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1.  Initiation of immunoglobulin therapy by subcutaneous administration in immunodeficiency patients naive to replacement therapy 
Patients with immunodeficiency diseases require lifelong treatment with immunoglobulin (Ig), yet few studies have vetted dosing strategies and effectiveness of Ig in older patient populations. Patients requiring subcutaneous (SC) Ig (SCIG) typically start with intravenous dosing before transitioning to SCIG weekly maintenance. In this retrospective review, we investigated an alternate strategy with higher initial SC doses among an older patient population with antibody deficiency syndromes.
Records of 13 patients (mean age, 70 years) with antibody deficiencies who were naive to treatment with Ig were assessed. SCIG (Vivaglobin® [Immune Globulin Subcutaneous (Human), 16% Liquid] or Hizentra® [Immune Globulin Subcutaneous (Human), 20% Liquid]) was given twice weekly (100 mg/kg) for 2 weeks, followed by weekly (100 mg/kg) administration The mean pretreatment IgG level was 460 mg/dL; at 1, 3, and 6 months after SCIG initiation, mean IgG serum levels were 852, 907, and 943 mg/dL, respectively. Maintenance doses were unchanged during 6 months of follow-up. All patients remain on SCIG (median, 44 months). One patient developed sepsis/cholangitis unrelated to treatment 3 months after starting SCIG; no other serious bacterial infections were reported.
Initiation of SCIG by doubling the maintenance dose over 2 weeks may be a well-tolerated and effective option for patients with antibody deficiencies requiring Ig replacement, especially among older patients.
PMCID: PMC4273447  PMID: 25535489
Globulins; Immune; Immunoglobulins; Subcutaneous; Immunoglobulins; Intravenous; Immunoglobulin therapy; Immunological deficiency syndromes
2.  TargetingTumor MetabolismWith 2-Deoxyglucose in Patients With Castrate-Resistant Prostate Cancer and Advanced Malignancies 
The Prostate  2010;70(13):1388-1394.
A profound difference between cancer and normal tissues is the preferential utilization of glycolysis by cancer cells. To translate this paradigm in the clinic, we completed a phase I study of 2-deoxyglucose (2DG), and assessed 2DG uptake with fluorodeoxyglucose (FDG) positron emission tomography (PET) and the autophagy substrate p62 as a marker of 2DG resistance.
Patients received 2DG orally on days 1–14 of a 21-day cycle in cohorts of three in a dose-escalating manner. Correlative assessments included PET scans at baseline and day 2 and p62 protein in peripheral blood mononuclear cells as a potential marker of 2DG resistance.
The dose of 45 mg/kg was defined as the recommended phase II dose, secondary to dose-limiting toxicity of grade 3 asymptomatic QTc prolongation at a dose of 60 mg/kg. PK evaluation of 2DG revealed linear pharmacokinetics with Cmax 45 μg/ml (277 μM), 73.7 μg/ml (449 μM), and 122 μg/ml (744 μM) in dose levels 30, 45, and 60 mg/kg, respectively. Five of eight patients assessed with FDG-PET scanning demonstrated decreased FDG uptake by day 2 of therapy, suggesting competition of 2DG with FDG. Five of six patients assessed for p62 had a decrease in p62 at 24 hr.
These data support the safety of 2DG, defined 2DG PK, demonstrated the effect of 2DG on FDG-PET imaging, and demonstrated the feasibility of assessment of p62 as an autophagic resistance marker. These data support future studies of 2DG alone or in combination with approaches to abrogate autophagy.
PMCID: PMC4142700  PMID: 20687211
deoxyglucose; metabolism; prostate cancer; autophagy; p62
3.  Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer 
Asian Journal of Andrology  2014;16(3):387-400.
Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.
PMCID: PMC4023364  PMID: 24759590
androgen synthesis; castration-resistant prostate cancer; treatment
4.  Enrichment of human prostate cancer cells with tumor initiating properties in mouse and zebrafish xenografts by differential adhesion 
The Prostate  2013;74(2):187-200.
Prostate tumor-initiating cells (TICs) have intrinsic resistance to current therapies. TICs are commonly isolated by cell sorting or dye exclusion, however, isolating TICs from limited primary prostate cancer (PCa) tissues is inherently inefficient. We adapted the collagen adherence feature to develop a combined immunophenotypic and time-of-adherence assay to identify human prostate TICs.
PCa cells from multiple cell lines and primary tissues were allowed to adhere to several matrix molecules, and fractions of adherent cells were examined for their TIC properties.
Collagen-I rapidly-adherent PCa cells have significantly higher clonogenic, migration, and invasion abilities, and initiated more tumor xenografts in mice when compared to slowly-adherent and no-adherent cells. To determine the relative frequency of TICs among PCa cell lines and primary PCa cells, we utilized zebrafish xenografts to define the tumor initiation potential of serial dilutions of rapidly-adherent α2β1hi/CD44hi cells compared to non-adherent cells with α2β1low/CD44low phenotype. Tumor initiation from rapidly-adherent α2β1hi/CD44hi TICs harboring the TMPRSS2:ERG fusion generated xenografts comprising of PCa cells expressing Erg, AMACR, and PSA. Moreover, PCa-cell dissemination was consistently observed in the immune-permissive zebrafish microenvironment from as-few-as 3 rapidly-adherent α2β1hi/CD44hi cells. In zebrafish xenografts, self-renewing prostate TICs comprise 0.02–0.9% of PC3 cells, 0.3–1.3% of DU145 cells, and 0.22–14.3% of primary prostate adenocarcinomas.
Zebrafish PCa xenografts were used to determine that the frequency of prostate TICs varies among PCa cell lines and primary PCa tissues. These data support a paradigm of utilizing zebrafish xenografts to evaluate novel therapies targeting tumor initiating cells in prostate cancer.
PMCID: PMC3939797  PMID: 24154958
Prostate cancer stem cells; tumor-initiating cells; zebrafish
5.  Eastern Cooperative Oncology Group Phase II Trial of Lapatinib in Men with Biochemically Relapsed, Androgen Dependent Prostate Cancer 
Urologic oncology  2011;31(2):211-218.
Activation of the epidermal growth factor pathway is important in prostate cancer development and the transcription of androgen receptor regulated genes. This study evaluated the potential activity of lapatinib in men with biochemically-relapsed androgen-dependent (stage D0) prostate cancer.
Experimental Design
Patients with a rising PSA after primary therapy for prostate cancer were enrolled. A PSA doubling time (PSADT) <12 months was required. Lapatinib was administered at 1,500 mg orally daily. Outcome measures were changes in PSA kinetics. Primary tumor blocks were obtained and assessed for EGFR expression, EGFR Q787Q polymorphism, and Kras 38 mutational status.
49 patients were enrolled (14 ineligible), resulting in 35 pts for analysis. No PSA response was observed; best response was stable disease (n=28, 80.0%). Pre-treatment average slope was 0.19 log (PSA)/month (PSADT=3.70 months), in contrast to on-treatment average slope of 0.13 log (PSA)/month (PSADT=5.44 months) using linear mixed effects models (p=0.006). Median progression-free survival (PFS) was 17.4 months for the high EGFR group and 6.0 months for the low EGFR group (p=0.50). Patients with Kras 38 mutation had shorter PFS than those without Kras 38 mutation (p=0.09).
Although no PSA responses (primary endpoint) was observed, lapatinib may have biologic activity in men with stage D0 prostate cancer as evidenced by a decrease in PSA slope in this non-randomized study. Additional trials assessing the role of EGFR overexpression and Kras wild type status in prostate cancer should be investigated.
PMCID: PMC3223557  PMID: 21784672
Epidermal growth factor receptor; tyrosine kinase inhibitors; clinical trial
6.  Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma 
Journal of Clinical Oncology  2012;31(2):181-186.
Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC.
Patients and Methods
Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR).
Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli.
Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.
PMCID: PMC3532390  PMID: 23213094
The Prostate  2012;72(12):10.1002/pros.22487.
Targeting multiple anti-apoptotic proteins is now possible with the small molecule BH3 domain mimetics such as ABT-737. Given recent studies demonstrating that autophagy is a resistance mechanism to multiple therapeutic agents in the setting of apoptotic inhibition, we hypothesized that hydroxychloroquine (HCQ), an anti-malarial drug that inhibits autophagy, will increase cytotoxicity of ABT-737.
Experimental Design
Cytotoxicity of ABT-737 and HCQ was assessed in vitro in PC-3 and LNCaP cells, and in vivo in a xenograft mouse model. The role of autophagy as a resistance mechanism was assessed by siRNA knockdown of the essential autophagy gene beclin1. ROS was measured by flow cytometry, and mitophagy assessed by the mCherry-Parkin reporter.
Induction of autophagy by ABT-737 was a mechanism of resistance in prostate cancer cell lines. Therapeutic inhibition of autophagy with HCQ increased cytotoxicity of ABT-737 both in vitro and in vivo. ABT-737 induced LC-3 and decreased p62 expression by immunoblot in cell lines and by immunohistochemistry in tumors in vivo. Assessment of ROS and mitochondria demonstrated that ROS production by ABT-737 and HCQ was a mechanism of cytotoxicity.
We demonstrated that autophagy inhibition with HCQ enhances ABT-737 cytotoxicity in vitro and in vivo, that LC-3 and p62 represent assessable markers in human tissue for future clinical trials, and that ROS induction is a mechanism of cytotoxicity. These results support a new paradigm of dual targeting of apoptosis and autophagy in future clinical studies.
PMCID: PMC3840901  PMID: 22241682
Prostate Cancer; Autophagy; Metabolism; Bcl-2; BH3; ABT-737; ABT-263
8.  Abiraterone in Prostate Cancer: a new angle to an old problem 
Abiraterone acetate is an orally administered potent inhibitor of cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1 or CYPc17), which is essential for synthesis of testosterone from cholesterol. While decreasing serum testosterone through inhibition of testicular function is the first line of treatment for men with metastatic prostate cancer, residual androgens may still be detected in patients treated with LHRH agonists. Treatment with abiraterone results in rapid, and complete, inhibition of androgen synthesis in the adrenal glands and within the tumor itself. An overall survival benefit of maximal androgen suppression was recently demonstrated in a randomized placebo controlled phase III clinical trial of abiraterone with prednisone versus prednisone in men with metastatic castrate resistant prostate cancer previously treated with docetaxel chemotherapy. Abiraterone’s efficacy demonstrates the importance of androgen signaling in patients with castrate resistant metastastic disease, and the importance of studies of other novel agents such as MDV3100, an androgen receptor inhibitor, that additionally targets androgen receptor translocation. These promising results now pose a new angle to an old problem regarding hormonal therapy and raise new questions about how resistance develops, how to best sequence therapy, and how to optimize combinations with other emerging novel targeted agents.
PMCID: PMC3761800  PMID: 22451619
Abiraterone; Prostate Cancer; CYP17A1; CYP17; CYPc17
9.  A validated HPLC assay for the determination of R-(-)-gossypol in human plasma and its application in clinical pharmacokinetic studies 
R-(-)-gossypol acetic acid (AT-101), a natural BH3 mimetic, is investigated in a Phase I/II clinical trial for the treatment of advanced solid tumor malignancies. Gossypol undergoes rapid degradation in solution phase, which causes major technical difficulty for its quantitation in plasma. We developed and validated a sensitive HPLC assay for pharmacokinetic evaluation of gossypol. Acetonitrile deproteinization method was chosen for sample preparation and Schiff's base derivative, R-(-)-gossypol-diamino-propanol (GDP), was used as internal standard. Chromatographic separation of gossypol in plasma was performed using a Zorbax Eclipse XDB column C18 at 30°C. The mobile phase consists of 10 mmol/L KH2PO4 (pH=3.0) and acetonitrile (20:80) at 1.0 mL/min flow rate. Linearity ranged over 56-3585 ng/mL (R2=0.9997±0.0003, n=4), and the limit of detection was 28 ng/mL. The intra- and inter-assay precision was less than 13.7% and the bias ranged from -7.4 to 7.0%. The method was successfully applied to characterize the pharmacokinetics of AT-101 in a Phase I clinical trial. The validated assay is accurate, and sensitive with minimum loss and rapid analysis time and suitable for quantification of gossypol for pharmacokinetics evaluation.
PMCID: PMC3358459  PMID: 22483642
R-(-)-gossypol; HPLC-UV; pharmacokinetics
10.  ADHD Treatments, Sleep, and Sleep Problems: Complex Associations 
Neurotherapeutics  2012;9(3):509-517.
ADHD, sleep, and ADHD treatments are highly interrelated. In this review, we describe the effects of stimulants and non stimulant medications on sleep in children, adolescents, and adults with ADHD. Clinical predictors of sleep problems during pharmacotherapy include age, sleep problems prior to initiating treatment, and dose and dosing schedule. As yet, we have little understanding of the biological or genetic factors related to individual variation in drug response and sleep.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0130-0) contains supplementary material, which is available to authorized users.
PMCID: PMC3441938  PMID: 22718078
ADHD; Sleep; Psychopharmacology
11.  Risk Profiles and Treatment Patterns among Men diagnosed with Prostate Cancer and a Prostate Specific Antigen Level Below 4.0 ng/ml 
Archives of internal medicine  2010;170(14):1256-1261.
Despite controversy over the benefit of prostate specific antigen (PSA) screening, little is known about risk profiles and treatment patterns in men diagnosed with prostate cancer who have a PSA value less than or equal to 4 ng/mL.
We utilized data from the Surveillance, Epidemiology, End Results system to describe patient characteristics and treatment patterns of 123,934 men with newly diagnosed prostate cancer in 2004–2006. Age-standardized treatment rates were calculated in five-year age strata. Logistic regression was used to quantify the odds ratios (OR) of men with low– and high–risk disease and the use of radical prostatectomy (RP) or radiation therapy (RT).
Men with a PSA of 4.0 ng/ml or less represent 14% of incident prostate cancer cases. Fifty-four percent of men diagnosed with prostate cancer and PSA ≤ 4.0 ng/mL harbor low-risk disease (stage ≤ T2a, PSA level ≤ 10 ng/mL, and Gleason score ≤ 6), but over 75% of them received RP or RT. Men with screen-detected prostate cancer and PSA values ≤ 4 ng/mL were 1.49 (CI 1.38–1.62) and 1.39 (CI 1.30–1.49) times more likely to receive RP and RT, respectively, and were less likely to have high-grade disease than men who had non-screen detected prostate cancer (OR=0.67; 95% CI:0.60–0.76).
Most men diagnosed with prostate cancer with a PSA threshold ≤ 4.0 ng/mL had low-risk disease but underwent aggressive local therapy. Lowering biopsy threshold, while lacking the ability to distinguish indolent cancers from aggressive cancers, may increase overdiagnosis and overtreatment.
PMCID: PMC3651841  PMID: 20660846
12.  Newborn thyroxine levels and childhood ADHD 
Clinical biochemistry  2002;35(2):131-136.
Normal brain development is highly dependent on adequate levels of iodine and thyroid hormone. It has been suggested that Attention Deficit Hyperactivity Disorder (ADHD) is the consequence of prenatal thyroidal endocrine disruption. The hypothesis was examined using neonatal thyroxine levels as a bio-marker of prenatal thyroid status and comparing it to subsequent development of ADHD.
Design and methods
In a matched case-control study, cases were defined as children diagnosed with ADHD, while children born in the same hospital and tested on the same day served as matched controls. Conditional logistic regression analysis with unequal numbers of controls was performed.
The neonatal thyroxine levels were within normal limits for each of the children who were subsequently diagnosed as having ADHD, and their distribution was no different from that of their controls.
Children diagnosed with ADHD do not demonstrate prenatal thyroidal dysfunction as reflected in the newborn thyroxine levels, therefore neonatal thyroxine levels are not a bio-marker for the subsequent development of ADHD.
PMCID: PMC3635835  PMID: 11983348
Neonatal thyroxine (T4); Thyroid hormone; Attention deficit hyperactivity disorder; ADHD; Thyroid dysfunction
13.  Identification of the DNA Repair Defects in a Case of Dubowitz Syndrome 
PLoS ONE  2013;8(1):e54389.
Dubowitz Syndrome is an autosomal recessive disorder with a unique set of clinical features including microcephaly and susceptibility to tumor formation. Although more than 140 cases of Dubowitz syndrome have been reported since 1965, the genetic defects of this disease has not been identified. In this study, we systematically analyzed the DNA damage response and repair capability of fibroblasts established from a Dubowitz Syndrome patient. Dubowitz syndrome fibroblasts are hypersensitive to ionizing radiation, bleomycin, and doxorubicin. However, they have relatively normal sensitivities to mitomycin-C, cisplatin, and camptothecin. Dubowitz syndrome fibroblasts also have normal DNA damage signaling and cell cycle checkpoint activations after DNA damage. These data implicate a defect in repair of DNA double strand break (DSB) likely due to defective non-homologous end joining (NHEJ). We further sequenced several genes involved in NHEJ, and identified a pair of novel compound mutations in the DNA Ligase IV gene. Furthermore, expression of wild type DNA ligase IV completely complement the DNA repair defects in Dubowitz syndrome fibroblasts, suggesting that the DNA ligase IV mutation is solely responsible for the DNA repair defects. These data suggests that at least subset of Dubowitz syndrome can be attributed to DNA ligase IV mutations.
PMCID: PMC3556036  PMID: 23372718
14.  Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: A randomized phase II trial by the Prostate Cancer Clinical Trials Consortium 
Investigational new drugs  2010;29(6):1432-1440.
Integrins are involved in prostate cancer metastasis by regulating cell adhesion, migration, invasion, motility, angiogenesis and bone metabolism. We evaluated the efficacy of two dose levels of cilengitide in patients (pts) with castrate resistant prostate cancer (CRPC).
Chemotherapy-naïve, asymptomatic metastatic CRPC pts were randomized to cilengitide 500mg or 2000mg IV twice weekly using parallel 2-stage design. The primary endpoint was rate of objective clinical progression at six-months. Secondary endpoints included clinical and PSA response rates, safety and effects of cilengitide treatment on circulating tumor cells (CTCs) and bone remodeling markers.
Forty-four pts were accrued to first stage (22/arm). Median number of cycles was three in both arms (500mg arm: 1–8; 2000 mg arm: 1–15). At six months, two pts (9%) on the 500mg arm and five pts (23%) on the 2000mg arm had not progressed. Best objective response was stable disease (SD) in seven pts for 9.9[8.1,20.9] months. There were three grade 3 and no grade 4 toxicities. At 12 weeks, analysis of bone markers did not reveal significant trends. At progression, bone specific alkaline phosphatase and N-telopeptide increased in all pts, less so in pts on the 2000mg arm and in pts on both arms who obtained SD at 6 months. CTCs increased over time in both arms.
Cilengitide was well tolerated with modest clinical effect in favor of the higher dose. The unique trial design including a shift from response rate to objective progression as the endpoint, and not acting on PSA increases was feasible.
PMCID: PMC2917503  PMID: 20336348
prostate cancer; metastatic disease; integrins; angiogenesis; cilengitide; bone biomarkers
15.  Dose Effects and Comparative Effectiveness of Extended Release Dexmethylphenidate and Mixed Amphetamine Salts 
To compare the dose effects of long-acting extended-release dexmethylphenidate (ER d-MPH) and ER mixed amphetamine salts (ER MAS) on attention-deficit/hyperactivity disorder (ADHD) symptom dimensions, global and specific impairments, and common adverse events associated with stimulants.
Fifty-six children and adolescents with ADHD participated in an 8-week, double-blind, crossover study comparing ER d-MPH (10, 20, 25–30 mg) and ER MAS (10, 20, 25–30) with a week of randomized placebo within each drug period. Efficacy was assessed with the ADHD Rating Scale-IV (ADHD-RS-IV), whereas global and specific domains of impairment were assessed with the Clinical Global Impressions Severity and Improvement Scales and the parent-completed Weiss Functional Impairment Scale, respectively. Insomnia and decreased appetite, common stimulant-related adverse events, were measured with the parent-completed Stimulant Side Effects Rating Scale.
Both ER d-MPH and ER MAS were associated with significant reductions in ADHD symptoms. Improvement in Total ADHD and Hyperactivity/Impulsivity symptoms were strongly associated with increasing dose, whereas improvements in Inattentive symptoms were only moderately associated with dose. About 80% demonstrated reliable change on ADHD-RS-IV at the highest dose level of ER MAS compared with 79% when receiving ER d-MPH. Decreased appetite and insomnia were more common at higher dose levels for both stimulants. Approximately 43% of the responders were preferential responders to only one of the stimulant formulations.
Dose level, rather than stimulant class, was strongly related to medication response.
PMCID: PMC3243461  PMID: 22136094
16.  Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder 
Due to significant individual variability in Attention Deficit/Hyperactivity Disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examines the role of 4 catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response.
89 stimulant-naïve children with ADHD aged 7–11 participated in a randomized, double-blind, crossover trial of long-acting MPH. Parents and teachers assessed each child’s response on placebo and three MPH dosage levels using the Vanderbilt ADHD rating scales. Children were genotyped for polymorphisms in the dopamine transporter’s (DAT) 3’ untranslated region, dopamine receptor D4‘s (DRD4) exon 3, catechol-O-methyltransferase’s (COMT) codon 158, and adrenergic α2A-receptor’s (ADRA2A) promoter. Linear mixed models evaluated gene, dose (mg/kg/day), and gene*dose effects on inattentive and hyperactive-impulsive domain outcomes.
The most statistically significant gene*dose interactions were observed on hyperactive-impulsive symptoms for DRD4 and DAT polymorphisms, with participants lacking the DAT 10-repeat allele experiencing greater improvements in symptoms with increasing dose compared to 10-repeat carriers (p=0.008), and those lacking the DRD4 4-repeat allele showing less improvement across MPH doses compared to 4-repeat carriers (p=0.02).
This study suggests that DAT and DRD4 polymorphisms may be associated with individual variability in methylphenidate dose-response, although further research in larger samples is required to confirm these findings and their clinical utility.
PMCID: PMC3225067  PMID: 22024001
ADHD; pharmacogenetics; methylphenidate; dopamine receptor D4; dopamine transporter
17.  Rationally designed treatment for solid tumors with MAPK pathway activation: a Phase I study of paclitaxel and bortezomib using an adaptive dose-finding approach 
Molecular cancer therapeutics  2011;10(8):1509-1519.
In the preclinical setting, phosphorylation and subsequent proteosomal degradation of the proapoptotic protein BIM confers resistance to paclitaxel in solid tumors with RAS/RAF/MAPK pathway activation. Concurrent administration of the proteasome inhibitor bortezomib enables paclitaxel-induced BIM accumulation, restoring cancer cell apoptosis in vitro and producing tumor regression in mice in vivo. A Phase I study was conducted to determine the MTD of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors commonly exhibiting MAPK pathway activation were treated with weekly paclitaxel and bortezomib. Starting doses were 40 mg/m2 for paclitaxel and 0.7 mg/m2 for bortezomib. A modified continual reassessment method (MCRM) adapted for 2-drug escalation was used for MTD determination with 3-patient cohorts treated at each dose level. MTD was reached at 60 mg/m2 paclitaxel and 1.0 mg/m2 bortezomib, the recommended phase II dose. Therapy was overall well tolerated. Most frequently observed toxicities included anemia (in 43.75% of patients, one Grade 3 event), fatigue (in 43.75% of patients, one Grade 3 event beyond cycle 1) and neuropathy (in 31.25% of patients, one Grade 3 event after cycle 1). Of 15 evaluable patients, one NSCLC patient with paclitaxel exposure at the adjuvant setting had a PR and five patients had SD; median disease stabilization was 143.5 days; three NSCLC patients had SD lasting 165 days or longer. Thus, rationally designed weekly treatment with paclitaxel and bortezomib in solid tumors with MAPK pathway activation, including previously taxane-treated malignancies, is a tolerable regimen with preliminary signals of antitumor activity worthy of further investigation.
PMCID: PMC3155243  PMID: 21680752
MAPK; paclitaxel; bortezomib; BIM; apoptosis
18.  Autophagy Suppresses RIP Kinase-Dependent Necrosis Enabling Survival to mTOR Inhibition 
PLoS ONE  2012;7(7):e41831.
mTOR inhibitors are used clinically to treat renal cancer but are not curative. Here we show that autophagy is a resistance mechanism of human renal cell carcinoma (RCC) cell lines to mTOR inhibitors. RCC cell lines have high basal autophagy that is required for survival to mTOR inhibition. In RCC4 cells, inhibition of mTOR with CCI-779 stimulates autophagy and eliminates RIP kinases (RIPKs) and this is blocked by autophagy inhibition, which induces RIPK- and ROS-dependent necroptosis in vitro and suppresses xenograft growth. Autophagy of mitochondria is required for cell survival since mTOR inhibition turns off Nrf2 antioxidant defense. Thus, coordinate mTOR and autophagy inhibition leads to an imbalance between ROS production and defense, causing necroptosis that may enhance cancer treatment efficacy.
PMCID: PMC3406086  PMID: 22848625
19.  A phase I trial of MK-0731, a Kinesin Spindle Protein (KSP) inhibitor, in patients with solid tumors 
Investigational New Drugs  2011;30(3):1088-1095.
The kinesin spindle protein (KSP) is essential for separation of spindle poles during mitosis. Its inhibition results in mitotic arrest. This phase I trial examined safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic parameters, and anti-tumor activity of MK-0731, a potent inhibitor of KSP.
Experimental design
In part 1, patients with advanced solid tumors received MK-0731 intravenously over 24 h every 21 days starting at 6 mg/m2, escalating until MTD was reached. In part 2, patients with taxane-resistant tumors received the MTD. Plasma samples were collected to analyze the pharmacokinetics of MK-0731. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0.
In part 1, 21 patients (median age 63 years) were treated with MK-0731 at doses ranging from 6 to 48 mg/m2/24 h for median four cycles. The dose-limiting toxicity was neutropenia and the MTD was 17 mg/m2/24 h. At the MTD, AUC (±SD) was 10.5 (±7.3) μM × hour, clearance (±SD) was 153 mL/min (±84), and t1/2 was 5.9 h. In part 2, 22 patients received the MTD and there were no DLTs. Although there were no objective tumor responses, four patients (with cervical, non-small cell lung, and ovarian cancers) had prolonged stable disease.
MK-0731 at the MTD of 17 mg/m2/day every 21 days in patients with solid tumors had few grade 3 and 4 toxicities with the major DLTs at higher doses being myelosuppression. Anti-tumor efficacy was suggested by the length of stable disease in selected patients with taxane-resistant tumors.
PMCID: PMC3394096  PMID: 21424701
Kinesin spindle protein; Oncology; Neutropenia
20.  Transdermal estradiol in castrate and chemotherapy resistant prostate cancer 
Given prior studies demonstrating the marked clinical activity of oral estrogens in prostate cancer, more recent data demonstrating the safety of transdermal estradiol, and the renewed interest in targeting testosterone metabolism and androgen receptor pathways, we report the results of a trial of transdermal estradiol in advanced heavily pre-treated castrate and chemotherapy refractory patients.
Patients with prostate cancer progressing after androgen ablation therapy and chemotherapy were treated with transdermal estradiol patches (0.4 mg per 24 hours total) applied weekly and assessed for tolerability and biochemical activity.
Twenty-two patients were treated on study with all patients evaluable for safety and 20 patients evaluable for response. All patients had aggressive and resistant disease, as demonstrated by a median PSA of 170 ng/mL (range 14 to 5030 ng/mL), with more than 60% having been treated with two or more prior chemotherapy regimens, and 20% with visceral disease. Nine patients had a decrease in PSA, of which two patients had a PSA response defined as a decline in PSA by 50%. Therapy was well tolerated and no thrombotic events were observed.
In heavily pre-treated patients with advanced castrate and chemotherapy refractory metastatic prostate cancer, transdermal estradiol was safe and had biochemical activity. These data support further studies to understand if transdermal estradiol can be useful following multiple standard therapies.
PMCID: PMC3560819  PMID: 22460098
estradiol; abiraterone; testosterone; prostate cancer
21.  Safety, Efficacy and Pharmacokinetics of a New 10% Liquid Intravenous Immunoglobulin (IVIG) in Patients with Primary Immunodeficiency 
Journal of Clinical Immunology  2012;32(4):663-669.
An investigational 10% liquid intravenous immunoglobulin (IVIG) was studied in 63 patients with primary immunodeficiency (PID) at 15 study sites.
Patients were treated every 3 or 4 weeks with 254–1029 mg/kg/infusion of IVIG.
Overall, Biotest-IVIG infusions were well tolerated. The proportion of infusions that were associated with adverse events during infusion, and up to 72 h after infusion, including those unrelated to study product, was 27.7% with an upper 95% confidence limit ≤30.6%. Two serious bacterial infections (SBIs) were observed resulting in a serious bacterial infection rate of 0.035 per person per year and an upper one-sided 99% confidence limit of ≤0.136 SBI/patient/year. The number of days of work or school missed due to infection were relatively low at 2.28 days/patient/year. Two patients were hospitalized for infection producing a rate of 0.21 hospitalization days/patient/year. The IgG half-life was approximately 30 days with variation among individuals.
Pharmacokinetic parameters of specific antibody activities were essentially the same as those of total IgG. Biotest-IVIG is safe and effective in the treatment of PID.
PMCID: PMC3389237  PMID: 22392046
Intravenous immunoglobulin (IVIG); primary immunodeficiency (PID); clinical trial; safety; efficacy; pharmacokinetics
22.  Variable sleep schedules and outcomes in children with psychopathological problems: preliminary observations 
Night-to-night variability in sleep of children with attention deficit hyperactivity disorder (ADHD) may be a mediator of behavioral phenotype. We examined the potential association between alertness, sleep, and eating behaviors in children with ADHD and comorbid problems.
Sleep was monitored by actigraphy for 7 days. Questionnaires were used to assess sleep complaints, habits and food patterns by parental report, and sleep complaints and sleepiness by child report.
The group comprised 18 children, including 15 boys, aged 9.4 ± 1.7 years, 88.9% Caucasian, who took one or multiple medications. Children slept on average for 6 hours and 58 minutes with a variability of 1 hour 3 minutes relative to the mean, and their sleepiness scores were highly variable from day to day. Most children had a normal body mass index (BMI). Sleepiness and BMI were associated with sleep schedules and food patterns, such that they accounted for 76% of variance, predominantly by the association of BMI with mean wake after sleep onset and by bedtime sleepiness, with wake after sleep onset variability. Similarly, 97% of variance was shared with eating behaviors, such as desserts and snacks, and fast food meals were associated with morning sleepiness.
Disrupted sleep and sleepiness appears to favor unhealthy food patterns and may place children with ADHD at increased risk for obesity.
PMCID: PMC3630967  PMID: 23616725
sleep; child; attention deficit hyperactivity disorder; actigraphy
23.  Effect of dopamine transporter genotype on caudate volume in childhood ADHD and controls 
Polymorphism of the dopamine transporter genotype (DAT1) confers a small but significant susceptibility to Attention Deficit Hyperactivity Disorder (ADHD). We examined whether the volume of the head of caudate, a striatal structure with high DAT expression that is important for inhibitory function, differs by DAT1 in a children diagnosed with the disorder relative to age and IQ matched controls.
Volume of the head of caudate was delineated in the right and left hemisphere and compared between 7–13 year old children with and without ADHD (Combined type) who were carriers of two (10/10) or one (9/10) copy of the 10-repeat DAT1 allele.
Caudate volumes were overall smaller 10/10 than 9/10 children, particularly in the left than right hemisphere. While DAT1 effects did not vary by ADHD diagnosis, overall caudate volumes were smaller in ADHD relative to control children.
Altered caudate development associated with 10-repeat homozygosity of DAT1 may contribute susceptibility to ADHD.
PMCID: PMC3010298  PMID: 20957668
Brain; structure; VNTR; polymorphism; striatal
24.  New Frontiers in Subcutaneous Immunoglobulin Treatment 
Biologics in Therapy  2011;1(1):3.
Subcutaneous immunoglobulin (SCIG) treatment provides stable serum immunoglobulin G (IgG) levels, is associated with fewer systemic adverse events than intravenous immunoglobulin (IVIG) treatment, and offers the convenience of home therapy. In clinical practice, IVIG is still used preferentially for initiation of treatment in newly diagnosed patients with primary immunodeficiency (PI) and for immunomodulatory therapy, such as treatment of peripheral neuropathies, when high doses are believed to be necessary. The authors discuss recent experience in using SCIG in place of IVIG in these settings. SCIG has been successfully used for initiation of therapy in previously untreated PI patients. Seventeen of 18 PI patients achieved serum IgG levels ≥5 g/L after the loading phase. Daily treatment was well tolerated and provided opportunities for patient/parent training in self-infusion. SCIG has been used for maintenance therapy in multifocal motor neuropathy (MMN) in three recent clinical trials, with good efficacy and tolerability results. Seven of eight MMN patients maintained serum IgG levels of 14–22 g/L with a mean dose of 272 mg/kg/week, had stable muscle strength, and felt comfortable with self-administration. Four patients with polymyositis or dermatomyositis achieved improvement in serum creatine kinase levels and muscle strength with SCIG therapy. Recent experience with SCIG suggests that traditional concepts of immunoglobulin therapy may be challenged to increase available therapy options. SCIG can be used to achieve high IgG levels within several days in untreated PI patients and to maintain high serum levels, as shown in patients with MMN.
PMCID: PMC3873072  PMID: 24392293
immunoglobulin G; immunoglobulin therapy; multifocal motor neuropathy; primary immunodeficiencies; serum levels; subcutaneous administration
25.  New Frontiers in Subcutaneous Immunoglobulin Treatment 
Biologics in Therapy  2011;1(1):3.
Subcutaneous immunoglobulin (SCIG) treatment provides stable serum immunoglobulin G (IgG) levels, is associated with fewer systemic adverse events than intravenous immunoglobulin (IVIG) treatment, and offers the convenience of home therapy. In clinical practice, IVIG is still used preferentially for initiation of treatment in newly diagnosed patients with primary immunodeficiency (PI) and for immunomodulatory therapy, such as treatment of peripheral neuropathies, when high doses are believed to be necessary. The authors discuss recent experience in using SCIG in place of IVIG in these settings. SCIG has been successfully used for initiation of therapy in previously untreated PI patients. Seventeen of 18 PI patients achieved serum IgG levels ≥5 g/L after the loading phase. Daily treatment was well tolerated and provided opportunities for patient/parent training in self-infusion. SCIG has been used for maintenance therapy in multifocal motor neuropathy (MMN) in three recent clinical trials, with good efficacy and tolerability results. Seven of eight MMN patients maintained serum IgG levels of 14–22 g/L with a mean dose of 272 mg/kg/week, had stable muscle strength, and felt comfortable with self-administration. Four patients with polymyositis or dermatomyositis achieved improvement in serum creatine kinase levels and muscle strength with SCIG therapy. Recent experience with SCIG suggests that traditional concepts of immunoglobulin therapy may be challenged to increase available therapy options. SCIG can be used to achieve high IgG levels within several days in untreated PI patients and to maintain high serum levels, as shown in patients with MMN.
PMCID: PMC3873072  PMID: 24392293
immunoglobulin G; immunoglobulin therapy; multifocal motor neuropathy; primary immunodeficiencies; serum levels; subcutaneous administration

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