: 25884855
Breast cancer; Zoledronic acid; Activin; Follistatin; Phosphorylated Smad2
9.  A Phase I Study of Vorinostat in Combination with Bortezomib in Patients with Advanced Malignancies 
Investigational new drugs  2013;31(6):1539-1546.
A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors.
Patients received vorinostat orally once daily on days 1–14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m2). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1.
Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m2 to 1.5 mg/m2. The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m2. DLTs consisted of grade 3 fatigue in three patients (1 mg/m2,1.3 mg/m2 and 1.5 mg/m2) and grade 3 hyponatremia in one patient (1.5 mg/m2). The most common grade 1/2 toxicities included nausea (60.9%), fatigue (34.8%), diaphoresis (34.8%), anorexia (30.4%) and constipation (26.1%). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1.
This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily x 14 days and bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle.
PMCID: PMC3901262  PMID: 24114121
SAHA; vorinostat; PS-341; bortezomib; phase I
10.  Zoledronic acid has differential anti-tumour activity in the pre-and post-menopausal bone microenvironment in vivo 
Clinical trials in early breast cancer have suggested that benefits of adjuvant bone targeted treatments are restricted to women with established menopause. We developed models that mimic pre- and post-menopausal status to investigate effects of altered bone turnover on growth of disseminated breast tumour cells. Here we report a differential anti-tumour effect of zoledronic acid (ZOL) in these two settings.
Experimental design
12-week old female Balb/c-nude mice with disseminated MDA-MB-231 breast tumour cells in bone underwent sham operation or ovariectomy (OVX), mimicking the pre- and post-menopausal bone microenvironment, respectively. To determine the effects of bone-targeted therapy, sham/OVX animals received saline or 100ug/kg ZOL weekly. Tumour growth was assessed by in vivo imaging and effects on bone by RT-PCR, microCT, histomorphometry and measurements of bone markers. Disseminated tumour cells were detected by two-photon microscopy.
OVX increased bone resorption and induced growth of disseminated tumour cells in bone. Tumours were detected in 83% of animals following OVX (post-menopausal model) compared to 17% following sham operation (pre-menopausal model). OVX had no effect on tumours outside of bone. OVX-induced tumour growth was completely prevented by ZOL, despite the presence of disseminated tumour cells. ZOL did not affect tumour growth in bone in the sham-operated animals. ZOL increased bone volume in both groups.
This is the first demonstration that tumour growth is driven by osteoclast-mediated mechanisms in models that mimic post-but not pre-menopausal bone, providing a biological rationale for the differential anti-tumour effects of ZOL reported in these settings.
PMCID: PMC4040234  PMID: 24687923
Breast cancer; ménopause; zoledronic acid; mouse models
11.  Subsarcolemmal lipid droplet responses to a combined endurance and strength exercise intervention 
Physiological Reports  2014;2(11):e12187.
Muscle lipid stores and insulin sensitivity have a recognized association although the mechanism remains unclear. We investigated how a 12‐week supervised combined endurance and strength exercise intervention influenced muscle lipid stores in sedentary overweight dysglycemic subjects and normal weight control subjects (n = 18). Muscle lipid stores were measured by magnetic resonance spectroscopy (MRS), electron microscopy (EM) point counting, and direct EM lipid droplet measurements of subsarcolemmal (SS) and intramyofibrillar (IMF) regions, and indirectly, by deep sequencing and real‐time PCR of mRNA of lipid droplet‐associated proteins. Insulin sensitivity and VO2max increased significantly in both groups after 12 weeks of training. Muscle lipid stores were reduced according to MRS at baseline before and after the intervention, whereas EM point counting showed no change in LD stores post exercise, indicating a reduction in muscle adipocytes. Large‐scale EM quantification of LD parameters of the subsarcolemmal LD population demonstrated reductions in LD density and LD diameters. Lipid droplet volume in the subsarcolemmal LD population was reduced by ~80%, in both groups, while IMF LD volume was unchanged. Interestingly, the lipid droplet diameter (n = 10 958) distribution was skewed, with a lack of small diameter lipid droplets (smaller than ~200 nm), both in the SS and IMF regions. Our results show that the SS LD lipid store was sensitive to training, whereas the dominant IMF LD lipid store was not. Thus, net muscle lipid stores can be an insufficient measure for the effects of training.
We have investigated the muscle storage lipids responses to exercise, finding that subsarcolemmal lipid droplets are reduced 80%. Interestingly, we find that the lipid droplet diameter distribution was skewed, with a marked lack of lipid droplets smaller than 200 nm.
PMCID: PMC4255802  PMID: 25413318
Electron microscopy; exercise; insulin sensitivity; lipid droplets; lipophagy; muscle
12.  A phase I study of sorafenib, oxaliplatin and two days of high dose capecitabine in advanced pancreatic and biliary tract cancer: A Wisconsin Oncology Network Study 
Investigational new drugs  2012;31(4):943-948.
Chemotherapy has yielded minimal clinical benefit in pancreatic and biliary tract cancer. A high-dose, short course capecitabine schedule with oxaliplatin, has shown some efficacy with a lower incidence of palmar-plantar erythrodysesthesia. Achieving high exposures of the targeted agent sorafenib may be possible with this shorter schedule of capecitabine by avoiding dermatologic toxicity. All patients had pancreatic or biliary tract cancer. Patients in both cohorts received oxaliplatin 85 mg/m2 followed by capecitabine 2250 mg/m2 PO every 8 hours × 6 doses starting on days 1 and 15 of a 28 day cycle, or 2DOC (2 Day Oxaliplatin/Capecitabine). Cohort 1 used sorafenib 200 mg BID, and cohort 2 used sorafenib 400 mg BID. Sixteen patients were enrolled. Across all cycles the most common grade 1 or 2 adverse events were fatigue (10 pts), diarrhea (10 pts), nausea (9 pts), vomiting (8 pts), sensory neuropathy (8 pts), thrombocytopenia (7 pts), neutropenia (5 pts), and hand-foot syndrome (5 pts). Grade 3 toxicites included neutropenia, mucositis, fatigue, vomiting and diarrhea. Cohort 1 represented the MTD. Two partial responses were seen, one each in pancreatic and biliary tract cancers. The recommended phase II dose of sorafenib in combination with 2DOC is 200 mg BID. There were infrequent grade 3 toxicities, most evident with sorafenib at 400 mg BID.
PMCID: PMC4199231  PMID: 23263993
Pancreatic cancer; bile duct cancer; oxaliplatin; sorafenib; capecitabine; chemotherapy
13.  A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose 
To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of SB-743921 when administered as a 1-h infusion every 21 days to patients with advanced solid tumors or relapsed/refractory lymphoma.
Patients who failed prior standard therapy or those without any standard options were eligible. Forty-four patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase. An additional 20 patients were enrolled at the recommended phase II dose to obtain additional safety and pharmacokinetic data. The doses evaluated ranged from 2 to 8 mg/m2. The pharmacokinetics of SB-743921 was evaluated at 19 time-points over 48 h following during administration during cycle 1. Toxicity was assessed by the NCI Common Terminology Criteria version 3.0. Response evaluation was performed every 6 weeks.
The most common and consistent DLT was neutropenia. Other DLTs observed included hypophosphatemia, pulmonary emboli, SVC syndrome, transaminitis, hyponatremia, and hyperbilirubinemia. The MTD of SB-743921 as a 1-h infusion every 21 days was established as 4 mg/m2. The maximum plasma concentration and area under the plasma concentration time curve appeared to increase proportionally to dose. One durable objective response was seen in a patient with metastatic cholangiocarcinoma who was on treatment 11 months and 6 patients had stable disease for over four cycles.
The recommended phase II dose of SB-743921 on this specific schedule of a 1-h infusion every 3 weeks is 4 mg/m2. The promising efficacy and lack of severe toxicities in this study warrant the continued development of SB-743921.
PMCID: PMC4160065  PMID: 20461380
SB-743921; Phase I; Pharmacokinetics; Kinesin spindle protein; Mitosis; Safety
14.  Modifying the osteoblastic niche with zoledronic acid in vivo—Potential implications for breast cancer bone metastasis 
Bone  2014;66(100):240-250.
Bone metastasis is the most common complication of advanced breast cancer. The associated cancer-induced bone disease is treated with bone-sparing agents like zoledronic acid. Clinical trials have shown that zoledronic acid also reduces breast cancer recurrence in bone; potentially by modifying the bone microenvironment surrounding disseminated tumour cells. We have characterised the early effects of zoledronic acid on key cell types of the metastatic niche in vivo, and investigated how these modify the location of breast tumour cells homing to bone.
Female mice were treated with a single, clinically achievable dose of zoledronic acid (100 μg/kg) or PBS. Bone integrity, osteoclast and osteoblast activity and number/mm trabecular bone on 1, 3, 5 and 10 days after treatment were assessed using μCT, ELISA (TRAP, PINP) and bone histomorphometry, respectively. The effect of zoledronic acid on osteoblasts was validated in genetically engineered mice with GFP-positive osteoblastic cells. The effects on growth plate cartilage were visualised by toluidine blue staining. For tumour studies, mice were injected i.c. with DID-labelled MDA-MB-231-NW1-luc2 breast cancer cells 5 days after zoledronic acid treatment, followed by assessment of tumour cell homing to bone and soft tissues by multiphoton microscopy, flow cytometry and ex vivo cultures.
As early as 3 days after treatment, animals receiving zoledronic acid had significantly increased trabecular bone volume vs. control. This rapid bone effect was reflected in a significant reduction in osteoclast and osteoblast number/mm trabecular bone and reduced bone marker serum levels (day 3–5). These results were confirmed in mice expressing GFP in osteoblastic linage cells. Pre-treatment with zoledronic acid caused accumulation of an extra-cellular matrix in the growth plate associated with a trend towards preferential [1] homing of tumour cells to osteoblast-rich areas of bone, but without affecting the total number of tumour cells. The number of circulating tumour cells was reduced in ZOL treated animals.
A single dose of zoledronic acid caused significant changes in the bone area suggested to contain the metastatic niche. Tumour cells arriving in this modified bone microenvironment appeared to preferentially locate to osteoblast-rich areas, supporting that osteoblasts may be key components of the bone metastasis niche and therefore a potential therapeutic target in breast cancer.
•A single, clinically relevant, dose of zoledronic acid rapidly reduces activity and number of both osteoblasts and osteoclasts in vivo.•This is accompanied by significant increased extra-cellular matrix content in areas of the metaphysis comprising the bone metastatic niche.•Breast cancer cells appear to preferentially home to osteoblast- and extra-cellular matrix rich regions of the metaphysis.•Osteoblasts are suggested to be a key component of the bone metastatic niche.
PMCID: PMC4127787  PMID: 24971713
BP, Bisphosphonate; ECM, Extracellular matrix; GFP, Green fluorescent protein; HSC, Hematopoietic stem cell; NBP, Nitrogen-containing bisphosphonate; PBS, Phosphate buffered saline; ROI, Region of interest; TRAP, Tartrate resistant alkaline phosphatase; PINP, Procollagen type 1N-terminal propeptide; ZOL, Zoledronic acid; Metastatic niche; Osteoblast; Osteoclast; Breast cancer; Homing
15.  Regulation of angiopoietin‐like protein 4 production during and after exercise 
Physiological Reports  2014;2(8):e12109.
Angiopoietin‐like protein 4 (ANGPTL4) may regulate lipoprotein lipase‐dependent plasma clearance of triacylglycerol from skeletal muscle during exercise. The aim of this study was to examine the importance of muscle in regulating ANGPTL4 in response to exercise. We sampled muscle biopsies and serum before, immediately after, and 2 h after 45 min of ergometer cycling. Sampling was done before and after a 12‐week training intervention in controls and dysglycemic subjects. Moreover, fat biopsies were taken before and after the training intervention. The regulation of ANGPTL4 was also investigated in several tissues of exercising mice, and in cultured myotubes. ANGPTL4 levels in serum and expression in muscle were highest 2 h after exercise in both groups. Whereas ANGPTL4 was higher in muscle of exercising controls as compared to dysglycemic subjects, the opposite was observed in serum. In exercising mice, Angptl4 mRNA showed both higher basal expression and induction in liver compared to muscle. Angptl4 mRNA was much higher in adipose tissue than muscle and was also induced by exercise. We observed two mRNA isoforms of ANGPTL4 in muscle and fat in humans. Both were induced by exercise in muscle; one isoform was expressed 5‐ to 10‐fold higher than the other. Studies in mice and cultured myotubes showed that both fatty acids and cortisol have the potential to increase ANGPTL4 expression in muscle during exercise. In conclusion, ANGPTL4 is markedly induced in muscle in response to exercise. However, liver and adipose tissue may contribute more than muscle to the exercise‐induced increase in circulating ANGPTL4.
The Production of ANGPTL4 is markedly induced in skeletal muscle in response to exercise. However, liver and adipose tissue may contribute more than skeletal muscle to the exercise‐induced increase in circulatory ANGPTL4.
PMCID: PMC4246580  PMID: 25138789
Adipose tissue; ANGPTL4; exercise; skeletal muscle
16.  Awareness of Implicit Attitudes 
Research on implicit attitudes has raised questions about how well people know their own attitudes. Most research on this question has focused on the correspondence between measures of implicit attitudes and measures of explicit attitudes, with low correspondence interpreted as showing that people have little awareness of their implicit attitudes. We took a different approach and directly asked participants to predict their results on upcoming IAT measures of implicit attitudes toward five different social groups. We found that participants were surprisingly accurate in their predictions. Across four studies, predictions were accurate regardless of whether implicit attitudes were described as true attitudes or culturally learned associations (Studies 1 and 2), regardless of whether predictions were made as specific response patterns (Study 1) or as conceptual responses (Studies 2–4), and regardless of how much experience or explanation participants received before making their predictions (Study 4). Study 3 further suggested that participants’ predictions reflected unique insight into their own implicit responses, beyond intuitions about how people in general might respond. Prediction accuracy occurred despite generally low correspondence between implicit and explicit measures of attitudes, as found in prior research. All together, the research findings cast doubt on the belief that attitudes or evaluations measured by the IAT necessarily reflect unconscious attitudes.
PMCID: PMC4038711  PMID: 24294868
Implicit attitudes; IAT; introspection; unconscious; racial bias
17.  The role of preclinical SPECT in oncological and neurological research in combination with either CT or MRI 
Preclinical imaging with SPECT combined with CT or MRI is used more and more frequently and has proven to be very useful in translational research. In this article, an overview of current preclinical research applications and trends of SPECT combined with CT or MRI, mainly in tumour imaging and neuroscience imaging, is given and the advantages and disadvantages of the different approaches are described. Today SPECT and CT systems are often integrated into a single device (commonly called a SPECT/CT system), whereas at present combined SPECT and MRI is almost always carried out with separate systems and fiducial markers to combine the separately acquired images. While preclinical SPECT/CT is most widely applied in oncology research, SPECT combined with MRI (SPECT/MRI when integrated in one system) offers the potential for both neuroscience applications and oncological applications. Today CT and MRI are still mainly used to localize radiotracer binding and to improve SPECT quantification, although both CT and MRI have additional potential. Future technology developments may include fast sequential or simultaneous acquisition of (dynamic) multimodality data, spectroscopy, fMRI along with high-resolution anatomic MRI, advanced CT procedures, and combinations of more than two modalities such as combinations of SPECT, PET, MRI and CT all together. This will all strongly depend on new technologies. With further advances in biology and chemistry for imaging molecular targets and (patho)physiological processes in vivo, the introduction of new imaging procedures and promising new radiopharmaceuticals in clinical practice may be accelerated.
PMCID: PMC4003405
18.  Vorinostat in Combination with Bortezomib in Patients with Advanced Malignancies Directly Alters Transcription of Target Genes 
Vorinostat is a small molecule inhibitor of class I and II histone deacetylase (HDAC) enzymes which alters expression of target genes including the cell cycle gene p21, leading to cell cycle arrest and apoptosis.
Patients enrolled in a phase I trial were treated with vorinostat alone on day 1 and vorinostat and bortezomib in combination on day 9. Paired biopsies were obtained in eleven subjects. Blood samples were obtained on days 1 and 9 of cycle 1 prior to dosing, and 2 hours and 6 hours post dosing in all 60 subjects. Gene expression of p21, HSP70, AKT, nur77, ERB1 and ERB2 were evaluated in peripheral blood mononuclear cells and tissue samples. Chromatin immunoprecipitation of p21, HSP70 and Nur77 was also performed in biopsy samples.
In peripheral blood mononuclear cells, Nur77 was significantly and consistently decreased two hours after vorinostat administration on both days 1 and 9, median ratio of gene expression relative to baseline of 0.69 with interquartile range (IQR) 0.49-1.04 (p<0.001); 0.28 (0.15-0.7) (p<0.001), respectively, with more pronounced decrease on day 9, when patients received both vorinostat and bortezomib. p21, a downstream target of nur77, was significantly decreased on day 9 two hours and six hours after administration of vorinostat and bortezomib, 0.67 (0.41-1.03) (p<0.01); 0.44 (0.25-1.3) (p<0.01), respectively. The ChiP assay demonstrateed a protein DNA interaction, in this case interaction of Nur77, HSP70 and p21 with acetylated histone H3, at baseline and at day 9 after treatment with vorinostat in tissue biopsies in most patients.
Vorinostat inhibits Nur77 expression, which in turn may decrease p21 and AKT expression in PBMCs. The influence of vorinostat on target gene expression in tumor tissue was variable, however, most patients demonstrated interaction of acetylated H3 with Nur77, HSP70 and p21 which provides evidence of interaction with the transcriptions active acetylated H3.
PMCID: PMC3926898  PMID: 23903894
SAHA; vorinostat; PS-341; bortezomib; phase I
19.  Disentangling taste and toxicity in aposematic prey 
Many predators quickly learn to avoid attacking aposematic prey. If the prey vary in toxicity, the predators may alternatively learn to capture and taste-sample prey carefully before ingesting or rejecting them (go-slow behaviour). An increase in prey toxicity is generally thought to decrease predation on prey populations. However, while prey with a higher toxin load are more harmful to ingest, they may also be easier to recognize and reject owing to greater distastefulness, which can facilitate a taste-sampling foraging strategy. Here, the classic diet model is used to study the separate effects of taste and toxicity on predator preferences. The taste-sampling process is modelled using signal detection theory. The model is applicable to automimicry and Batesian mimicry. It shows that when the defensive toxin is sufficiently distasteful, a mimicry complex may be less profitable to the predator and better protected against predation if the models are moderately toxic than if they are highly toxic. Moreover, taste mimicry can reduce the profitability of the mimicry complex and increase protection against predation. The results are discussed in relation to the selection pressures acting on prey defences and the evolution of mimicry.
PMCID: PMC3574352  PMID: 23256198
predation; taste-rejection; toxin; aposematism; Batesian mimicry; automimicry
20.  Gender and offender status predicting treatment success in refugees and asylum seekers with PTSD 
European Journal of Psychotraumatology  2014;5:10.3402/ejpt.v5.20803.
Current knowledge is limited regarding patient characteristics related to treatment outcome of posttraumatic stress disorders (PTSD) in refugees and asylum seekers.
Gender, torture status, offender status, level of anger, and level of depression were investigated for possible effects on the treatment outcome.
Patient characteristics were explored in 54 refugees and asylum seekers who had completed a treatment program for PTSD. Non-responders (10), those who had the same or higher levels of symptom severity after treatment, were compared with responders, those who had lower symptom severity after treatment (44). Symptom severity was measured by Clinician-Administered PTSD Scale. The non-responders and responders constituted the dichotomous, dependent variable. The independent variables were gender, torture status, offender status, level of anger, and level of depression. T-tests and Exact Unconditional Homogeneity/Independence Tests for 2×2 Tables were used to study the relationship to treatment outcome.
Being male and reporting to have been a violent offender were significantly more frequent characteristics among the non-responders compared to the responders. The levels of pretreatment anger, depression and torture status did not affect the treatment outcome.
The study adds support to findings that females benefit more from treatment of PTSD than males and that violent offenders are difficult to treat within the standard treatment programs.
PMCID: PMC3909238  PMID: 24494062
Treatment; patient characteristics; gender; offender; trauma; torture
21.  An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma 
Investigational new drugs  2010;30(1):387-394.
Background and Rationale Bortezomib
(PS-341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitinproteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients.
The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted.
Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1–12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months.
This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib.
PMCID: PMC3896232  PMID: 20839030
Boronic acids; Antineoplastic agents; Biologic agents; Treatment outcome
22.  Phase 2 Study of Bevacizumab Plus Erlotinib in Patients With Advanced Hepatocellular Cancer 
Cancer  2011;118(9):2424-2430.
Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC).
Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child’s Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point.
Twenty-seven patients with advanced HCC (median age, 60 years) were enrolled in this multi-institutional study. The proportion of patients with Child’s A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8-7.1). Median survival time was 9.5 months (95% CI, 7.1-17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea.
In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression-free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients.
PMCID: PMC3896238  PMID: 21953248
hepatocellular cancer; erlotinib; bevacizumab; vascular endothelial growth factor; epidermal growth factor receptor
23.  Nondirective meditation activates default mode network and areas associated with memory retrieval and emotional processing 
Nondirective meditation techniques are practiced with a relaxed focus of attention that permits spontaneously occurring thoughts, images, sensations, memories, and emotions to emerge and pass freely, without any expectation that mind wandering should abate. These techniques are thought to facilitate mental processing of emotional experiences, thereby contributing to wellness and stress management. The present study assessed brain activity by functional magnetic resonance imaging (fMRI) in 14 experienced practitioners of Acem meditation in two experimental conditions. In the first, nondirective meditation was compared to rest. Significantly increased activity was detected in areas associated with attention, mind wandering, retrieval of episodic memories, and emotional processing. In the second condition, participants carried out concentrative practicing of the same meditation technique, actively trying to avoid mind wandering. The contrast nondirective meditation > concentrative practicing was characterized by higher activity in the right medial temporal lobe (parahippocampal gyrus and amygdala). In conclusion, the present results support the notion that nondirective meditation, which permits mind wandering, involves more extensive activation of brain areas associated with episodic memories and emotional processing, than during concentrative practicing or regular rest.
PMCID: PMC3935386  PMID: 24616684
fMRI; meditation; attention; nondirective; brain; default mode network; mind wandering
24.  Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders 
Mutations in ATP13A2 lead to Kufor-Rakeb syndrome, a parkinsonism with dementia. ATP13A2 belongs to the P-type transport ATPases, a large family of primary active transporters that exert vital cellular functions. However, the cellular function and transported substrate of ATP13A2 remain unknown. To discuss the role of ATP13A2 in neurodegeneration, we first provide a short description of the architecture and transport mechanism of P-type transport ATPases. Then, we briefly highlight key P-type ATPases involved in neuronal disorders such as the copper transporters ATP7A (Menkes disease), ATP7B (Wilson disease), the Na+/K+-ATPases ATP1A2 (familial hemiplegic migraine) and ATP1A3 (rapid-onset dystonia parkinsonism). Finally, we review the recent literature of ATP13A2 and discuss ATP13A2's putative cellular function in the light of what is known concerning the functions of other, better-studied P-type ATPases. We critically review the available data concerning the role of ATP13A2 in heavy metal transport and propose a possible alternative hypothesis that ATP13A2 might be a flippase. As a flippase, ATP13A2 may transport an organic molecule, such as a lipid or a peptide, from one membrane leaflet to the other. A flippase might control local lipid dynamics during vesicle formation and membrane fusion events.
PMCID: PMC4033846  PMID: 24904274
alpha-synuclein; mitochondria; mitophagy; lysosome; dystonia; parkinsonism; flippase; heavy metal toxicity
25.  Estimating the prevalence and burden of major disorders of the brain in Nepal: methodology of a nationwide population-based study 
The major disorders of the brain (MDBs), in terms of their prevalence and the burdens of ill health, disability and financial cost that they impose on individuals and society, are headache, depression and anxiety. No population-based studies have been conducted in Nepal.
Our purpose was to assess the prevalence and burden attributable to MDBs in Nepal in order to inform health policy. Here we report the methodology.
The unusual sociocultural diversity and extreme geographical variation of the country required adaptation of standard methodology. We ran pre-pilot and pilot studies before embarking on the main study. The study design was cross-sectional. The population of interest were adults aged 18–65 years who were Nepali speaking and living in Nepal. We selected, employed and trained groups of interviewers to visit randomly selected households by cold-calling. Households were selected from 15 representative districts out of 75 in the country through multistage cluster sampling. One participant was selected randomly from each household. We used structured questionnaires (the HARDSHIP questionnaire, Hospital Anxiety and Depression Scale, and Eysenck Personality Questionnaire -Neuroticism), culturally adapted and translated into Nepali. We recorded blood pressure, weight, height and waist circumference, and altitude of each household. We implemented various quality-assurances measures.
We completed the survey in one month, prior to onset of the monsoon. Among 2,210 selected households, all were contacted, 2,109 were eligible for the study and, from these, 2,100 adults participated. The participation rate was 99.6%.
Standard methodology was successfully applied in Nepal, with some adaptations. The sociocultural and extraordinary geographic diversity were challenging, but did not require us to compromise the scientific quality of the study.
PMCID: PMC4144696  PMID: 25146939
Anxiety; Depression; Headache; Migraine; Prevalence; Burden of disease; Global campaign against Headache

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