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1.  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
Breast cancer; Zoledronic acid; Activin; Follistatin; Phosphorylated Smad2
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  Estimating prevalence and burden of major disorders of the brain in Nepal: cultural, geographic, logistic and philosophical issues of methodology 
Headache, anxiety and depression are major disorders of the brain in terms of their prevalence and the burdens and costs they impose on society. Nationwide population-based studies of these disorders are necessary to inform health policy but, in research-naïve and resource-poor countries such as Nepal, a host of methodological problems are encountered: cultural, geographic, logistic and philosophical.
Expert consensus was sought among researchers from different professional and cultural backgrounds in planning and conceptualizing an epidemiological study and adapting established methods to the special situation and circumstances of Nepal.
The methodological problems were sorted into different themes: study design; climate; geography, access and transport; sociocultural issues; safety of interviewers. Each of these was dealt with separately, and their inter-relationships explored, in finding solutions that were sometimes pragmatic. A cross-sectional questionnaire-based study, with teams of interviewers visiting households across the three physiographic divisions (with extremes in altitude) in each of the five development regions of the country, would enable national sampling with sociocultural representativeness. However, the study instruments and interviews would be in Nepali only. Transport and access challenges were considerable, and their solutions combined travel by air, bus, river and foot, with allowances for rain-damaged roads, collapsed bridges and cancelled scheduled flights. The monsoon would render many routes impassable, and therefore set an absolute time limitation. Engaging participants willingly in the enquiry would be the key to success, and several tactics would be employed to enhance the success of this, most importantly enlisting the support of local community volunteers in each study site.
Anticipating problems in advance of investing substantial resources in a large nationwide epidemiological study in Nepal was a sensible precaution. The difficulties could be resolved or circumvented without expected compromise in scientific quality. Expert consensus was an effective means of achieving this outcome.
PMCID: PMC4149310  PMID: 25127664
Nepal; Burden of disease; Population-based survey; Headache; Anxiety; Depression; Global campaign against headache
22.  An Assessment of Biases Against Latinos and African Americans Among Primary Care Providers and Community Members 
American journal of public health  2012;103(1):10.2105/AJPH.2012.300812.
This study assessed implicit and explicit bias against both Latinos and African Americans, among experienced primary care providers (PCPs) and community members (CMs) in the same geographic area.
210 PCPs and 190 CMs from three health care organizations in the Denver metro area completed Implicit Association Tests and self-report measures of implicit and explicit bias, respectively.
With a 60% participation rate, the PCPs demonstrated substantial implicit bias against both Latinos and African Americans, but this was no different from CMs. Explicit bias was largely absent in both groups. Adjustment for background characteristics showed the PCPs to have slightly weaker ethnic/racial bias than CMs.
This research provides the first evidence of implicit bias against Latinos in health care, as well as confirming prior findings of implicit bias against African Americans. The lack of substantive differences in bias between the experienced PCPs and CMs suggests a wider societal problem. At the same time, the wide range of implicit bias suggests that bias in healthcare is neither uniform nor inevitable, and important lessons may be learned from providers who do not exhibit bias.
PMCID: PMC3518332  PMID: 23153155
23.  Competitive cobalt for zinc substitution in mammalian methionine sulfoxide reductase B1 overexpressed in E. coli: structural and functional insight 
Expression of the mammalian enzyme methionine sulfoxide reductase B1 (MsrB1) in Escherichia coli growing in cobalt-containing media resulted in the reproducible appearance of the stable cobalt-containing protein MsrB1-Co. NMR studies and biocomputing using the programs AnisoFit and Amber allowed us to generate a structure of MsrB1-Co sharing the overall fold with the native zinc-containing protein MsrB1-Zn. Our data suggest that the N-terminus containing resolving cysteine tends to be closer to the protein’s catalytic center than was previously reported. It is argued that this proximity supports the proposed catalytic mechanism and ensures high catalytic efficiency of MsrB1. Functional studies showed that both MsrB1-Zn and MsrB1-Co exhibit similar levels of activity, in agreement with the structural studies performed. The proposed metal ion substitution approach may have a methodological significance in determining whether methionine sulfoxide reductase B proteins contain a metal ion.
Electronic supplementary material
The online version of this article (doi:10.1007/s00775-013-1064-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3889830  PMID: 24271273
Cell metabolism; Metal homeostasis; Metalloenzymes; Protein–metal ion interaction; NMR
24.  Important challenges for coordination and inter-municipal cooperation in health care services: a Delphi study 
Demographical changes have stimulated a coordination reform in the Norwegian health care sector, creating new working practices and extending coordination within and between primary and hospital care, increasing the need for inter-municipal cooperation (IMC). This study aimed to identify challenges to coordination and IMC in the Norwegian health care sector as a basis for further theorizing and managerial advice in this growing area of research and practice.
A Delphi study of consensus development was used. Experts in coordination and IMC in health care services were selected by the healthcare manager or the councillor in their respective municipalities. In the first round, an expert panel received open-ended questions addressing possible challenges, and their answers were categorized and consolidated as the basis for further validation in the second round. The expert panel members were then asked to point out important statements in the third round, before the most important statements ranked by a majority of the members were rated again in the fourth round, including the option to explain the ratings. The same procedure was used in round five, with the exception that the expert panel members could view the consolidated results of their previous rankings as the basis for a new and final rating. The statements reaching consensus in round five were abstracted and themed.
Nineteen experts consented to participate. Nine experts (47%) completed all of the five rounds. Eight statements concerning coordination reached consensus, resulting in four themes covering these challenges: different culture, uneven balance of power, lack of the possibility to communicate electronically, and demanding tasks in relation to resources. Three statements regarding challenges to IMC reached consensus, resulting in following themes: coopetition, complex leadership, and resistance to change.
This study identified several important challenges for coordination and it supports previous research. IMC in health care services deals with challenges other than coordination, and these must be addressed specifically. Our study contributes to extended knowledge of theoretical and practical implications in the field of coordination and IMC in health care sector.
PMCID: PMC4228434  PMID: 24171839
IMC; Delphi; Coordination; Cooperation; Municipality; Health; Reform
25.  Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer 
Eccles, Suzanne A | Aboagye, Eric O | Ali, Simak | Anderson, Annie S | Armes, Jo | Berditchevski, Fedor | Blaydes, Jeremy P | Brennan, Keith | Brown, Nicola J | Bryant, Helen E | Bundred, Nigel J | Burchell, Joy M | Campbell, Anna M | Carroll, Jason S | Clarke, Robert B | Coles, Charlotte E | Cook, Gary JR | Cox, Angela | Curtin, Nicola J | Dekker, Lodewijk V | dos Santos Silva, Isabel | Duffy, Stephen W | Easton, Douglas F | Eccles, Diana M | Edwards, Dylan R | Edwards, Joanne | Evans, D Gareth | Fenlon, Deborah F | Flanagan, James M | Foster, Claire | Gallagher, William M | Garcia-Closas, Montserrat | Gee, Julia M W | Gescher, Andy J | Goh, Vicky | Groves, Ashley M | Harvey, Amanda J | Harvie, Michelle | Hennessy, Bryan T | Hiscox, Stephen | Holen, Ingunn | Howell, Sacha J | Howell, Anthony | Hubbard, Gill | Hulbert-Williams, Nick | Hunter, Myra S | Jasani, Bharat | Jones, Louise J | Key, Timothy J | Kirwan, Cliona C | Kong, Anthony | Kunkler, Ian H | Langdon, Simon P | Leach, Martin O | Mann, David J | Marshall, John F | Martin, Lesley Ann | Martin, Stewart G | Macdougall, Jennifer E | Miles, David W | Miller, William R | Morris, Joanna R | Moss, Sue M | Mullan, Paul | Natrajan, Rachel | O’Connor, James PB | O’Connor, Rosemary | Palmieri, Carlo | Pharoah, Paul D P | Rakha, Emad A | Reed, Elizabeth | Robinson, Simon P | Sahai, Erik | Saxton, John M | Schmid, Peter | Smalley, Matthew J | Speirs, Valerie | Stein, Robert | Stingl, John | Streuli, Charles H | Tutt, Andrew N J | Velikova, Galina | Walker, Rosemary A | Watson, Christine J | Williams, Kaye J | Young, Leonie S | Thompson, Alastair M
Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.
More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.
The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working.
With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.
PMCID: PMC3907091  PMID: 24286369

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