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2.  Profiling Bortezomib Resistance Identifies Secondary Therapies in a Mouse Myeloma Model 
Molecular cancer therapeutics  2013;12(6):1140-1150.
Multiple myeloma is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. Although the first-to-market proteasome inhibitor bortezomib (Velcade) has been successfully used to treat patients with myeloma, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive (BzS) and bortezomib-resistant (BzR) cell lines created from the Bcl-XL/Myc double-transgenic mouse model of multiple myeloma. Notably, these BzR cell lines show cross-resistance to the next-generation proteasome inhibitors, MLN2238 and carfilzomib (Kyprolis) but not to other antimyeloma drugs. We further characterized the response to bortezomib using the Connectivity Map database, revealing a differential response between these cell lines to histone deacetylase (HDAC) inhibitors. Furthermore, in vivo experiments using the HDAC inhibitor panobinostat confirmed that the predicted responder showed increased sensitivity to HDAC inhibitors in the BzR line. These findings show that GEP may be used to document bortezomib resistance in myeloma cells and predict individual sensitivity to other drug classes. Finally, these data reveal complex heterogeneity within multiple myeloma and suggest that resistance to one drug class reprograms resistant clones for increased sensitivity to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy for patients with multiple myeloma.
PMCID: PMC4076840  PMID: 23536725
3.  Genetic Signature of Histiocytic Sarcoma Revealed by a Sleeping Beauty Transposon Genetic Screen in Mice 
PLoS ONE  2014;9(5):e97280.
Histiocytic sarcoma is a rare, aggressive neoplasm that responds poorly to therapy. Histiocytic sarcoma is thought to arise from macrophage precursor cells via genetic changes that are largely undefined. To improve our understanding of the etiology of histiocytic sarcoma we conducted a forward genetic screen in mice using the Sleeping Beauty transposon as a mutagen to identify genetic drivers of histiocytic sarcoma. Sleeping Beauty mutagenesis was targeted to myeloid lineage cells using the Lysozyme2 promoter. Mice with activated Sleeping Beauty mutagenesis had significantly shortened lifespan and the majority of these mice developed tumors resembling human histiocytic sarcoma. Analysis of transposon insertions identified 27 common insertion sites containing 28 candidate cancer genes. Several of these genes are known drivers of hematological neoplasms, like Raf1, Fli1, and Mitf, while others are well-known cancer genes, including Nf1, Myc, Jak2, and Pten. Importantly, several new potential drivers of histiocytic sarcoma were identified and could serve as targets for therapy for histiocytic sarcoma patients.
PMCID: PMC4020815  PMID: 24827933
4.  Peri-gestational Dietary Folic Acid Deficiency Protects Against Medulloblastoma Formation in a Mouse Model of Nevoid Basal Cell Carcinoma Syndrome 
Nutrition and cancer  2013;65(6):857-865.
Hereditary nevoid basal cell carcinoma syndrome (NBCCS) is caused by PTCH1 gene mutations that result in diverse neoplasms including medulloblastoma (MB). Epidemiological studies report reduced pediatric brain tumor risks associated with maternal intake of prenatal vitamins containing folic acid (FA) and FA supplements specifically. We hypothesized that low maternal FA intake during the peri-gestational period would increase MB incidence in a transgenic NBCCS mouse model, which carries an autosomal dominant mutation in the Ptch1 gene. Female wild-type C57BL/6 mice (n=126) were randomized to one of three diets with differing FA amounts: 0.3 mg/kg (low), 2.0 mg/kg (control), and 8.0 mg/kg (high) one month prior to mating with Ptch1+/− C57BL/6 males. Females were maintained on the diet until pup weaning; the pups were then aged for tumor development. Compared to the control group, offspring MB incidence was significantly lower in the low FA group (Hazard Ratio (HR)=0.47; 95% confidence interval (CI) 0.27–0.80) at one year. No significant difference in incidence was observed between the control and high FA groups. Low maternal peri-gestational FA levels may decrease MB incidence in mice genetically predisposed to tumor development. Our results could have implications for prenatal FA intake recommendations in the presence of cancer syndromes.
PMCID: PMC3771499  PMID: 23909730
5.  Utilization of Translational Bioinformatics to Identify Novel Biomarkers of Bortezomib Resistance in Multiple Myeloma 
Journal of Cancer  2014;5(9):720-727.
Multiple myeloma (MM) is an incurable malignant neoplasm hallmarked by a clonal expansion of plasma cells, the presence of a monoclonal protein in the serum and/or urine (M-spike), lytic bone lesions, and end organ damage. Clinical outcomes for patients with MM have improved greatly over the last decade as a result of the re-purposing of compounds such as thalidomide derivatives, as well as the development of novel chemotherapeutic agents including first and second generation proteasome inhibitors, bortezomib (Bz) and carfilzomib. Unfortunately, despite these improvements, the majority of patients relapse following treatment. While Bz, one of the most commonly used proteasome inhibitors, has been successfully incorporated into clinical practice, some MM patients have de novo resistance to Bz, and the majority of the remainder subsequently develop drug resistance following treatment. A significant gap in clinical care is the lack of a reliable clinical test that would predict which MM patients have or will subsequently develop Bz resistance. Thus, as Bz resistance remains a significant challenge, research efforts are needed to identify novel biomarkers of early Bz resistance, particularly when an early therapeutic intervention can be initiated. Recent advances in MM research indicate that genomic data can be extracted to identify novel biomarkers that can be utilized to select more effective, personalized treatment protocols for individual patients. Computationally integrating large patient databases with data from whole transcriptome profiling and laboratory-based models can potentially revolutionize our understanding of MM disease mechanisms. This systems-wide approach can provide rational therapeutic targets and novel biomarkers of risk and treatment response. In this review, we discuss the use of high-content datasets (predominantly gene expression profiling) to identify novel biomarkers of treatment response and resistance to Bz in MM.
PMCID: PMC4216795  PMID: 25368671
Multiple myeloma; biomarkers
6.  Bortezomib Resistance Can Be Reversed by Induced Expression of Plasma Cell Maturation Markers in a Mouse In Vitro Model of Multiple Myeloma 
PLoS ONE  2013;8(10):e77608.
Multiple myeloma (MM), the second most common hematopoietic malignancy, remains an incurable plasma cell (PC) neoplasm. While the proteasome inhibitor, bortezomib (Bz) has increased patient survival, resistance represents a major treatment obstacle as most patients ultimately relapse becoming refractory to additional Bz therapy. Current tests fail to detect emerging resistance; by the time patients acquire resistance, their prognosis is often poor. To establish immunophenotypic signatures that predict Bz sensitivity, we utilized Bz-sensitive and -resistant cell lines derived from tumors of the Bcl-XL/Myc mouse model of PC malignancy. We identified significantly reduced expression of two markers (CD93, CD69) in “acquired” (Bz-selected) resistant cells. Using this phenotypic signature, we isolated a subpopulation of cells from a drug-naïve, Bz-sensitive culture that displayed “innate” resistance to Bz. Although these genes were identified as biomarkers, they may indicate a mechanism for Bz-resistance through the loss of PC maturation which may be induced and/or selected by Bz. Significantly, induction of PC maturation in both “acquired” and “innate” resistant cells restored Bz sensitivity suggesting a novel therapeutic approach for reversing Bz resistance in refractory MM.
PMCID: PMC3812176  PMID: 24204892
7.  Targeted overexpression of an activated N-ras gene results in B- and plasma cell lymphoproliferation and cooperates with c-myc to induce fatal B-cell neoplasia 
Experimental Hematology  2011;40(3):216-227.
Multiple myeloma (MM) is an incurable malignant expansion of plasma cells in the bone marrow. Although there is no pathognomonic genetic lesion among MM patients, activation of the ras gene has been identified as a common mutation. We have previously described the use of the 3′ kappa immunoglobulin light chain enhancer (3′KE) to target transgenic expression in murine B- and plasma cells, resulting in bcl-XL and c-myc driven murine models of MM. In this report, we characterize the role of activated mutant N-ras in B- and plasma cells in transgenic mice. We constructed transgenic mice that use the 3′KE to direct expression of a mutant activated N-ras. We also crossed the N-ras mice to mice bearing a c-myc transgene to study the cooperative effects of the transgenic constructs. Mice were sacrificed when moribund or at specific time intervals and characterized by serology, light microscopy, and flow cytometry. The transgenic N-ras animals develop B- and plasma cell lymphoproliferation, and aged mice develop immunoglobulinemia, renal hyaline tubular casts, and microscopic foci of abnormal plasma cells in extramedullary sites, including the liver and kidney. Bitransgenic 3′KE/N-Ras V12 x Eμ-c-Myc mice develop fatal B-cell neoplasia with a median survival of 10 weeks. These data indicate that activated N-ras can play a role in B- and plasma cell homeostasis and that activated N-Ras and c-Myc can cooperate to induce B-cell neoplasia.
PMCID: PMC3279594  PMID: 22120021
Multiple Myeloma; Lymphoma; N-Ras; oncogenes
8.  Standardization of the Korean Version of the Posttraumatic Embitterment Disorder Self-Rating Scale 
Psychiatry Investigation  2012;9(4):368-372.
Embitterment is a persistent feeling of being let down or insulted, feeling like a "loser", or feeling revengeful but helpless. In South Korea, social injustice experienced during rapid industrial development and protracted unemployment during the Asian economic crisis may lead to strong feelings of embitterment. North Korean defectors and victims of industrial disasters may also experience humiliation and feelings of injustice. Posttraumatic Embitterment Disorder (PTED) is a recent conceptualization of a new psychiatric disorder. This study tested the reliability and validation of the Korean version of the PTED Scale.
Subjects aged 18 years or older were recruited from a psychiatric outpatient clinic. All subjects were diagnosed with a depressive disorder. Subjects completed the Korean version of the PTED Scale, the Patient Health Questionnaire (PHQ-9) and the Patient Health Questionnaire (PHQ-15) at baseline and two weeks later.
Approximately 15.4% of subjects could be categorized as having PTED. The test-retest reliability of the PTED Scale was good (r=0.76) and the internal consistency was very high (Cronbach's alpha=0.962). Positive correlations were found between the PTED Scale, the PHQ-9 and the PHQ-15, indicating substantial convergent validity of the PTED Scale.
The Korean version of the PTED Scale is a reliable and valid measurement of embitterment in Korean adults as an emotional reaction to a negative life event.
PMCID: PMC3521113  PMID: 23251201
Embitterment; PTED; PHQ-9; PHQ-15
9.  Statistical Methods for Tissue Array Images – Algorithmic Scoring and Co-training 
The annals of applied statistics  2012;6(3):1280-1305.
Recent advances in tissue microarray technology have allowed immunohistochemistry to become a powerful medium-to-high throughput analysis tool, particularly for the validation of diagnostic and prognostic biomarkers. However, as study size grows, the manual evaluation of these assays becomes a prohibitive limitation; it vastly reduces throughput and greatly increases variability and expense. We propose an algorithm—Tissue Array Co-Occurrence Matrix Analysis (TACOMA)—for quantifying cellular phenotypes based on textural regularity summarized by local inter-pixel relationships. The algorithm can be easily trained for any staining pattern, is absent of sensitive tuning parameters and has the ability to report salient pixels in an image that contribute to its score. Pathologists’ input via informative training patches is an important aspect of the algorithm that allows the training for any specific marker or cell type. With co-training, the error rate of TACOMA can be reduced substantially for a very small training sample (e.g., with size 30). We give theoretical insights into the success of co-training via thinning of the feature set in a high dimensional setting when there is “sufficient” redundancy among the features. TACOMA is flexible, transparent and provides a scoring process that can be evaluated with clarity and confidence. In a study based on an estrogen receptor (ER) marker, we show that TACOMA is comparable to, or outperforms, pathologists’ performance in terms of accuracy and repeatability.
PMCID: PMC3441061  PMID: 22984376
10.  Acute Appendicitis in a Man Undergoing Therapy for Mantle Cell Lymphoma 
Case Reports in Hematology  2012;2012:868151.
A 71-year-old man was diagnosed with an aggressive mantle cell lymphoma and was started on six cycles of R-CHOP chemotherapy. Approximately two weeks after starting his first cycle of chemotherapy, he complained of severe right lower quadrant abdominal pain, and an abdominal CT scan demonstrated an enlarged appendix with evidence of contained perforation. The man underwent open appendectomy for acute appendicitis and recovered. The appendectomy specimen was submitted for routine pathological analysis. There was histologic evidence of perforation in association with an inflammatory infiltrate with fibrin adhered to the serosal surface; scattered small lymphoid aggregates were present on the mucosal surface. Although the lymphoid aggregates in the submucosa and lamina propria were rather unremarkable by routine histologic examination, immunohistochemistry revealed the lymphocytes to be predominantly Cyclin D1-overexpressing B cells. To our knowledge, this is the first reported case of acute appendicitis in association with appendiceal involvement by mantle cell lymphoma.
PMCID: PMC3420562  PMID: 22953079
11.  Early reduction in painful physical symptoms is associated with improvements in long-term depression outcomes in patients treated with duloxetine 
BMC Psychiatry  2011;11:150.
To investigate the association of the change of painful physical symptoms (PPS) after 4 weeks, with the 6-month treatment outcomes of depressive symptoms in patients treated with duloxetine in clinical practice.
Multicenter, prospective, 6-month, non-interventional study in adult outpatients with a depressive episode and starting treatment with duloxetine. Depression severity was assessed by the clinician (Inventory for Depressive Symptomatology [IDS-C]) and patient (Kurz-Skala Stimmung/Aktivierung [KUSTA]). Somatic symptoms and PPS were assessed using the patient-rated Somatic Symptom Inventory (SSI) and visual analog scales (VAS) for pain items. Association of change in PPS with outcomes of depressive symptoms was analyzed based on mean KUSTA scores (mean of items mood, activity, tension/relaxation, sleep) and achievement of a 50% reduction in the total IDS-C score after 6 months using linear and logistic regression models, respectively.
Of the 4,517 patients enrolled (mean age: 52.2 years, 71.8% female), 3,320 patients (73.5%) completed the study. 80% of the patients had moderate to severe overall pain (VAS > 30 mm) at baseline. A 50% VAS overall pain reduction after 4 weeks was associated with a 13.32 points higher mean KUSTA score after 6 months, and a 50% pain reduction after 2 weeks with a 6.33 points improvement. No unexpected safety signals were detected in this naturalistic study.
Pain reduction after 2 and 4 weeks can be used to estimate outcomes of long-term treatment with duloxetine. PPS associated with depression have a potential role in predicting remission of depressive symptoms in clinical practice.
PMCID: PMC3184053  PMID: 21933428
Depression; painful physical symptoms; non-interventional study; duloxetine
12.  Association of a Single-Nucleotide Polymorphism in CD40 With the Rate of Joint Destruction in Rheumatoid Arthritis 
Arthritis and rheumatism  2009;60(8):2242-2247.
The severity of joint destruction in rheumatoid arthritis (RA) is highly variable from patient to patient and is influenced by genetic factors. Genome-wide association studies have enormously boosted the field of the genetics of RA susceptibility, but risk loci for RA severity remain poorly defined. A recent meta-analysis of genome-wide association studies identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, KIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14. The purpose of this study was to investigate whether these newly described genetic regions are associated with the rate of joint destruction.
RA patients enrolled in the Leiden Early Arthritis Clinic were studied (n = 563). Yearly radiographs were scored using the Sharp/van der Heijde method (median followup 5 years; maximum followup 9 years). The rate of joint destruction between genotype groups was compared using a linear mixed model, correcting for age, sex, and treatment strategies. A total of 393 anti–citrullinated protein antibody (ACPA)–positive RA patients from the North American Rheumatoid Arthritis Consortium (NARAC) who had radiographic data available were used for the replication study.
The TT and CC/CG genotypes of 2 single-nucleotide polymorphisms, rs4810485 (CD40) and rs42041 (CDK6), respectively, were associated with a higher rate of joint destruction in ACPA-positive RA patients (P = 0.003 and P = 0.012, respectively), with rs4810485 being significant after Bonferroni correction for multiple testing. The association of the CD40 minor allele with the rate of radiographic progression was replicated in the NARAC cohort (P = 0.021).
A polymorphism in the CD40 locus is associated with the rate of joint destruction in patients with ACPA-positive RA. Our findings provide one of the first non–HLA-related genetic severity factors that has been replicated.
PMCID: PMC3121053  PMID: 19644859
13.  A Randomised Controlled Experimental Study on the Influence of Patient Age on Medical Decisions in Respect to the Diagnosis and Treatment of Depression in the Elderly 
Background. Elderly patients are often treated differently than younger patients, even when suffering from the same disorder. Objective. The study examines the influence of “patient age” on the perception of symptoms and conclusions of physicians in respect to diagnosis and treatment. Methods. In a randomised controlled experimental study on medical decision-making, 121 general practitioners were given two case vignettes which contained all the criteria for major depression according to ICD-10, but differed in respect to the age of the patient (39 or 81). Reaction time, diagnostic conclusions and therapeutic recommendations were assessed by computer. Results. Depression and anxiety were significantly seen as more probable in the young cases and dementia and physical illness in the old. In young age, psychotherapy, pharmacotherapy and referral to a specialist or inpatient treatment were significantly more recommended than in old age, for whom supportive counselling was significantly more recommended. The time needed for a decision was significantly longer in the older patients. Conclusion. Ageing stereotypes can also form medical illness concepts and have a significant influence on diagnostic and therapeutic decisions.
PMCID: PMC2825546  PMID: 20182532
14.  Contents of General Practitioner-Patient Consultations in the Treatment of Depression 
Journal of General Internal Medicine  2008;23(10):1567-1570.
Counseling of patients is an indispensable part of any drug treatment and even more so in the treatment of depression.
To describe the content of counseling additional to prescribing an antidepressant drug.
Sixty-three general practices from all over Germany.
Three hundred two patients with the diagnosis of either a depressive episode or a recurrent depressive disorder.
Assessment of the content of the physician-patient encounter by content analysis following the pivotal topic method.
Qualitative study embedded in a drug utilization study on mirtazapine.
In the initial sessions general practitioners focused on building a good therapeutic alliance, assessing the symptoms of illness, explaining the course of treatment, assuring medication compliance, and discussing problems of life. In the middle phase of treatment, physicians also dealt with building a therapeutic alliance, medication compliance, and the progress and course of illness. In the last phase relapse prevention was an important topic. Psychological topics were more important than medication topics. Almost no importance was given to management of side effects, change of cognitions, or suicidal tendencies.
No information is available on how content was actually discussed. Only encounters were observed where an antidepressant was prescribed.
Counseling plays an important part in day-to-day encounters of general practitioners. Pharmacotherapy is embedded in comprehensive psychological care. Training programs for general practitioners should be specific in respect to different tasks and parts of the physician-patient encounter (e.g., building a therapeutic alliance, support for life problems or change of cognitions).
PMCID: PMC2533385  PMID: 18618203
depression; pivotal topic method; antidepressant; counseling
15.  Association of the 6q23 region with the rate of joint destruction in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2009;69(3):567-570.
Two novel genetic polymorphisms on chromosome 6q23 are associated with susceptibility to rheumatoid arthritis (RA). Both polymorphisms (rs6920220 and rs10499194) reside in a region close to the gene encoding tumour necrosis factor α-induced protein 3 (TNFAIP3). TNFAIP3 is a negative regulator of NF-κB and is involved in inhibiting TNF-receptor-mediated signalling effects. Interestingly, the initial associations were detected in patients with longstanding RA. However, no association was found for rs10499194 in a Swedish cohort with early arthritis. This might be caused by over-representation of patients with severe disease in cohorts with longstanding RA.
To analyse the effect of the 6q23 region on the rate of joint destruction.
Five single nucleotide polymorphisms in 6q23 were genotyped in 324 Dutch patients with early RA. Genotypes were correlated with progression of radiographic joint damage for a follow-up time of 5 years.
Two polymorphisms (rs675520 and rs9376293) were associated with severity of radiographic joint damage in patients positive for anti-citrullinated protein/peptide antibodies (ACPA). Importantly, the effects were present after correction for confounding factors such as secular trends in treatment.
These data associate the 6q23 region with the rate of joint destruction in ACPA+ RA.
PMCID: PMC2927680  PMID: 19366996
16.  Novel targeted deregulation of c-Myc cooperates with Bcl-XL to cause plasma cell neoplasms in mice 
Journal of Clinical Investigation  2004;113(12):1763-1773.
Deregulated expression of both Myc and Bcl-XL are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and Bcl-XL in mouse plasma cells might lead to an improved model of human PCN, we generated Myc transgenics by inserting a single-copy histidine-tagged mouse Myc gene, MycHis, into the mouse Ig heavy-chain Cα locus. We also generated Bcl-XL transgenic mice that contain a multicopy Flag-tagged mouse Bcl-xFlag transgene driven by the mouse Ig κ light-chain 3′ enhancer. Single-transgenic Bcl-XL mice remained tumor free by 380 days of age, whereas single-transgenic Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast, double-transgenic Myc/Bcl-XL mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). These tumors produced monoclonal Ig, infiltrated the bone marrow, and contained elevated amounts of MycHis and Bcl-XLFlag proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-XL mice. Our findings demonstrate that the enforced expression of Myc and Bcl-XL by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates some features of human multiple myeloma.
PMCID: PMC420503  PMID: 15199411

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