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1.  A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors 
Breast Cancer Research : BCR  2013;15(6):R110.
Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling.
Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule.
A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206.
Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation.
Trial registration; identifier: NCT00963547.
PMCID: PMC3979046  PMID: 24252402
2.  Burn from car seat heater in a man with paraplegia: case report 
Heated car seats are a common feature in newer automobiles. They are increasingly being recognized as potential hazards as there have been multiple reports of significant burns to its users. The potential for harm is considerably increased in those with impaired sensation with the possibility of a devastating injury.
Case report and literature review.
A 26-year-old male with a T8 ASIA A paraplegia presented to the outpatient clinic for management of a hip burn. Two weeks prior to his visit he was driving a 2004 Jeep Cherokee for approximately 30 minutes. He was unaware that the driver's side seat warmer was set on high. He denied that his seat belt was in direct contact with the skin of his right hip. He presented to an acute care hospital that evening with a hip burn where he was prescribed silver sulfadiazine cream and instructed to apply it until his scheduled follow-up clinic visit. In clinic, the hip wound was unstageable with approximately 95% eschar. A dressing of bismuth tribromophenate in petrolatum was applied to the wound and he was instructed to change the dressing daily. This was later changed to an antimicrobial alginate dressing. The ulcer eventually healed.
This case illustrates the significant risk of car seat heaters in individuals with spinal cord injuries or neurological impairment who have decreased sensation. Additionally, it highlights an atypical area of potential for burn. Furthermore, it emphasizes the need for a heightened awareness for this unique and dangerous situation.
PMCID: PMC3127368  PMID: 21756574
Burns; Paraplegia; Rehabilitation; Injury prevention; Wound care
3.  Hydropathic analysis and biological evaluation of stilbene derivatives as colchicine site microtubule inhibitors with anti-leukemic activity 
The crucial role of the microtubule in the cell division has identified tubulin as a target for the development of therapeutics for cancer; in particular tubulin is a target for antineoplastic agents that act by interfering with the dynamic stability of microtubules. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of stilbene-based tubulin inhibitors that bind at the αβ-tubulin colchicine site. Computational docking along with HINT score analysis fitted these inhibitors into the colchicine site and revealed detailed structure-activity information useful for inhibitor design. Quantitative analysis of the results was in good agreement with the in vitro antiproliferative activity of these derivatives (ranging from 3 nM to 100 μM) such that calculated and measured free energies of binding correlate with an r2 of 0.89 (standard error ± 0.85 kcal mol−1). This correlation suggests that the activity of unknown compounds may be predicted.
PMCID: PMC2782887  PMID: 19912057
stilbene; colchicine; microtubule inhibitors; hydropathy; HINT
4.  Hypermetabolism, Hyperphagia, and Reduced Adiposity in Tankyrase-Deficient Mice 
Diabetes  2009;58(11):2476-2485.
Tankyrase (TNKS) is a Golgi-associated poly-ADP-ribose polymerase that is implicated in the regulation of GLUT4 trafficking in 3T3-L1 adipocytes. Its chromosomal locus 8p23.1 is linked to monogenic forms of diabetes in certain kindred. We hypothesize that TNKS is involved in energy homeostasis in mammals.
Gene-trap techniques were used to ablate TNKS expression in mice. Homozygous and wild-type littermates maintained on standard chow were compared.
Wild-type mice express the TNKS protein abundantly in adipose tissue, the brain, and the endocrine pancreas but scarcely in the exocrine pancreas and skeletal muscle. TNKS-deficient mice consume increased amounts of food (by 34%) but have decreased plasma leptin levels and a >50% reduction in epididymal and perirenal fat pad size. Their energy expenditure is increased as assessed by metabolic cage studies and core body temperatures. These changes are not attributable to an increase in physical activity or uncoupled respiration (based on oxygraph analyses of mitochondria isolated from brown fat and skeletal muscle). The heightened thermogenesis of TNKS-deficient mice is apparently fueled by increases in both fatty acid oxidation (based on muscle and liver gene expression analyses and plasma ketone levels) and insulin-stimulated glucose utilization (determined by hyperinsulinemic-euglycemic clamps). Although TNKS deficiency does not compromise insulin-stimulated GLUT4 translocation in primary adipocytes, it leads to the post-transcriptional upregulation of GLUT4 and adiponectin in adipocytes and increases plasma adiponectin levels.
TNKS-deficient mice exhibit increases in energy expenditure, fatty acid oxidation, and insulin-stimulated glucose utilization. Despite excessive food intake, their adiposity is substantially decreased.
PMCID: PMC2768175  PMID: 19651815
5.  Vorinostat and sorafenib synergistically kill tumor cells via FLIP suppression and CD95 activation 
Purpose and Design
Mechanism(s) by which the multi-kinase inhibitor sorafenib and the histone deacetylase inhibitor vorinostat interact to kill hepatic, renal and pancreatic adenocarcinoma cells have been defined.
Low doses of sorafenib and vorinostat interacted in vitro in a synergistic fashion to kill hepatic, renal and pancreatic adenocarcinoma cells in multiple short term viability (24–96h) and in long term colony formation assays. Cell killing was suppressed by inhibition of cathepsin proteases and caspase 8, and to a lesser extent by inhibition of caspase 9. Twenty four hours after exposure, the activities of ERK1/2, AKT and NFκB were only modestly modulated by sorafenib and vorinostat treatment. However, 24h after exposure, sorafenib and vorinostat- treated cells exhibited markedly diminished expression of c-FLIP-s, full length BID, BCL-2, BCLXL, MCL-1, XIAP, increased expression of BIM, and increased activation of BAX, BAK and BAD. Expression of eIF2α S51A blocked sorafenib and vorinostat –induced suppression of c-FLIP-s levels and over-expression of c-FLIP-s abolished lethality. Sorafenib and vorinostat treatment increased surface levels of CD95 and CD95 association with caspase 8. Knock down of CD95 or FADD expression significantly reduced sorafenib / vorinostat -mediated lethality.
These data demonstrate that combined exposure of epithelial tumor cell types to sorafenib and vorinostat diminishes expression of multiple anti-apoptotic proteins, promotes activation of the CD95 extrinsic apoptotic and the lysosomal protease pathways, and that suppression of c-FLIP-s expression represents a critical event in transduction of the pro-apoptotic signals from CD95 to promote mitochondrial dysfunction and death.
PMCID: PMC2561272  PMID: 18765530
Vorinostat; Sorafenib; CD95; c-FLIP-s; caspase 8; cathepsin; cell death
6.  Proteolytic cleavage of Livin (ML-IAP) in apoptotic melanoma cells potentially mediated by a non-canonical caspase 
Journal of dermatological science  2006;43(3):189-200.
Several inhibitor of apoptosis proteins (IAPs) are cleaved during apoptosis. Studies of the melanoma-associated IAP (ML-IAP) Livin, using recombinant molecules, have implicated both caspases 3/7 and the serine protease Omi/HtrA2 in its proteolytic cleavage.
To characterize the apoptotic cleavage of Livin in melanocytic cells, and evaluate the role of known proteases.
We assessed the capacity of a variety of stimuli to induce Livin cleavage in human melanoma cell lines and normal human melanocytes. The role of caspases and Omi was examined using caspase inhibitors and RNAi, respectively. A potential caspase substrate was further examined by site-directed mutagenesis. Deletion mapping was used to identify the cleavage site.
Livin cleavage was observed in multiple human melanoma cell lines in response to a variety of apoptotic stimuli (UVB, 4-TBP, cisplatin, TNF, Bax), and not affected by the addition of various protease inhibitors or RNAi-mediated silencing of Omi/HtrA2. Livin cleavage induced by 4-TBP, but not UVB or cisplatin, was blocked by the pan-caspase inhibitor zVAD-fmk. Mutation of Asp52 to Glu in Livin did not affect cleavage, while either mutation of Asp52 to Ala, deletion of Asp52, or deletion of the adjacent region (residues 53–61) abrogated cleavage.
Livin cleavage, induced by multiple apoptotic stimuli in melanoma cells, likely occurs in an Omi-independent fashion at residue 52 within its potential caspase substrate (DHVD52). However, relative insensitivity of the apoptotic cleavage to zVAD-fmk, or Asp52 to Glu mutation, suggests the involvement of a non-canonical caspase.
PMCID: PMC2292408  PMID: 16806840
Livin; Cleavage; Inhibitor of apoptosis (IAP); Apoptosis; Melanoma
7.  Activation of Dual Apoptotic Pathways in Human Melanocytes and Protection by Survivin 
Apoptosis resistance in melanoma is a primary cause of treatment failure. Apoptotic pathways in melanocytes, from which melanoma arises, are poorly characterized. Human melanocytes were susceptible to apoptosis following exposure to UV radiation (UVB, 24–48 hours), 4- tert-butylphenol (4-TBP, 1–4 hours), and cisplatin (24–48 hours). These responses were associated with Bid cleavage, caspase activation (caspases 3, 8, and 9), mitochondrial depolarization and release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor (AIF), but not endonuclease G. The apoptotic responses and AIF release were caspase-independent, as they were not blocked by zVal-Ala-Asp(OMe)-fluoromethyl ketone (zVAD-fmk). While RNA interference-mediated knockdown of AIF protected melanocytes against apoptosis induced by serum withdrawal, apoptotic responses to UVB, cisplatin, and 4-TBP were not compromised by AIF knockdown, even in the presence of zVAD-fmk. Finally, adenoviral-mediated expression of Survivin, an inhibitor of apoptosis expressed in melanoma but not melanocytes, protected melanocytes against UVB-induced apoptosis. Survivin expression in melanocytes partially blocked caspase activation and release of mitochondrial release of AIF, cytochrome c, and Smac induced by UVB. These data indicate that multiple stimuli can activate both caspase-dependent and caspaseindependent apoptotic pathways in melanocytes, and that endogenous expression of Survivin in melanoma may contribute to apoptosis resistance by multiple mechanisms.
PMCID: PMC2292407  PMID: 16728972
8.  Lumped-Element Planar Strip Array (LPSA) for Parallel MRI 
The recently introduced planar strip array (PSA) can significantly reduce scan times in parallel MRI by enabling the utilization of a large number of RF strip detectors that are inherently decoupled, and are tuned by adjusting the strip length to integer multiples of a quarter-wavelength (λ/4) in the presence of a ground plane and dielectric substrate. In addition, the more explicit spatial information embedded in the phase of the signals from the strip array is advantageous (compared to loop arrays) for limiting aliasing artifacts in parallel MRI. However, losses in the detector as its natural resonance frequency approaches the Larmor frequency (where the wavelength is long at 1.5 T) may limit the signal-to-noise ratio (SNR) of the PSA. Moreover, the PSA’s inherent λ/4 structure severely limits our ability to adjust detector geometry to optimize the performance for a specific organ system, as is done with loop coils. In this study we replaced the dielectric substrate with discrete capacitors, which resulted in both SNR improvement and a tunable lumped-element PSA (LPSA) whose dimensions can be optimized within broad constraints, for a given region of interest (ROI) and MRI frequency. A detailed theoretical analysis of the LPSA is presented, including its equivalent circuit, electromagnetic fields, SNR, and g-factor maps for parallel MRI. Two different decoupling schemes for the LPSA are described. A four-element LPSA prototype was built to test the theory with quantitative measurements on images obtained with parallel and conventional acquisition schemes.
PMCID: PMC2013307  PMID: 14705058
strip array; MRI; parallel imaging; lumped-element; decoupling
9.  Four-Angle Saturation Transfer (FAST) Method for Measuring Creatine Kinase Reaction Rates In Vivo 
A new fast method of measuring kinetic reaction rates for two-site chemical exchange is described. The method employs saturation transfer magnetic resonance spectroscopy (MRS) and acquisition of only four spectra under partially saturated, high signal-to-noise ratio (SNR) conditions. In two acquisitions one of the exchanging species is saturated; the other two employ a control saturation. Each pair of acquisitions is applied with two different flip angles, and the equilibrium magnetization, relaxation times, and reaction rates are calculated therefrom. This four-angle saturation transfer (FAST) method is validated theoretically using the Bloch equations modified for two-state chemical exchange. Potential errors in the rate measurements due to the effects of exchange are evaluated for creatine kinase (CK) metabolism modeled for skeletal and heart muscle, and are found to be <5% for forward CK flux rates of 0.05 ≤ kf ≤ 1.0 s−1, and up to a 90% depletion of phosphocreatine (PCr). The effect of too much or too little saturating irradiation on FAST appears to be comparable to that of the conventional saturation transfer method, although the relative performance deteriorates when spillover irradiation cuts the PCr signal by 50% or more. “FASTer” and “FASTest” protocols are introduced for dynamic CK studies wherein [PCr] and/or kf changes. These protocols permit the omission of one or two of the four acquisitions in repeat experiments, and the missing information is recreated from initial data via a new iterative algorithm. The FAST method is validated empirically in phosphorus (31P) MRS studies of human calf muscle at 1.5 T. FAST measurements of 10 normal volunteers yielded the same CK reaction rates measured by the conventional method (0.29 ± 0.06 s−1) in the same subjects, but an average of seven times faster. Application of the FASTer algorithm to these data correctly restored missing information within seven iterations. Finally, the FAST method was combined with 1D spatially localized 31P MRS in a study of six volunteers, yielding the same kf values independent of depth, in total acquisition times of 17–39 min. These timesaving FAST methods are enabling because they permit localized measurements of metabolic flux, which were previously impractical due to intolerably long scan times.
PMCID: PMC1995126  PMID: 11979563
saturation transfer; reaction rates; creatine kinase; high-energy phosphate; energy metabolism
10.  An Analytical SMASH Procedure (ASP) for Sensitivity-Encoded MRI 
The simultaneous acquisition of spatial harmonics (SMASH) method of imaging with detector arrays can reduce the number of phase-encoding steps, and MRI scan time several-fold. The original approach utilized numerical gradient-descent fitting with the coil sensitivity profiles to create a set of composite spatial harmonics to replace the phase-encoding steps. Here, an analytical approach for generating the harmonics is presented. A transform is derived to project the harmonics onto a set of sensitivity profiles. A sequence of Fourier, Hilbert, and inverse Fourier transform is then applied to analytically eliminate spatially dependent phase errors from the different coils while fully preserving the spatial-encoding. By combining the transform and phase correction, the original numerical image reconstruction method can be replaced by an analytical SMASH procedure (ASP). The approach also allows simulation of SMASH imaging, revealing a criterion for the ratio of the detector sensitivity profile width to the detector spacing that produces optimal harmonic generation. When detector geometry is suboptimal, a group of quasi-harmonics arises, which can be corrected and restored to pure harmonics. The simulation also reveals high-order harmonic modulation effects, and a demodulation procedure is presented that enables application of ASP to a large numbers of detectors. The method is demonstrated on a phantom and humans using a standard 4-channel phased-array MRI system.
PMCID: PMC1941706  PMID: 10800037
image reconstruction; phased-arrays MRI; SMASH; harmonics; phase-encoding; phase correction; ASP
11.  Planar Strip Array (PSA) for MRI 
Parallel, spatial-encoded MRI requires a large number of independent detectors that simultaneously acquire signals. The loop structure and mutual coupling in conventional phased arrays limit the number of coils and therefore the potential reduction in minimum scan time achievable by parallel MRI tchniques. A new near-field MRI detector array, the planar strip array (PSA), is presented that eliminates the coupling problems and can be extended to a very large number of detectors and high MRI frequencies. Its basic structure is an array of parallel microstrips with a high permittivity substrate and overlay. The electromagnetic (EM) wavelength can be adjusted with the permittivity, and the strip lengths tuned to a preselected fraction of the wavelength of the MRI frequency. EM wave analysis and measurements on a prototype four-element PSA reveal that the coupling between the strips vanishes when the strip length is either an integer times a quarter wavelength for a standing-wave PSA, or a half wavelength for a travelling-wave PSA, independent of the spacing between the strips. The analysis, as well as phantom and human MRI experiments performed by conventional and parallel-encoded MRI with the PSA at 1.5 T, show that the decoupled strips produce a relatively high-quality factor and signal-to-noise ratio, provided that the strips are properly terminated, tuned, and matched or coupled to the preamplifiers.
PMCID: PMC1941687  PMID: 11283996
MRI detector; phased array; planar strip array (PSA); sensitivity encoding; SMASH; SENSE; ASP; standing wave detector; surface coil

Results 1-11 (11)