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1.  Classification of Thyroid Nodules Using a Resonance-Frequency–Based Electrical Impedance Spectroscopy: A Preliminary Assessment 
Thyroid  2013;23(7):854-862.
Ultrasound and ultrasound-guided fine-needle aspiration biopsy are considered the most effective approaches for both identifying and classifying thyroid nodules. However, despite continuing improvements in scanner technology and refinements in ultrasound/cytological classification guidelines, indeterminate findings still lead to diagnostic lobectomy under general anesthesia. This study aims to investigate the feasibility of applying a modified noninvasive electrical impedance spectroscopy (EIS) approach to classifying thyroid nodules.
To increase nodule classification sensitivity, we developed a new EIS-based model that introduces an optimized inductance component, which increases the measured signal-to-noise ratio of capacitance variation in and about thyroid nodules. Our model then measures the change of resonance frequency when the positive reactance of the system inductor cancels out the negative reactance of the nodule capacitance in a multi-frequency electrical signal scan. The system is termed “resonance-frequency–based electrical impedance spectroscopy” (REIS). A portable REIS system with multiple probes was assembled and preliminarily tested in our clinical facility. From an ongoing prospective study, an initial data set of 160 REIS examinations including 27 verified cancer cases was used. From the data set, a number of EIS signal features was extracted and analyzed. A multi-feature–based Bayesian Belief Network was built to classify the detected thyroid nodules. A receiver operating characteristic data analysis method was applied to evaluate classification performance.
The results showed that (i) the median resonance frequency measured by the probe nearest to malignant nodules was in general lower than that measured in benign cases, and (ii) the median descending slope of EIS signal sweep curves computed from cancer cases was larger than that computed from benign cases. The Bayesian Belief Network yielded a classification performance as measured by the area under the receiver operating characteristic curve of 0.794 [with a 95% confidence interval of 0.709–0.863].
The study demonstrates that noninvasive measurement of REIS signal features may potentially provide useful supplementary information to assist in classifying between malignant and benign thyroid nodules. Such an approach may ultimately lead to a reduction in the number of unnecessary thyroid surgeries.
PMCID: PMC3704105  PMID: 23259723
2.  Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment 
The Journal of Clinical Investigation  2014;124(7):3121-3128.
BACKGROUND. Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo–expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment.
METHODS. In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls.
RESULTS. No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively.
CONCLUSION. UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell–containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation.
FUNDING. Gamida Cell Ltd.
PMCID: PMC4071379  PMID: 24911148
3.  Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF versus G-CSF alone 
Bone marrow transplantation  2013;48(11):10.1038/bmt.2013.80.
Chemotherapy plus granulocyte colony stimulating factor (G-CSF) (C+G) and G-CSF alone are two of the most common methods of mobilizing CD34+ cells for autologous hematopoietic stem cell transplantation (AHSCT). In order to compare and determine real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 multiple myeloma), of whom 55% and 66% received C+G. Patients with C+G collected more CD34+ cells/day than G-CSF alone (lymphoma: average 5.51x106 cells/kg on day 1 vs. 2.92x106 cells/kg, p=0.0231; myeloma: 4.16x106 cells/kg vs. 3.69x106 cells/kg, p<0.00001) and required fewer days of apheresis (lymphoma: average 2.11 days vs. 2.96, p=0.012; myeloma: 2.02 vs. 2.83 days, p=0.0015), though nearly all patients ultimately reached the goal of 2x106 cells/kg. With the exception of higher rates of febrile neutropenia in myeloma patients with C+G (17% vs. 2%, p<0.05), toxicities and other outcomes were similar. Mobilization with C+G cost significantly more (lymphoma: median $10,300 vs. $7,300, p<0.0001; myeloma: $8,800 vs. $5,600, p<0.0001), though re-mobilization adds $6,700 for drugs alone. Our results suggest that while both C+G and G-CSF alone are effective mobilization strategies, C+G may be more cost-effective for patients at high risk of insufficient mobilization.
PMCID: PMC3797171  PMID: 23749109
Autologous hematopoietic stem cell transplantation; Mobilization; Chemo-mobilization; G-CSF; Lymphoma; Multiple myeloma
4.  Non-invasive neuromodulation to improve gait in chronic multiple sclerosis: a randomized double blind controlled pilot trial 
This study sought to examine the effect of targeted physical therapy with and without cranial nerve non-invasive neuromodulation (CN-NINM), on the walking ability of people with MS who exhibited a dysfunctional gait. We hypothesized that subjects who received electrical stimulation would have greater improvement than those who had a control device after a 14-week intervention. Gait disturbance is a common problem for people with multiple sclerosis (MS). Current management may include exercise, pharmacology, functional electrical stimulation, compensatory strategies, use of assistive devices, and implanted electrical devices. We have developed an effective rehabilitative strategy using neuromodulation of the cranial nerves via electrical stimulation of the tongue to enhance the plasticity of the brain.
The study is a within-subject blinded randomized control design. Twenty chronic MS subjects with an identified gait disturbance were assigned to either an active or control group. Both groups completed a 14-week intervention program using a standardized combination of exercise and a device that provided electrical stimulation to the tongue. Those in the active group received electrical stimulation on the tongue that they could perceive. Those in the control group used a device that did not provide a physiologically significant stimulus and was not perceivable. Subjects were assessed with the Dynamic Gait Index (DGI).
The DGI scores improved for both groups. There were significant between-group differences, with the active group showing statistically greater improvement than the control group mean.
People with MS demonstrated improved gait with CN-NINM training in a pilot randomized controlled trial. This study suggests that tongue-based neurostimulation may amplify the benefits of exercise for improving gait in people with chronic MS.
PMCID: PMC4017705  PMID: 24885412
Multiple sclerosis; Neuromodulation; Balance; Gait; Tongue; Neurostimulation; Non-invasive; Electrical stimulation
5.  Evidence of a role for SNCA in impulse control in humans 
Neurogenetics  2013;15(1):77-78.
PMCID: PMC3969776  PMID: 24196876
6.  Effects of Alcohol on Tests of Executive Functioning in Men and Women: A Dose Response Examination 
Alcohol has been shown to affect performance on tasks associated with executive functioning. However, studies in this area have generally been limited to a single dose or gender or have used small sample sizes. The purpose of this study was to provide a more nuanced and systematic examination of alcohol's effects on commonly used tests of executive functioning at multiple dosages in both men and women. Research volunteers (91 women and 94 men) were randomly assigned to one of four drink conditions (alcohol doses associated with target blood alcohol concentrations of .000%, .050%, .075% and .100%). Participants then completed three tasks comprising two domains of executive functioning: two set shifting tasks, the Trail Making Test and a computerized version of the Wisconsin Card Sorting Task, and a response inhibition task, the GoStop Impulsivity Paradigm. Impaired performance on set shifting tasks was found at the .100% and .075% dosages, but alcohol intoxication did not impair performance on the GoStop. No gender effects emerged. Thus, alcohol negatively affects set shifting at moderately high levels of intoxication in both men and women, likely due to alcohol's interference with prefrontal cortex function. Although it is well-established that alcohol negatively affects response inhibition as measured by auditory stop-signal tasks, alcohol does not appear to exert a negative effect on response inhibition as measured by the GoStop, a visual stop-signal task.
PMCID: PMC3968820  PMID: 20939644
7.  Safety and Preliminary Efficacy Analysis of the mTOR Inhibitor Ridaforolimus in Patients With Taxane-Treated, Castration-Resistant Prostate Cancer 
Clinical genitourinary cancer  2012;10(4):232-238.
The mammalian target of rapamycin (mTOR) pathway is associated with castration-resistant prostate cancer (CRPC). Thirty-nine taxane-treated CRPC patients were enrolled in a phase II trial assessing the safety and efficacy of targeted therapy with the mTOR inhibitor, Ridaforolimus (Merck & Co, Inc/ARIAD Pharmaceuticals, Inc). Treatment with Ridaforolimus was generally well tolerated. No objective responses were observed, but some patients experienced disease stabilization. Ridaforolimus may be an option in combination therapy.
Few options are available after taxane-based therapy in men with CRPC. Genetic alterations involving the mTOR pathway have been associated with CRPC development, raising the hypothesis that blocking mTOR signaling may be an effective targeted approach to treatment.
Patients and Methods
In this open-label phase II study, the mTOR inhibitor Ridaforolimus was administered at a dose of 50 mg intravenous once weekly to 38 patients with taxane-treated CRPC. The primary end point was best overall response according to modified Response Evaluation Criteria in Solid Tumors guidelines. Serum prostate-specific antigen levels were prospectively monitored as a biomarker for cancer activity.
No objective responses were observed, but 18 patients (47.4%) had stable disease as their best response. Based on progression-free survival analysis, median time to progression with Ridaforolimus was 28 days (95% confidence interval, 27–29). Eight patients (21.1%) had stable disease as their best overall prostate-specific antigen response. The median number of days from first to last dose was 109.5 days (range, 1–442 days). Ridaforolimus was generally well tolerated, with a safety profile similar to that observed in patients with advanced malignancies. The most common side effects were typically mild or moderate in severity.
Ridaforolimus was generally well tolerated. Treatment did not produce objective responses, but stable disease was observed in some patients with taxane-treated CRPC. Alternative treatment regimens, such as combination therapy with a taxane or in a maintenance treatment paradigm, should be considered for further evaluation in this patient population.
PMCID: PMC3963491  PMID: 22695254
Combination therapy; Disease stabilization; Phase II; Prostate-specific antigen; Targeted therapy
8.  Quantitative Proteomic profiling identifies protein correlates to EGFR kinase inhibition 
Molecular cancer therapeutics  2012;11(5):1071-1081.
Clinical oncology is hampered by a lack of tools to accurately assess a patient’s response to pathway-targeted therapies. Serum and tumor cell surface proteins whose abundance, or change in abundance in response to therapy, differentiates patients responding to a therapy from patients not-responding to a therapy could be usefully incorporated into tools for monitoring response. Here we posit and then verify that proteomic discovery in in vitro tissue culture models can identify proteins with concordant in vivo behavior and further, can be a valuable approach for identifying tumor-derived serum proteins. In this study we use Stable Isotope Labeling of Amino acids in Culture (SILAC) with proteomic technologies to quantitatively analyze the gefitinib-related protein changes in a model system for sensitivity to EGFR targeted tyrosine kinase inhibitors. We identified 3,707 intracellular proteins, 1,276 cell surface proteins, and 879 shed proteins. More than 75% of the proteins identified had quantitative information and a subset consisting of [400] proteins showed a statistically significant change in abundance following gefitinib treatment. We validated the change in expression profile in vitro and screened our panel of response markers in an in vivo isogenic resistant model and demonstrated that these were markers of gefitinib response and not simply markers of phospho-EGFR downregulation. In doing so, we also were able to identify which proteins might be useful as markers for monitoring response and which proteins might be useful as markers for a priori prediction of response.
PMCID: PMC3959865  PMID: 22411897
NSCLC; EGFR; Gefitinib; Proteomics; SILAC
9.  Mental health training experiences among Haitian healthcare workers post-earthquake 2010 
International nursing review  2013;60(4):528-535.
After the 2010 earthquake in Haiti, the large number of persons with major limb damage, amputations, shock, trauma, anxiety and depression placed a severe strain on mental health (MH) services.
This qualitative study describes the impact and acceptability of a Mental Health Training Program (MHTP) implemented in the north of Haiti after the earthquake.
A total of 113 healthcare workers (HCWs) participated in a training program designed to build local MH care capacity. The training curriculum draws on literature related to MH and the impact of the Haiti earthquake. Two focus groups were conducted with 16 HCWs; discussions centred on the personal and professional impact and acceptability of the training program.
Results demonstrated that the MHTP changed the HCWs’ perceptions about MH issues and provided them with the knowledge and skills to respond to growing community MH needs. Acceptability of the MHTP was related to the content covered, to the delivery mode of the content and to the cultural appropriateness of the program.
Disasters of different types will continue to occur and to impact MH in communities around the world. MH training will allow nurses to quickly and effectively respond to disasters. A coordinated emergency plan that is subject to frequent review, rehearsal and evaluation is also essential.
PMCID: PMC3933925  PMID: 24251943
Disaster; Earthquake; Haiti; Healthcare; Mental Health; Prevention; Training; Trauma
10.  Altered Connectivity of the Balance Processing Network After Tongue Stimulation in Balance-Impaired Individuals 
Brain Connectivity  2013;3(1):87-97.
Some individuals with balance impairment have hypersensitivity of the motion-sensitive visual cortices (hMT+) compared to healthy controls. Previous work showed that electrical tongue stimulation can reduce the exaggerated postural sway induced by optic flow in this subject population and decrease the hypersensitive response of hMT+. Additionally, a region within the brainstem (BS), likely containing the vestibular and trigeminal nuclei, showed increased optic flow-induced activity after tongue stimulation. The aim of this study was to understand how the modulation induced by tongue stimulation affects the balance-processing network as a whole and how modulation of BS structures can influence cortical activity. Four volumes of interest, discovered in a general linear model analysis, constitute major contributors to the balance-processing network. These regions were entered into a dynamic causal modeling analysis to map the network and measure any connection or topology changes due to the stimulation. Balance-impaired individuals had downregulated response of the primary visual cortex (V1) to visual stimuli but upregulated modulation of the connection between V1 and hMT+ by visual motion compared to healthy controls (p≤1E–5). This upregulation was decreased to near-normal levels after stimulation. Additionally, the region within the BS showed increased response to visual motion after stimulation compared to both prestimulation and controls. Stimulation to the tongue enters the central nervous system at the BS but likely propagates to the cortex through supramodal information transfer. We present a model to explain these brain responses that utilizes an anatomically present, but functionally dormant pathway of information flow within the processing network.
PMCID: PMC3621359  PMID: 23216162
brain stem; cranial nerve disorders; neural plasticity; statistics; visual system
11.  Secondary Psychopathy, but not Primary Psychopathy, is Associated with Risky Decision-Making in Noninstitutionalized Young Adults 
Although risky decision-making has been posited to contribute to the maladaptive behavior of individuals with psychopathic tendencies, the performance of psychopathic groups on a common task of risky decision-making, the Iowa Gambling Task (IGT; Bechara, Damasio, Damasio, & Anderson, 1994), has been equivocal. Different aspects of psychopathy (personality traits, antisocial deviance) and/or moderating variables may help to explain these inconsistent findings. In a sample of college students (N = 129, age 18 to 27), we examined the relationship between primary and secondary psychopathic features and IGT performance. A measure of impulsivity was included to investigate its potential as a moderator. In a joint model including main effects and interactions between primary psychopathy, secondary psychopathy and impulsivity, only secondary psychopathy was significantly related to risky IGT performance, and this effect was not moderated by the other variables. This finding supports the growing literature suggesting that secondary psychopathy is a better predictor of decision-making problems than the primary psychopathic personality traits of lack of empathy and remorselessness.
PMCID: PMC3505104  PMID: 23185100
primary psychopathy; secondary psychopathy; impulsivity; risk-taking; decision-making; gambling task; noninstitutionalized
Bone marrow transplantation  2011;47(8):10.1038/bmt.2011.217.
Plerixafor, given on day 4 of G-CSF treatment is more effective than G-CSF alone in mobilizing hematopoietic progenitor cells. We tested a strategy of preemptive plerixafor use following assessment of the peak mobilization response to 5 days of G-CSF. Patients were eligible for plerixafor if, on day 5 of G-CSF, there were less than 7 circulating CD34+ cells/μl or if <1.3 × 106 CD34+ cells/kg were collected on the first day of apheresis. Plerixafor (0.24 mg/kg subcutaneous) was given on day 5 of G-CSF followed by apheresis on day 6. This was repeated for up to two additional doses of plerixafor. The primary endpoint of the study was the percentage of patients who collected at least 2 × 106 CD34+ cells/kg. Twenty candidates for autologous stem cell transplantation enrolled on the trial. The circulating CD34+ cell level increased a median of 3.1 fold (range 1–8 fold) after the first dose of plerixafor and a median of 1.2 fold (range 0.3–6.5 fold) after the second dose of plerixafor. Fifteen of 20 (75%) patients achieved the primary endpoint. In conclusion, the decision to administer plerixafor can be delayed until after the peak mobilization response to G-CSF has been fully assessed.
PMCID: PMC3877677  PMID: 22080963
13.  Adult Dual Umbilical Cord Blood Transplantation Using Myeloablative Total Body Irradiation (1350cGy) and Fludarabine Conditioning 
High treatment-related mortality and high graft failure rate are serious concerns in HLA-mismatched umbilical cord blood (UCB) transplantation with myeloablative conditioning. We conducted a prospective trial of dual UCB transplantation using modified myeloablation consisting of total body irradiation (TBI; 1350 cGy) and fludarabine (160 mg/m2). Twenty-seven patients (median age, 33 years; range, 20–58 years) with hematologic malignancies were enrolled. The median combined cryopreserved total nucleated cell (TNC) dose was 4.3 × 107/kg (range, 3.2–7.7 × 107/kg). The cumulative incidences of neutrophil (≥500/μl) and platelet (≥50,000/μl) engraftment were 80% (95% confidence interval (CI), 58–91%) and 68% (95% CI, 46–83%), respectively. Among engrafted patients, a single cord blood unit was predominant by 100 days post transplantation. A higher cryopreserved and infused TNC dose and infused CD3+ cell dose were significant factors associated with the predominant UCB unit (P = 0.032, 0.020, and 0.042, respectively). Treatment-related mortality and relapse rates at 2 years were 28% (95% CI, 12–47%) and 20% (95% CI, 7–37%), respectively. Cumulative incidences of grades II–IV and grades III–IV acute GVHD were 37% (95% CI, 20–55%) and 11% (95% CI, 3–26%), respectively, and that of chronic GVHD was 31% (95% CI, 15–49%). With a median follow-up of 23 months, overall and disease-free survival rates at 2 years were 58% (95% CI, 34–75%) and 52% (95% CI, 29–70%), respectively. This study supports the use of TBI 1350cGy/fludarabine as an alternative to conventional myeloablative conditioning for dual UCB transplantation.
PMCID: PMC3877679  PMID: 20868761
adult; dual umbilical cord blood transplantation; myeloablative; fludarabine; total body irradiation
14.  Case report: post-stroke interventional BCI rehabilitation in an individual with preexisting sensorineural disability 
Therapies involving new technologies such as brain-computer interfaces (BCI) are being studied to determine their potential for interventional rehabilitation after acute events such as stroke produce lasting impairments. While studies have examined the use of BCI devices by individuals with disabilities, many such devices are intended to address a specific limitation and have been studied when this limitation or disability is present in isolation. Little is known about the therapeutic potential of these devices for individuals with multiple disabilities with an acquired impairment overlaid on a secondary long-standing disability. We describe a case in which a male patient with congenital deafness suffered a right pontine ischemic stroke, resulting in persistent weakness of his left hand and arm. This patient volunteer completed four baseline assessments beginning at 4 months after stroke onset and subsequently underwent 6 weeks of interventional rehabilitation therapy using a closed-loop neurofeedback BCI device with visual, functional electrical stimulation, and tongue stimulation feedback modalities. Additional assessments were conducted at the midpoint of therapy, upon completion of therapy, and 1 month after completing all BCI therapy. Anatomical and functional MRI scans were obtained at each assessment, along with behavioral measures including the Stroke Impact Scale (SIS) and the Action Research Arm Test (ARAT). Clinically significant improvements in behavioral measures were noted over the course of BCI therapy, with more than 10 point gains in both the ARAT scores and scores for the SIS hand function domain. Neuroimaging during finger tapping of the impaired hand also showed changes in brain activation patterns associated with BCI therapy. This case study demonstrates the potential for individuals who have preexisting disability or possible atypical brain organization to learn to use a BCI system that may confer some rehabilitative benefit.
PMCID: PMC4067954
stroke rehabilitation; brain-computer interface; case study; disability; BCI therapy; UE motor rehabilitation; BCI-FES-TDU
15.  Immune Recovery in Adult Patients Following Myeloablative Dual Umbilical Cord Blood, Matched Sibling, and Matched Unrelated Donor Hematopoietic Cell Transplantation 
Immunologic reconstitution following allogeneic hematopoietic cell transplantation (HCT) is a critical component of successful outcome. Umbilical cord blood (UCB) transplantation in adult recipients is associated with slow and often inadequate immune recovery. We characterized the kinetics and extent of immune recovery in 95 adult recipients following a dual UCB (n=29), and matched sibling (MSD) (n=33) or unrelated donor (MUD) (n=33) transplantation. All patients were treated with myeloablative conditioning. There were no differences in the immune recovery profile of MSD and MUD recipients. Significantly lower levels of CD3+, CD4+ and CD8+ T-cells were observed in UCB recipients until 6 months following transplantation. Lower levels of regulatory T-cells persisted until 1 year following transplantation. Thymopoiesis as measured by T-cell receptor rearrangement excision circle (TREC) was comparable among all recipients by 6 months following transplantation. In a subset of patients 1 year following transplantation with similar levels of circulating T-cells and TREC, there was no difference in T-cell receptor diversity. Compared to HLA-identical MSD and MUD adult HCT recipients, quantitative lymphoid recovery in UCB transplant recipients is slower in the first 3 months, but these differences disappeared by 6–12 months following transplantation.
PMCID: PMC3472115  PMID: 22698485
adult; dual umbilical cord blood transplantation; matched sibling transplantation; matched unrelated donor transplantation; immune recovery; T-cell receptor excision DNA circles (TRECs); post-thymic T-cell reconstitution
17.  Newborn TSH in children with optic nerve hypoplasia: Associations with hypothyroidism and vision 
To assess in children with optic nerve hypoplasia (ONH) whether newborn screening (NBS) thyroid-stimulating hormone (TSH) measurements can detect central hypothyroidism and whether newborn TSH or subsequent thyroidal status is associated with visual function.
A subset of patients in the registry of children with ONH at Children’s Hospital Los Angeles who were born in California was used to make a retrospective comparison of NBS TSH levels and subsequent postnatal thyroid status. Another subset of registry subjects with vision and thyroid status data at age 5 years was assessed for the relationship of vision to NBS TSH levels and ultimate thyroidal status.
A total of 135 subjects from the ONH registry were included in this study. Approximately 50% of subjects in each analysis were hypothyroid. Those diagnosed with hypothyroidism had lower median NBS TSH levels than did euthyroid subjects (3.2 vs 4.5 μIU/mL; P = 0.006) and significantly worse quantitative vision outcomes (median visual acuity, logMAR 3.0 vs 1.0; P = 0.039). Receiver operating characteristic analysis suggested an optimal NBS TSH cut-point of 3.3 μIU/mL. Serum TSH over this level (30/43) was associated with relatively better vision outcomes (median visual acuity, logMAR 1.2 vs 3.3; P = 0.04).
Children with ONH and lower NBS TSH levels are more likely to have central hypothyroidism and less likely to experience good vision than those with higher NBS TSH levels.
PMCID: PMC3481172  PMID: 23084376
18.  Selected Approaches for Rational Drug Design and High Throughput Screening to Identify Anti-Cancer Molecules 
Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specific-promoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity. The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy.
PMCID: PMC3763986  PMID: 22931411
Progression Elevated Gene-3; Sabutoclax; Apogossypol; BI-97C1; Gossypol; AP-1; PEA3; ETV4; E1AF; c-fos; c-jun; Cancer Terminator Virus
19.  DNAJB6 governs a novel regulatory loop determining Wnt/β-catenin signaling activity 
The Biochemical journal  2012;444(3):573-580.
Dickkopf 1 (DKK1) is a secreted inhibitor of the Wnt signaling pathway and a critical modulator of tumor promotion and the tumor microenvironment. However, mechanisms regulating DKK1 expression are understudied. DNAJB6 is an HSP40 family member whose expression is compromised during progression of breast cancer and melanoma. Inhibition of Wnt/β-catenin signaling pathway, by up-regulation of DKK1, is one of the key mechanisms by which DNAJB6 suppresses tumor, metastasis and epithelial-mesenchymal transition (EMT). Analysis of the DKK1 promoter to define the cis-site responsible for its up regulation by DNAJB6 revealed the presence of two binding sites for a transcriptional repressor, MSX1 (muscle segment homeobox gene). Our investigations showed that MSX1 binds the DKK1 promoter and inhibits DKK1 transcription. Interestingly, silencing DNAJB6 resulted in up-regulation of MSX1 concomitant with increased stabilization of β-catenin. ChIP studies revealed that β-catenin binds MSX1 promoter and stabilization of β-catenin elevates MSX1 transcription, indicating that β-catenin works as a transcription co-activator for MSX1. Functionally, exogenous expression of MSX1 in DNAJB6 expressing cells promotes the mesenchymal phenotype by suppression of DKK1. Thus we have identified a novel regulatory mechanism of DNAJB6 mediated DKK1 transcription up-regulation that can influence epithelial-mesenchymal transition. DKK1 is a feedback regulator of β-catenin levels. Thus our studies also define an additional negative control of this β-catenin-DKK1 feedback loop by MSX1, which may potentially contribute to excessive stabilization of β-catenin.
PMCID: PMC3712349  PMID: 22455953
20.  Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: Risk factors and response to treatment 
Bone marrow transplantation  2013;48(7):926-931.
High fever and/or rash prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (≥12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (≥13.2Gy)-based myeloablative conditioning. Tacrolimus (n=35) or cyclosporine (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (≥38.5°C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% CI) of PES was 77% (66%–88%). The incidence of PES was significantly higher in patients who received cyclosporine as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact overall survival or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of cyclosporine for GVHD prophylaxis increases the risk of PES following dual umbilical cord blood transplantation.
PMCID: PMC3701735  PMID: 23334274
pre-engraftment syndrome; dual umbilical cord blood transplantation; myeloablative
21.  Cellular stress stimulates nuclear localization signal (NLS) independent nuclear transport of MRJ 
Experimental Cell Research  2012;318(10):1086-1093.
HSP40 family member MRJ (DNAJB6) has been in the spot light for its relevance to Huntington’s, Parkinson’s diseases, limb-girdle muscular dystrophy, placental development, neural stem cells, cell cycle and malignancies such as breast cancer and melanoma. This gene has two spliced variants coding for 2 distinct proteins with significant homology. However, MRJ(L) (large variant) is predominantly localized to the nucleus whereas MRJ(S) (small variant) is predominantly cytoplasmic. Interestingly MRJ(S) translocates to the nucleus in response to heat shock. The classical heat shock proteins respond to crises (stress) by increasing the number of molecules, usually by transcriptional up-regulation. Our studies imply that a quick increase in the molar concentration of MRJ in the nuclear compartment is a novel method by which MRJ responds to stress. We found that MRJ(S) shows NLS (nuclear localization signal) independent nuclear localization in response to heat shock and hypoxia. The specificity of this response is realized due to lack of such response by MRJ(S) when challenged by other stressors, such as some cytokines or UV light. Deletion analysis has allowed us to narrow down on a 20 amino acid stretch at the C-terminal region of MRJ(S) as a potential stress sensing region. Functional studies indicated that constitutive nuclear localization of MRJ(S) promoted attributes of malignancy such as proliferation and invasiveness overall indicating distinct phenotypic characteristics of nuclear MRJ(S).
PMCID: PMC3406602  PMID: 22504047
MRJ; DnaJB6; NLS; Heat Shock
22.  Suspicious Ultrasound Characteristics Predict BRAFV600E-Positive Papillary Thyroid Carcinoma 
Thyroid  2012;22(6):585-589.
Current American Thyroid Association (ATA) guidelines recommend routine cervical ultrasound (US) in thyroid nodule evaluation. Specific US characteristics can help diagnose papillary thyroid carcinoma (PTC). The aim of this blinded cohort study was to determine whether these specific US characteristics can also reliably detect the more aggressive variants of PTC that are often associated with the BRAFV600E mutation.
After Institutional Review Board approval, we identified a cohort of patients from January 2007 to December 2009 with histologic PTC≥1 cm who had cervical US, initial thyroid surgery, and molecular testing for BRAFV600E on fine-needle aspiration biopsy or histology. Preoperative US images were evaluated by a single radiologist, who was blinded to BRAF status, for nodule size and the presence or absence of the following suspicious US features: taller-than-wide shape, ill-defined margins, hypoechogenicity, calcifications, noncystic composition, and absent halo.
BRAF-positivity was associated with most known suspicious US findings, including taller-than-wide shape (47% vs. 7%, p<0.001), ill-defined margins (42% vs. 9%, p<0.001), hypoechogenicity (83% vs. 36%, p<0.001), micro/macrocalcifications (87% vs. 24%, p<0.001), and absent halo (85% vs. 27%, p<0.001) but was not associated with noncystic composition. When ≥3 suspicious US features were present, BRAF-positivity was predicted with a positive predictive value of 82%. The absence of suspicious US features together with negative BRAF testing predicted PTC without extrathyroidal extension or lymph node metastasis (negative predictive value 88%).
With routine preoperative cervical US and molecular testing, a trained radiologist or surgeon can improve the preoperative characterization of PTC, potentially impacting risk stratification and initial surgical management.
PMCID: PMC3358112  PMID: 22524468
23.  Metabolic Abnormalities and Viral Replication is Associated with Biomarkers of Vascular Dysfunction in HIV-Infected Children 
HIV Medicine  2011;13(5):264-275.
Human immunodeficiency virus (HIV)-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction among HIV-infected children with and without hyperlipidemia to HIV-exposed, uninfected children (HEU) enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers.
Prospective cohort study
Biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP1)); coagulant dysfunction (fibrinogen and P-selectin); endothelial dysfunction (soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), and E-selectin); and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded.
The median ages were 12.3 y (HIV-infected) and 10.1 y (HEU). Body mass index (BMI) Z-scores, waist and hip circumference, and percent body fat were lower among HIV-infected. Total and non-HDL cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children had higher MCP-1, fibrinogen, sICAM, and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavorable lipid profiles were positively associated with IL6, MCP1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP1 and CRP) and endothelial dysfunction (sICAM and sVCAM).
HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavorable lipid levels and active HIV replication.
PMCID: PMC3297698  PMID: 22136114
Children; HIV/AIDS; vascular dysfunction; cardiovascular risk factors; biomarkers
24.  Differential Impact of Inhibitory and Activating Killer Immunoglobulin-Like Receptors (KIR) in High Risk Patients with Myeloid and Lymphoid Malignancies Undergoing Reduced Intensity Transplantation from Haploidentical Related Donors 
Bone marrow transplantation  2011;47(6):817-823.
Impact of activating (aKIR) and inhibitory (iKIR) on overall survival (OS), relapse-related mortality (RRM), and acute graft-vs.-host disease (aGVHD) were studied in 84 adults with high risk hematologic malignancies receiving reduced intensity conditioning (RIC) T-cell depleted hematopoietic stem cell transplantation (HSCT) from haploidentical related donors. In this clinical model, freedom from RRM was more dependent on graft-vs-leukemia (GVL) effect. Patients were divided into myeloid (n=49) and lymphoid (n=35) malignancy groups. KIR-ligand and ligand-ligand models were studied in both directions and statistically correlated with outcome measures. In the myeloid group, OS was higher (p=0.009) and RRM lower (p=0.036) in patients missing HLA-C group2 ligand to donor inhibitory KIR. OS was higher if patients had >1 missing ligand (p=0.018). In lymphoid malignancy, missing ligand to donor KIR had no impact on OS or RRM. However, OS was longer with donor activating KIR 2DS2 (p=0.028). There was a trend toward shorter OS in recipient with KIR 2DS1, 2DS5 and 3DS1, although sample sizes are too small to provide inferential statistics. These results suggest that absence of appropriate HLA ligands in the recipient to donor iKIR may induce GVL without aGVHD in myeloid malignancy patients undergoing TCD-RIC transplants.
PMCID: PMC3629554  PMID: 22139069
KIR; Activating KIR; Inhibitory KIR; Haploidentical; Reduced Intensity Conditioning (RIC); Hematopoietic Stem Cell Transplantation (HSCT)
25.  Dickkopf1: A tumor suppressor or metastasis promoter? 
Dickkopf1 (DKK1), a secreted inhibitor of the Wnt/β-catenin pathway, is a negative regulator of bone formation. DKK1 acts as a switch that transitions prostate cancer bone metastases from osteolytic to osteoblastic and also is an active indicator of poor outcome for multiple myeloma. However, in other tumor types, DKK1 up-regulation or over-expression suppresses tumor growth. Thus, the role of DKK1 in cancer appears to be diverse. This raises a question: Could the increased levels of DKK1 still be tumor protective when observed in high levels in the serum of patients? Here, we summarize the diverse, seemingly contradicting roles of DKK1 and attempt to explain the apparent dichotomy in its activity. We propose that DKK1 is a critical secreted factor that modulates microenvironment. Based on the location and components of the microenvironment DKK1 will support different outcomes.
PMCID: PMC3253198  PMID: 21953410

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