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1.  Spexin is a Novel Human Peptide that Reduces Adipocyte Uptake of Long Chain Fatty Acids and Causes Weight Loss in Rodents with Diet-induced Obesity* 
Obesity (Silver Spring, Md.)  2014;22(7):1643-1652.
Objective
Microarray studies identified Ch12:orf39 (Spexin) as the most dysregulated gene in obese human fat. Therefore we examined its role in obesity pathogenesis.
Design and Methods
Spexin effects on food intake, meal patterns, body weight, Respiratory Exchange Ratio (RER), and locomotor activity were monitored electronically in C57BL/6J mice or Wistar rats with dietary-induced obesity (DIO). Its effects on adipocyte [3H]-oleate uptake were determined.
Results
In humans, Spexin gene expression was down-regulated 14.9-fold in obese omental and subcutaneous fat. Circulating Spexin changed in parallel, correlating (r = −0.797) with Leptin. In rats, Spexin (35 μg/kg/day s.c) reduced caloric intake ~32% with corresponding weight loss. Meal patterns were unaffected. In mice, Spexin (25 μg/kg/day i.p.) significantly reduced the RER at night, and increased locomotion. Spexin incubation in vitro significantly inhibited facilitated fatty acid (FA) uptake into DIO mouse adipocytes. Conditioned taste aversion testing (70μg/kg/day i.p.) demonstrated no aversive Spexin effects.
Conclusions
Spexin gene expression is markedly down-regulated in obese human fat. The peptide produces weight loss in DIO rodents. Its effects on appetite and energy regulation are presumably central; those on adipocyte FA uptake appear direct and peripheral. Spexin is a novel hormone involved in weight regulation, with potential for obesity therapy.
doi:10.1002/oby.20725
PMCID: PMC4077920  PMID: 24550067
2.  Calcium and Vitamin D Supplementation and Loss of Bone Mineral Density in Women Undergoing Breast Cancer Therapy 
Critical reviews in oncology/hematology  2013;88(3):10.1016/j.critrevonc.2013.07.002.
An unintended consequence of breast cancer therapies is an increased risk of osteoporosis due to accelerated bone loss. We conducted a systematic review of calcium and/or vitamin D (Ca±D) supplementation trials for maintaining bone mineral density (BMD) in women with breast cancer using the “before-after” data from the Ca±D supplemented comparison group of trials evaluating the effect of drugs such as bisphosphonates on BMD. Whether Ca±D supplements increase BMD in women undergoing breast cancer therapy has never been tested against an unsupplemented control group. However, results from 16 trials indicate that the Ca±D doses tested (500-1500 mg calcium; 200-1000 IU vitamin D) were inadequate to prevent BMD loss in these women. Cardiovascular disease is the main cause of mortality in women with breast cancer. Because calcium supplements may increase cardiovascular disease risk, future trials should evaluate the safety and efficacy of Ca±D supplementation in women undergoing breast cancer therapy.
doi:10.1016/j.critrevonc.2013.07.002
PMCID: PMC3844003  PMID: 23932583
breast cancer; calcium; vitamin D; osteoporosis; bone mineral density
3.  Effect of Selumetinib versus Chemotherapy on Progression-Free Survival in Uveal Melanoma: A Randomized Clinical Trial 
JAMA  2014;311(23):2397-2405.
Importance
Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in MAPK pathway activation.
Objective
To assess the efficacy of selumetinib, a selective, non-ATP competitive inhibitor of MEK1 and MEK2, in uveal melanoma.
Design
Randomized open-label phase II clinical trial comparing selumetinib versus chemotherapy. Those receiving chemotherapy could receive selumetinib at the time of radiographic progression.
Setting
Fifteen academic oncology centers.
Participants
120 patients with metastatic uveal melanoma.
Interventions
101 patients were randomized on a 1:1 ratio to selumetinib 75 mg orally twice daily on a continual basis (n=50) or chemotherapy (temozolomide 150 mg/m2 orally daily for 5 of every 28 days or DTIC 1000 mg/m2 intravenously every 21 days; investigator choice; n=51) until disease progression, death, intolerable toxicity, or withdrawal of consent. Following primary outcome analysis, enrollment continued in a non-randomized fashion to the superior therapy.
Main Outcomes
Final analysis of progression-free survival, the primary endpoint, was assessed as of April 22, 2013. Additional endpoints, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013.
Results
Median progression-free survival for those randomized to chemotherapy and selumetinib was 7 (95% CI, 4.3 – 8.4; median treatment duration of 8 weeks (IQR, 4.3–16)) and 15.9 weeks (95% CI, 8.4 – 21.1; median treatment duration of 16.1 weeks (IQR, 8.1–25.3)), respectively (hazard ratio 0.46; 95% CI, 0.30 – 0.71; p < 0.001). Median overall survival was 9.1 (95% CI, 6.1 – 11.1) and 11.8 months (95% CI, 9.8 – 15.7) for those randomized to chemotherapy and selumetinib, respectively (hazard ratio 0.66; 95% CI, 0.41–1.06; p=0.09). No objective responses were observed with chemotherapy. 49% of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% patients treated with selumetinib, with 37% requiring at least one dose reduction.
Conclusions and Relevance
In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high adverse event rate.
doi:10.1001/jama.2014.6096
PMCID: PMC4249701  PMID: 24938562
Uveal; melanoma; MEK; GNAQ; GNA11
4.  Immunologic Response to Xenogeneic gp100 DNA in Melanoma Patients: Comparison of Particle Mediated Epidermal Delivery with Intramuscular Injection 
Purpose
Prior studies show that intramuscular (IM) injection of xenogeneic orthologues of melanosomal antigens (tyrosinase, gp100) induces CD8+ T cell responses to the syngeneic protein. To further define the optimal vaccination strategy, we conducted a pilot clinical trial comparing IM injection with particle-mediated epidermal delivery (PMED).
Experimental Design
Human leukocyte antigen (HLA)-A*0201+ disease-free melanoma patients were randomized to the PMED or IM arm, receiving 8 vaccinations over 4 months. Patients received 4 μg or 2000 μg per injection, respectively, of mouse gp100 DNA. Peripheral blood mononuclear cells (PBMCs) were collected, cultured with gp100 peptides and analyzed by tetramer and intracellular cytokine staining (ICS) for responses to HLA-A*0201-restricted gp100 epitopes [gp100209-217 (ITDQVPFSV) and gp100280-288 (YLEPGPVTA)].
Results
Twenty seven patients with stage IIB-IV melanoma were analyzable for immune response. The only common toxicity was grade I injection site reaction in 9 patients with no intergroup difference, while one dose-limiting toxicity of acute hypersensitivity occurred in a PMED patient with undiagnosed gold allergy. Four of 27 patients produced gp100 tetramer+CD8+ T cells, all carrying the CCR7loCD45RAlo effector-memory phenotype. Five of 27 patients generated interferon-γ+ (IFN-γ) CD8+ T cells, one who was also tetramer-positive. Overall, vaccination induced a response in 30% of patients, which was not significantly associated with study arm or clinical outcome. However, the PMED group showed a trend toward increased IFN-γ+CD8+ T cell generation (p=0.07).
Conclusion
A comparable efficacy and safety profile was demonstrated between the IM and PMED arms, despite a significantly decreased dose of DNA used for PMED injection.
doi:10.1158/1078-0432.CCR-10-1093
PMCID: PMC4241567  PMID: 20647477
gp100; DNA; vaccine; PMED; melanoma
5.  The Treatment of Hypertension During Pregnancy: When Should Blood Pressure Medications Be Started? 
Current cardiology reports  2013;15(11):10.1007/s11886-013-0412-0.
Hypertensive pregnancy disorders (HPD) are important causes of maternal and fetal morbidity and mortality worldwide. In addition, a history of HPD has been associated with an increased risk for maternal cardiovascular disease later in life, possibly due to irreversible vascular and metabolic changes that persist beyond the affected pregnancies. Therefore, treatment of HPD may not only improve immediate pregnancy outcomes, but also the maternal long-term cardiovascular health. Unlike the recommendations for hypertension treatment in the general population, treatment recommendations of HPD have not changed substantially for more than two decades. This is particularly true for mild to moderate hypertension in pregnancy, defined as a blood pressure of 140–159/90–109 mm Hg.
This review focuses on the goals of therapy, treatment strategies, and new developments in the field of HPD that should be taken into account when considering blood pressure targets and pharmacological options for treatment of hypertension in pregnant women.
doi:10.1007/s11886-013-0412-0
PMCID: PMC3859314  PMID: 24057769
Hypertension; Treatment; Pregnancy induced; Antihypertensive agents; Cardiovascular diseases in women; Blood pressure medications
6.  Prenatal Polycyclic Aromatic Hydrocarbon, Adiposity, Peroxisome Proliferator-Activated Receptor (PPAR) γ Methylation in Offspring, Grand-Offspring Mice 
PLoS ONE  2014;9(10):e110706.
Rationale
Greater levels of prenatal exposure to polycyclic aromatic hydrocarbon (PAH) have been associated with childhood obesity in epidemiological studies. However, the underlying mechanisms are unclear.
Objectives
We hypothesized that prenatal PAH over-exposure during gestation would lead to weight gain and increased fat mass in offspring and grand-offspring mice. Further, we hypothesized that altered adipose gene expression and DNA methylation in genes important to adipocyte differentiation would be affected.
Materials and Methods
Pregnant dams were exposed to a nebulized PAH mixture versus negative control aerosol 5 days a week, for 3 weeks. Body weight was recorded from postnatal day (PND) 21 through PND60. Body composition, adipose cell size, gene expression of peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer-binding proteins (C/EBP) α, cyclooxygenase (Cox)-2, fatty acid synthase (FAS) and adiponectin, and DNA methylation of PPAR γ, were assayed in both the offspring and grand-offspring adipose tissue.
Findings
Offspring of dams exposed to greater PAH during gestation had increased weight, fat mass, as well as higher gene expression of PPAR γ, C/EBP α, Cox2, FAS and adiponectin and lower DNA methylation of PPAR γ. Similar differences in phenotype and DNA methylation extended through the grand-offspring mice.
Conclusions
Greater prenatal PAH exposure was associated with increased weight, fat mass, adipose gene expression and epigenetic changes in progeny.
doi:10.1371/journal.pone.0110706
PMCID: PMC4210202  PMID: 25347678
7.  Lysosomal drug sequestration as a mechanism of drug resistance in vascular sarcoma cells marked by high CSF-1R expression 
Vascular Cell  2014;6:20.
Background
Human angiosarcoma and canine hemangiosarcoma are thought to arise from vascular tissue or vascular forming cells based upon their histological appearance. However, recent evidence indicates a hematopoietic or angioblastic cell of origin for these tumors. In support of this idea, we previously identified an endothelial-myeloid progenitor cell population with high expression of endothelial cell markers and the myeloid cell marker, colony stimulating factor 1 receptor (CSF-1R). Here, we further characterized these cells to better understand how their cellular characteristics may impact current therapeutic applications.
Methods
We performed cell enrichment studies from canine hemangiosarcoma and human angiosarcoma cell lines to generate cell populations with high or low CSF-1R expression. We then utilized flow cytometry, side population and cell viability assays, and fluorescence based approaches to elucidate drug resistance mechanisms and to determine the expression of hematopoietic and endothelial progenitor cell markers.
Results
We demonstrated that cells with high CSF-1R expression enriched from hemangiosarcoma and angiosarcoma cell lines are more drug resistant than cells with little or no CSF-1R expression. We determined that the increased drug resistance may be due to increased ABC transporter expression in hemangiosarcoma and increased drug sequestration within cellular lysosomes in both hemangiosarcoma and angiosarcoma.
Conclusions
We identified drug sequestration within cellular lysosomes as a shared drug resistance mechanism in human and canine vascular sarcomas marked by high CSF-1R expression. Taken together, our results demonstrate that studies in highly prevalent canine hemangiosarcoma may be especially relevant to understanding and addressing drug resistance mechanisms in both the canine and human forms of this disease.
doi:10.1186/2045-824X-6-20
PMCID: PMC4188569  PMID: 25295160
Angiosarcoma; Chemoresistance; CSF-1R; Endothelial; Hemangiosarcoma; Lysosome; Myeloid
8.  Identification of a Loss-of-Function Mutation in Ube2l6 Associated With Obesity Resistance 
Diabetes  2013;62(8):2784-2795.
We previously mapped a locus on BALB/c chromosome 2 associated with protection from leptin-deficiency–induced obesity. Here, we generated the corresponding congenic mouse strain by introgression of a segment of C57BL/6J chromosome 2 to the BALB/c background to confirm the genotype–phenotype associations. We found that the BALB/c alleles decreased fat mass expansion by limiting adipocyte hyperplasia and adipocyte hypertrophy. This was concomitant to an increase in adipocyte triglyceride lipase (ATGL)-mediated triglyceride breakdown and prolongation of ATGL half-life in adipose tissue. In addition, BALB/c alleles on chromosome 2 exerted a cell-autonomous role in restraining the adipogenic potential of preadipocytes. Within a 9.8-Mb critical interval, we identified a nonsynonymous coding single nucleotide polymorphism in the gene coding for the ubiquitin-conjugating enzyme E2L6 (Ube2l6, also known as Ubch8) and showed that the BALB/c allele of Ube2l6 is a hypomorph leading to the lack of UBE2L6 protein expression. Ube2l6 knockdown in 3T3-L1 adipocytes repressed adipogenesis. Thus, altered adipogenic potential caused by Ube2l6 knockdown is likely critically involved in BALB/c obesity resistance by inhibiting adipogenesis and reducing adipocyte numbers. Overall, we have identified a loss-of-function mutation in Ube2l6 that contributes to the chromosome 2 obesity quantitative trait locus.
doi:10.2337/db12-1054
PMCID: PMC3717837  PMID: 23557705
9.  The Role of Plasma Renin Activity, Age, and Race in Selecting Effective Initial Drug Therapy for Hypertension 
American Journal of Hypertension  2013;26(8):957-964.
BACKGROUND
Strategies for initial drug therapy of hypertension are a thiazide diuretic for all or drug selection based on age/race criteria or on plasma renin activity (PRA). It is uncertain which of these strategies will achieve the highest control rate among patients with stage 1 essential hypertension. We sought to compare control rates among 3 drug selection strategies: (i) thiazide diuretic for all, (ii) thiazide diuretic for all black subjects and white subjects aged ≥50 years and a renin-angiotensin system blocker for white subjects aged <50 years, or (iii) thiazide diuretic for PRA < 0.6ng/ml/h (suppressed PRA) and a renin-angiotensin system blocker for PRA ≥ 0.6ng/ml/h (nonsuppressed PRA).
METHODS
Blood pressure responses from the Genetic Epidemiology of Responses to Antihypertensives (GERA) study were used to determine control rates for each of the 3 strategies. In GERA, hypertensive adults were treated with hydrochlorothiazide (n = 286 black subjects and 284 white subjects) or with candesartan (n = 248 black subjects and 278 white subjects).
RESULTS
In the overall sample, the PRA strategy was associated with the highest control rate of 69.4% vs. 61.3% with the age/race strategy (P < 0.001) and 53.8% with the thiazide for all strategy (P < 0.001). This was also true in each racial subgroup (in black subjects: 62.1% vs. 55.2% for the other 2 strategies, P = 0.02; in white subjects: 76.3% vs. 67.1% with the age/race strategy (P < 0.001) and 52.4% with the thiazide for all strategy (P < 0.001)).
CONCLUSIONS
This exploratory analysis suggests that choice of initial therapy for hypertension using a PRA strategy may be associated with higher control rates than alternative strategies recommended in current guidelines.
doi:10.1093/ajh/hpt047
PMCID: PMC3816320  PMID: 23591988
blood pressure; control rate; hypertension; pharmacotherapy.
10.  Genomic Association Analysis of Common Variants Influencing Antihypertensive Response to Hydrochlorothiazide 
Hypertension  2013;62(2):391-397.
To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of ≈1.1 million single nucleotide polymorphisms in a combined sample of 424 European Americans with primary hypertension treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses Study (N=228) and the Genetic Epidemiology of Responses to Antihypertensive Study (N=196). Polymorphisms associated with blood pressure response at p<10-5 were tested for replication of the associations in independent samples of hydrochlorothiazide-treated European hypertensives. The rs16960228 polymorphism in protein kinase C, alpha replicated for same-direction association with diastolic blood pressure response in the Nordic Diltiazem Study (N=420) and the Genetics of Drug Responsiveness in Essential Hypertension Study (N=206), and the combined four-study meta-analysis p-value achieved genome-wide significance (p=3.3 × 10-8). Systolic/diastolic blood pressure responses were consistently greater in carriers of the rs16960228 A allele than in GG homozygotes (4/4 mmHg greater) across study samples. The rs2273359 polymorphism in the GNAS-EDN3 region also replicated for same-direction association with systolic blood pressure response in the Nordic Diltiazem Study, and the combined three-study meta-analysis p-value approached genome-wide significance (p=5.5 × 10-8). The findings document clinically-important effects of genetic variation at novel loci on blood pressure response to a thiazide diuretic, which may be a basis for individualization of antihypertensive drug therapy and identification of new drug targets.
doi:10.1161/HYPERTENSIONAHA.111.00436
PMCID: PMC3780966  PMID: 23753411
Hypertension; high blood pressure; antihypertensive therapy/diuretics; hydrochlorothiazide; genomics; pharmacogenomics; protein kinase C
11.  A Phase 2 Study of Flavopiridol (Alvocidib) in Combination with Docetaxel in Refractory, Metastatic Pancreatic Cancer (NCI#6366) 
Background/Aims
Pancreatic adenocarcinoma (PC) harbors frequent alterations of p16, resulting in cell cycle dysregulation. A phase I study of docetaxel and flavopiridol, a pan-cyclin dependent kinase inhibitor, demonstrated encouraging clinical activity in PC. This phase II study was designed to further define the efficacy and toxicity of this regimen in patients with previously treated PC.
Methods
Patients with gemcitabine-refractory, metastatic PC were treated with docetaxel 35 mg/m2 followed by flavopiridol 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Tumor measurements were performed every two cycles. A Simon two-stage design was used to evaluate the primary endpoint of response.
Results
Ten patients were enrolled; nine were evaluable for response. No objective responses were observed; however, three patients (33%) achieved transient stable disease, with one of these patients achieving a 20% reduction in tumor size. Median survival was 4.2 months, with no patients alive at the time of analysis. Adverse events were significant, with seven patients (78%) requiring ≥1 dose reduction for transaminitis (11%), grade 4 neutropenia (33%), grade 3 fatigue (44%), and grade 3 diarrhea (22%)
Conclusions
The combination of flavopiridol and docetaxel has minimal activity and significant toxicity in this patient population. These results reflect the challenges of treating patients with PC in a second-line setting where the risk/benefit equation is tightly balanced.
doi:10.1159/000187135
PMCID: PMC4053191  PMID: 19451750
Docetaxel; Flavopiridol; Pancreatic adenocarcinoma
12.  Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients With Advanced CDK4-Amplified Well-Differentiated or Dedifferentiated Liposarcoma 
Journal of Clinical Oncology  2013;31(16):2024-2028.
Purpose
CDK4 is amplified in > 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS.
Patients and Methods
Patients age ≥ 18 years experiencing disease progression while receiving systemic therapy before enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day cycles. All were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥ 1+). The primary end point was progression-free survival (PFS) at 12 weeks, with 12-week PFS of ≥ 40% considered promising and ≤ 20% not promising. If ≥ nine of 28 patients were progression free at 12 weeks, PD0332991 would be considered active.
Results
We screened 48 patients (44 of 48 had CDK4 amplification; 41 of 44 were RB positive). Of those, 30 were enrolled, and 29 were evaluable for the primary end point. Grade 3 to 4 events included anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%). At 12 weeks, PFS was 66% (90% CI, 51% to 100%), significantly exceeding the primary end point. The median PFS was 18 weeks. There was one partial response.
Conclusion
Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.
doi:10.1200/JCO.2012.46.5476
PMCID: PMC3661937  PMID: 23569312
13.  Oral paricalcitol (19-nor-1,25-dihydroxyvitamin D2) in women receiving chemotherapy for metastatic breast cancer 
Cancer Biology & Therapy  2013;14(6):476-480.
The vitamin D hormone, [1,25(OH)2D, calcitriol], inhibits proliferation and angiogenesis in breast cancer but its therapeutic use is limited by hypercalcemia. Synthetic analogs of 1,25(OH)2D that are less calcemic, such as paricalcitol (19-nor-1,25-Dihydroxyvitamin D2), are used to treat hyperparathyroidism associated with chronic kidney disease. We sought to determine the safety and feasibility of taking oral paricalcitol with taxane-based chemotherapy in women with metastatic breast cancer (MBC). Oral paricalcitol was considered safe if it did not result in excessive toxicity, defined as grade 3 or higher serum calcium levels. It was considered feasible if the majority of women could take eight weeks of continuous therapy in the first three months. Serum calcium was monitored weekly and the paricalcitol dose was adjusted based on its calcemic effect. Intact parathyroid hormone (iPTH) was monitored as a marker of paricalcitol activity. Twenty-four women with MBC were enrolled. Twenty women (83%) received eight weeks of continuous therapy. Paricalcitol was well-tolerated with no instances of hypercalcemia grade 2 or greater. Fourteen women (54%) were able to escalate the dose. The dose range of paricalcitol in the first 3 mo was 2–7 ug/day. Serum iPTH levels at baseline were significantly higher in women with serum 25-Hydroxyvitamin D (25-OHD) levels less than 30 ng/ml (96.4 ± 40.9 pg/ml) vs. 46.2 ± 20.3 pg/ml (p = 0 0.001) (iPTH reference 12–72 pg/ml). We conclude that paricalcitol is safe and feasible in women with MBC who are receiving chemotherapy.
doi:10.4161/cbt.24350
PMCID: PMC3813563  PMID: 23760489
vitamin D; metastatic breast cancer; paricalcitol; cancer treatment
14.  Ipilimumab for Patients With Advanced Mucosal Melanoma 
The Oncologist  2013;18(6):726-732.
This multicenter, retrospective analysis assessed the efficacy and safety of ipilimumab in 33 patients with unresectable or metastatic mucosal melanoma. The study provides evidence that ipilimumab can result in durable antitumor effects in a subset of patients with mucosal melanoma, although the response rate was low.
The outcome of patients with mucosal melanoma treated with ipilimumab is not defined. To assess the efficacy and safety of ipilimumab in this melanoma subset, we performed a multicenter, retrospective analysis of 33 patients with unresectable or metastatic mucosal melanoma treated with ipilimumab. The clinical characteristics, treatments, toxicities, radiographic assessment of disease burden by central radiology review at each site, and mutational profiles of the patients' tumors were recorded. Available peripheral blood samples were used to assess humoral immunity against a panel of cancer-testis antigens and other antigens. By the immune-related response criteria of the 30 patients who underwent radiographic assessment after ipilimumab at approximately week 12, there were 1 immune-related complete response, 1 immune-related partial response, 6 immune-related stable disease, and 22 immune-related progressive disease. By the modified World Health Organization criteria, there were 1 immune-related complete response, 1 immune-related partial response, 5 immune-related stable disease, and 23 immune-related progressive disease. Immune-related adverse events (as graded by Common Terminology Criteria for Adverse Events version 4.0) consisted of six patients with rash (four grade 1, two grade 2), three patients with diarrhea (one grade 1, two grade 3), one patient with grade 1 thyroiditis, one patient with grade 3 hepatitis, and 1 patient with grade 2 hypophysitis. The median overall survival from the time of the first dose of ipilimumab was 6.4 months (range: 1.8–26.7 months). Several patients demonstrated serologic responses to cancer-testis antigens and other antigens. Durable responses to ipilimumab were observed, but the overall response rate was low. Additional investigation is necessary to clarify the role of ipilimumab in patients with mucosal melanoma.
doi:10.1634/theoncologist.2012-0464
PMCID: PMC4063400  PMID: 23716015
Mucosal melanoma; Ipilimumab; CTLA-4; Immunotherapy; Cancer-testis antigens
15.  Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis 
Journal of hepatology  2013;58(5):1000-1006.
Background & Aims
Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that Krüppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPARα-signaling.
Methods
Mice with either hepatocyte-specific depletion of KLF6 (‘DeltaHepKlf6’) or global KLF6 heterozygosity (Klf6 +/−) were fed a high fat diet (HFD) or chow for 8 or 16 weeks. Glucose and insulin tolerance tests were performed to assess insulin sensitivity. Overexpression and knockdown of KLF6 in cultured cells enabled the elucidation of underlying mechanisms. In liver samples from a cohort of 28 NAFLD patients, the expression of KLF6-related target genes was quantified.
Results
Mice with global- or hepatocyte-depletion of KLF6 have reduced body fat content and improved glucose and insulin tolerance, and are protected from HFD-induced steatosis. In hepatocytes, KLF6 deficiency reduces PPARα-regulated genes (Trb3, Pepck) with diminished PPARα-protein but no change in Pparα-mRNA which is explained by the discovery that KLF6 represses miRNA 10b, which leads to induction of PPARα. In NAFLD-patients with advanced disease and inflammation, the expression of miRNA 10b is significantly down-regulated, while PEPCK mRNA is up-regulated; KLF6 mRNA expression also correlates with TRB3 as well as PEPCK gene expression.
Conclusions
KLF6 increases PPAR -activity, whereas KLF6 loss leads to PPARα repression and attenuation of lipid and glucose abnormalities associated with a high fat diet. The findings establish KLF6 as a novel regulator of hepatic glucose and lipid metabolism in fatty liver.
doi:10.1016/j.jhep.2013.01.020
PMCID: PMC3631429  PMID: 23353867
KLF6; PPARα; TRB3; PEPCK; CD36; miRNA-10b; NAFLD
16.  Functional Organization of Neuronal and Humoral Signals Regulating Feeding Behavior 
Energy homeostasis- ensuring that energy availability matches energy requirements- is essential for survival. One way that energy balance is achieved is through coordinated action of neural and neuroendocrine feeding circuits, which promote energy intake when energy supply is limited. Feeding behavior engages multiple somatic and visceral tissues distributed throughout the body – contraction of skeletal and smooth muscles in the head and along the upper digestive tract required to consume and digest food, as well as stimulation of endocrine and exocrine secretions from a wide range of organs. Accordingly, neurons that contribute to feeding behaviors are localized to central, peripheral and enteric nervous systems. To promote energy balance, feeding circuits must be able to identify and respond to energy requirements, as well as the amount of energy available from internal and external sources, and then direct appropriate coordinated responses throughout the body.
doi:10.1146/annurev-nutr-071812-161125
PMCID: PMC3991304  PMID: 23642202
food intake; CNS circuits; energy balance; obesity
17.  Drug Synergy Screen and Network Modeling in Dedifferentiated Liposarcoma Identifies CDK4 and IGF1R as Synergistic Drug Targets 
Science signaling  2013;6(294):ra85.
Dedifferentiated liposarcoma (DDLS) is a rare but aggressive cancer with high recurrence and low response rates to targeted therapies. Increasing treatment efficacy may require combinations of targeted agents that counteract the effects of multiple abnormalities. To identify a possible multicomponent therapy, we performed a combinatorial drug screen in a DDLS-derived cell line and identified cyclin-dependent kinase 4 (CDK4) and insulin-like growth factor 1 receptor (IGF1R) as synergistic drug targets. We measured the phosphorylation of multiple proteins and cell viability in response to systematic drug combinations and derived computational models of the signaling network. These models predict that the observed synergy in reducing cell viability with CDK4 and IGF1R inhibitors depend on activity of the AKT pathway. Experiments confirmed that combined inhibition of CDK4 and IGF1R cooperatively suppresses the activation of proteins within the AKT pathway. Consistent with these findings, synergistic reductions in cell viability were also found when combining CDK4 inhibition with inhibition of either AKT or epidermal growth factor receptor (EGFR), another receptor similar to IGF1R that activates AKT. Thus, network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer-specific signaling mechanisms and aid in the design of effective combination therapies.
doi:10.1126/scisignal.2004014
PMCID: PMC4000046  PMID: 24065146
18.  A Phase 1 Dose-Escalation Study of Irinotecan in Combination with 17-allylamino-17-demethoxygeldanamycin (17AAG) in Patients with Solid Tumors 
Purpose
Both Hsp90 and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors.
Experimental Design
During the dose-escalation phase, patients received intravenous irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity.
Results
Twenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity (DLT) at dose level 4 (100 mg/m2 irinotecan and 375 mg/m2 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by coadministration of irinotecan, and vice versa. There was no partial response although tumor shrinkage was observed in 6 patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P=0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G2/M cell cycle checkpoint, and cell death could be demonstrated in tumor biopsy samples obtained at the MTD.
Conclusions
The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m2 irinotecan and 300 mg/m2 17AAG.
doi:10.1158/1078-0432.CCR-08-1006
PMCID: PMC3996559  PMID: 18927314
19.  Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K- mutated melanoma 
Purpose
Test the hypothesis that in BRAF-mutated melanomas, clinical responses to selumetinib, a MEK inhibitor, will be restricted to tumors in which the PI3K/AKT pathway is not activated.
Experimental Design
We conducted a phase II trial in melanoma patients whose tumors harbored a BRAF mutation. Patients were stratified by phosphorylated-AKT (pAKT) expression (high vs. low) and treated with selumetinib 75 mg po bid. Pretreatment tumors were also analyzed for genetic changes in 230 genes of interest using an exon-capture approach.
Results
The high pAKT cohort was closed after no responses were seen in the first 10 patients. The incidence of low pAKT melanoma tumors was low (approximately 25% of melanomas tested) and this cohort was eventually closed because of poor accrual. However, among the 5 melanoma patients accrued in the low pAKT cohort, there was 1 PR. Two other patients had near PRs before undergoing surgical resection of residual disease (1 patient) or discontinuation of treatment due to toxicity (1 patient). Among the 2 non-responding, low pAKT melanoma patients, co-mutations in MAP2K1, NF1, and/or EGFR were detected.
Conclusions
Tumor regression was seen in 3 of 5 patients with BRAF-mutated, low pAKT melanomas; no responses were seen in the high pAKT cohort.These results provide rationale for co-targeting MEK and PI3K/AKT in patients with BRAF mutant melanoma whose tumors express high pAKT. However, the complexity of genetic changes in melanoma indicates that additional genetic information will be needed for optimal selection of patients likely to respond to MEK inhibitors.
doi:10.1158/1078-0432.CCR-12-3476
PMCID: PMC3932005  PMID: 23444215
phosphorylated AKT; exon-capture; MEK inhibitor; Hedgehog pathway; EGFR mutation
20.  Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center and University Hospital of Lausanne experience 
Cancer  2013;119(20):3687-3695.
Background
Uveal melanoma exhibits a high incidence of metastases and no systemic therapy clearly improves outcomes. The anti-CTLA-4 antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined.
Methods
To assess ipilimumab in this setting, we performed a multicenter, retrospective analysis of four hospitals in the United States and Europe. Clinical characteristics, toxicities and radiographic disease burden as determined by central, blinded radiology review were determined.
Results
Thirty-nine patients were identified (34 treated with 3 mg/kg and 5 treated with 10 mg/kg). Using the immune-related response criteria and modified WHO criteria, response rate (RR) and combined response plus stable disease (SD) rate were assessed after 12 weeks, 23 weeks and total (median follow-up 50.4 weeks (12.6 months)). At week 12, the RR and response plus SD rate were 2.6% and 46.0%, at week 23: 2.6% and 28.2%. There was one complete response and one late partial response (at 100 weeks after initial SD) for irRR of 5.1%. Immune-related adverse events (irAE) were observed in 28 (71.8%) patients, with seven (17.9%) grade 3-4 events. irAEs were more frequent in patients receiving 10 mg/kg versus 3 mg/kg. The median overall survival from first dose of ipilimumab was 9.6 months (confidence interval 6.3-13.4 months, range: 1.6-41.6 months). Performance status, LDH and absolute lymphocyte count ≥1000 cells/μL at week 7 were significantly associated with survival.
Conclusions
In uveal melanoma, durable responses to ipilimumab and manageable toxicity were observed.
doi:10.1002/cncr.28282
PMCID: PMC3986037  PMID: 23913718
uveal melanoma; ipilimumab; CTLA-4; immunotherapy; absolute lymphocyte count
21.  KIT as a Therapeutic Target in Metastatic Melanoma 
Context
Some melanomas arising from acral, mucosal, and chronically sun-damaged sites harbor activating mutations and amplification of the type III transmembrane receptor tyrosine kinase KIT. We explored the effects of KIT inhibition using imatinib mesylate in this molecular subset of disease.
Objective
To assess clinical effects of imatinib mesylate in patients with melanoma harboring KIT alterations.
Design, Setting, and Patients
A single-group, open-label, phase 2 trial at 1 community and 5 academic oncology centers in the United States of 295 patients with melanoma screened for the presence of KIT mutations and amplification between April 23, 2007, and April 16, 2010. A total of 51 cases with such alterations were identified and 28 of these patients were treated who had advanced unresectable melanoma arising from acral, mucosal, and chronically sun-damaged sites.
Intervention
Imatinib mesylate, 400 mg orally twice daily.
Main Outcome Measures
Radiographic response, with secondary end points including time to progression, overall survival, and correlation of molecular alterations and clinical response.
Results
Two complete responses lasting 94 (ongoing) and 95 weeks, 2 durable partial responses lasting 53 and 89 (ongoing) weeks, and 2 transient partial responses lasting 12 and 18 weeks among the 25 evaluable patients were observed. The overall durable response rate was 16% (95% confidence interval [CI], 2%–30%), with a median time to progression of 12 weeks (interquartile range [IQR], 6–18 weeks; 95% CI, 11–18 weeks), and a median overall survival of 46.3 weeks (IQR, 28 weeks-not achieved; 95% CI, 28 weeks-not achieved). Response rate was better in cases with mutations affecting recurrent hotspots or with a mutant to wild-type allelic ratio of more than 1 (40% vs 0%, P=.05), indicating positive selection for the mutated allele.
Conclusions
Among patients with advanced melanoma harboring KIT alterations, treatment with imatinib mesylate results in significant clinical responses in a subset of patients. Responses may be limited to tumors harboring KIT alterations of proven functional relevance.
doi:10.1001/jama.2011.746
PMCID: PMC3986039  PMID: 21642685
22.  Extrarenal perivascular epithelioid cell tumors (PEComas) respond to mTOR inhibition: Clinical and molecular correlates 
Perivascular epithelioid cell tumors (PEComas) are a group of rare mesenchymal tumors that typically show both melanocytic and smooth muscle cell features. Some types of PEComa are seen at high frequency in tuberous sclerosis complex (TSC). The TSC1 and TSC2 genes are commonly mutated in both TSC-associated and sporadic PEComas, and mTOR signaling pathway activation is also common in these tumors. Preliminary reports have indicated that the mTOR inhibitors sirolimus and related drugs have activity in some patients with non-TSC-associated PEComa.
Here we report on the use of these medications in the treatment of five consecutive patients with extrarenal non-pulmonary PEComas seen at one institution. Three complete responses, one partial response and one case of progression were seen. Molecular studies identified TSC2 aberrations in four of these patients, and TFE3 translocation was excluded in the resistant case. A review of all published cases as well as those reported here indicates that partial or complete response was seen in 6 of 11 PEComas, with 5 of the 6 having a complete response. These findings highlight the consistent though incomplete activity of mTOR inhibitors in the treatment of PEComas.
doi:10.1002/ijc.27800
PMCID: PMC3558545  PMID: 22927055
perivascular epithelioid cell tumor; PEComa; mTOR; TSC2; sirolimus; everolimus
23.  Advances in Integrative Nanomedicine for Improving Infectious Disease Treatment in Public Health 
Introduction
Infectious diseases present public health challenges worldwide. An emerging integrative approach to treating infectious diseases is using nanoparticle (NP) forms of traditional and alternative medicines. Advantages of nanomedicine delivery methods include better disease targeting, especially for intracellular pathogens, ability to cross membranes and enter cells, longer duration drug action, reduced side effects, and cost savings from lower doses.
Methods
We searched Pubmed articles in English with keywords related to nanoparticles and nanomedicine. Nanotechnology terms were also combined with keywords for drug delivery, infectious diseases, herbs, antioxidants, homeopathy, and adaptation.
Results
NPs are very small forms of material substances, measuring 1–100 nanometers along at least one dimension. Compared with bulk forms, NPs’ large ratio of surface-area-to-volume confers increased reactivity and adsorptive capacity, with unique electromagnetic, chemical, biological, and quantum properties. Nanotechnology uses natural botanical agents for green manufacturing of less toxic NPs.
Discussion
Nanoparticle herbs and nutriceuticals can treat infections via improved bioavailability and antiinflammatory, antioxidant, and immunomodulatory effects. Recent studies demonstrate that homeopathic medicines may contain source and/or silica nanoparticles because of their traditional manufacturing processes. Homeopathy, as a form of nanomedicine, has a promising history of treating epidemic infectious diseases, including malaria, leptospirosis and HIV/AIDS, in addition to acute upper respiratory infections. Adaptive changes in the host’s complex networks underlie effects.
Conclusions
Nanomedicine is integrative, blending modern technology with natural products to reduce toxicity and support immune function. Nanomedicine using traditional agents from alternative systems of medicine can facilitate progress in integrative public health approaches to infectious diseases.
doi:10.1016/j.eujim.2012.11.002
PMCID: PMC3685499  PMID: 23795222
Nanomedicine; Drug delivery systems; Medicinal plants; Herbal medicine; Antioxidants; Homeopathy; Nanoparticles; Silica; Infectious disease treatment; Adaptation; Network medicine
24.  Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial 
The lancet oncology  2013;14(4):371-382.
Summary
Background
Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry.
Methods
We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015.
Findings
Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21–43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24–47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28–51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3–4. The most common grade 3–4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%).
Interpretation
The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination.
Funding
National Cancer Institute and Cycle for Survival Fund, Memorial Sloan-Kettering Cancer Center.
doi:10.1016/S1470-2045(13)70049-4
PMCID: PMC3766955  PMID: 23477833
25.  Central Leucine Sensing in the Control of Energy Homeostasis 
doi:10.1016/j.ecl.2012.12.001
PMCID: PMC3568262  PMID: 23391241
food intake; leucine; nutrient sensing; rapamycin; S6K1; diabetes; obesity; hypothalamus; brainstem

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