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John M Hoffman

Publications and source records attributed to John M Hoffman.

18 recordsLinked to original sources
PubMed2006

Switchable surface traps for injectable bead-based chromatography in PDMS microfluidic channels.

We report here a reversible microchannel surface capture system for stimuli-responsive grafted bioanalytical beads. Poly(N-isopropylacrylamide) (PNIPAAm) was grafted onto polydimethylsiloxane (PDMS) surfaces by a UV-mediated graft polymerization from a photoinitiator that was preadsorbed in the channel wall. The surface grafting density and resulting switchable hydrophilic/hydrophobic properties were controlled by varying the photo-illumination times and/or the initiator concentration. At limiting PNIPAAm-graft densities, the surfaces demonstrated minimal contact angles of 35 degrees below the lower critical solution temperature (LCST) and maximal contact angles of 82 degrees above it. These contact angles could be varied depending on the graft density. The surface grafts are spatially limited to the photo-illuminated region to define where the trap is constructed. The surface traps capture PNIPAAm-grafted nanobeads uniformly above the LCST and facilitate their rapid release as the temperature is reversed to below the LCST. This dual surface trap and injectable chromatography system could be useful in many applications, such as affinity separations, immunoassays, and enzyme bioprocesses, by providing for the controlled capture and release of chromatography beads.

Acrylic Resins↗
PubMed2005

The progress and promise of molecular imaging probes in oncologic drug development.

As addressed by the recent Food and Drug Administration Critical Path Initiative, tools are urgently needed to increase the speed, efficiency, and cost-effectiveness of drug development for cancer and other diseases. Molecular imaging probes developed based on recent scientific advances have great potential as oncologic drug development tools. Basic science studies using molecular imaging probes can help to identify and characterize disease-specific targets for oncologic drug therapy. Imaging end points, based on these disease-specific biomarkers, hold great promise to better define, stratify, and enrich study groups and to provide direct biological measures of response. Imaging-based biomarkers also have promise for speeding drug evaluation by supplementing or replacing preclinical and clinical pharmacokinetic and pharmacodynamic evaluations, including target interaction and modulation. Such analyses may be particularly valuable in early comparative studies among candidates designed to interact with the same molecular target. Finally, as response biomarkers, imaging end points that characterize tumor vitality, growth, or apoptosis can also serve as early surrogates of therapy success. This article outlines the scientific basis of oncology imaging probes and presents examples of probes that could facilitate progress. The current regulatory opportunities for new and existing probe development and testing are also reviewed, with a focus on recent Food and Drug Administration guidance to facilitate early clinical development of promising probes.

Antineoplastic Agents↗
PubMed2005

Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development.

2-[(18)F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) assesses a fundamental property of neoplasia, the Warburg effect. This molecular imaging technique offers a complementary approach to anatomic imaging that is more sensitive and specific in certain cancers. FDG-PET has been widely applied in oncology primarily as a staging and restaging tool that can guide patient care. However, because it accurately detects recurrent or residual disease, FDG-PET also has significant potential for assessing therapy response. In this regard, it can improve patient management by identifying responders early, before tumor size is reduced; nonresponders could discontinue futile therapy. Moreover, a reduction in the FDG-PET signal within days or weeks of initiating therapy (e.g., in lymphoma, non-small cell lung, and esophageal cancer) significantly correlates with prolonged survival and other clinical end points now used in drug approvals. These findings suggest that FDG-PET could facilitate drug development as an early surrogate of clinical benefit. This article reviews the scientific basis of FDG-PET and its development and application as a valuable oncology imaging tool. Its potential to facilitate drug development in seven oncologic settings (lung, lymphoma, breast, prostate, sarcoma, colorectal, and ovary) is addressed. Recommendations include initial validation against approved therapies, retrospective analyses to define the magnitude of change indicative of response, further prospective validation as a surrogate of clinical benefit, and application as a phase II/III trial end point to accelerate evaluation and approval of novel regimens and therapies.

Fluorodeoxyglucose F18↗
PubMed2005

New frontiers in translational research in neuro-oncology and the blood-brain barrier: report of the tenth annual Blood-Brain Barrier Disruption Consortium Meeting.

The blood-brain barrier (BBB) presents a major obstacle to the treatment of malignant brain tumors and other central nervous system (CNS) diseases. For this reason, a meeting partially funded by an NIH R13 grant was convened to discuss recent advances and future directions in translational research in neuro-oncology and the BBB. Cell biology and transport across the BBB, delivery of agents to the CNS, neuroimaging, angiogenesis, immunotherapy, and gene therapy, as well as glioma, primary CNS lymphoma, and metastases to the CNS were discussed. Transport across the BBB relates to the neurovascular unit, which consists not only of endothelial cells but also of pericyte, glia, and neuronal elements.

Antineoplastic Agents↗
PubMed2004

Effect of methylphenidate on executive functioning in adults with attention-deficit/hyperactivity disorder: normalization of behavior but not related brain activity.

BACKGROUND: We examined the effect of prolonged methylphenidate (MPH) treatment on the functional neuroanatomy of executive functioning in adult men with attention-deficit/hyperactivity disorder (ADHD). METHODS: Positron emission tomography with [(15)O] water measured alterations of regional cerebral blood flow (rCBF) during the Paced Auditory Serial Addition Task and a control task in 10 ADHD and 11 normal control men. Attention-deficit/hyperactivity disorder men were imaged unmedicated and after a clinically optimal dose of MPH for 3 weeks. RESULTS: Methylphenidate improved ADHD task performance, reduced rCBF in the prefrontal cortex (PFC), and increased rCBF in the right thalamus and precentral gyrus. Comparisons between the ADHD and normal control groups showed that normal control participants exhibited greater anterior cingulate cortex and temporal gyrus rCBF than ADHD participants under both conditions. Executive functioning was associated with greater subcortical (basal ganglia and cerebellar vermis) activation in the ADHD than normal control group under both conditions. CONCLUSIONS: Methylphenidate does not normalize task-related activity in ADHD. Task-related rCBF decreases in the PFC may be due to improved filtering out of task-irrelevant stimuli by way of MPH-mediated dopamine release in the PFC.

Adult↗
PubMed2004

A prospective analysis of positron emission tomography and conventional imaging for detection of stage IV metastatic melanoma in patients undergoing metastasectomy.

BACKGROUND: Positron emission tomography with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG-PET) is available for evaluation of patients with melanoma. This study evaluates the potential of FDG-PET to improve on conventional imaging (CI) in patients with stage IV melanoma undergoing metastasectomy. METHODS: This was a prospective study comparing radiological evaluation of patients who underwent metastasectomy for palliation or cure. Patients underwent preoperative evaluation by physical examination, CI by computed tomography and/or magnetic resonance imaging, and FDG-PET. Independent observers performed three separate analyses of CI alone, FDG-PET alone, or FDG-PET read with knowledge of CI (FDG-PET + CI). Abnormalities were reported as benign or malignant and assessed by pathologic analysis or by clinical outcome determined by disease progression detected on serial evaluations. RESULTS: Ninety-four lesions were noted in 18 patients who underwent preoperative assessment, metastasectomy, and long-term follow up (median, 24 months). Lesion-by-lesion analysis for CI demonstrated a sensitivity of 76%, a specificity of 87%, a positive predictive value (PPV) of 86%, and a negative predictive value (NPV) of 76%. FDG-PET demonstrated a sensitivity of 79%, a specificity of 87%, a PPV of 86%, and an NPV of 80%. For FDG-PET + CI, the sensitivity was 88%, specificity was 91%, and PPV and NPV were 91% and 88%, respectively. CONCLUSIONS: Combined use of FDG-PET and CI may be an accurate strategy to identify sites of disease in patients with stage IV melanoma being considered for metastasectomy. Interpreted independently, FDG-PET and CI seemed to be equivalent modalities. FDG-PET + CI had both the highest sensitivity on lesion-by-lesion analysis and the best accuracy on patient-by-patient analysis.

Adult↗
PubMed2003

A positron emission tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predicting treatment response.

A hallmark symptom of attention-deficit hyperactivity disorder (ADHD) is an excess of motoric behavior or hyperactivity. Methylphenidate (MPH) is known to reduce hyperactivity in individuals with ADHD. Yet little is known about how it alters neural activity and how this relates to its clinical effects. The goal of this study is to examine MPH-induced changes during resting brain metabolism, and to examine how these changes correlate with measures of behavioral response to the drug. Measures of regional cerebral blood flow (rCBF) using positron emission tomography (PET) were acquired at rest for ten adult subjects with ADHD during both an unmedicated state and after a 3-week period of chronic dosing with a clinically optimal dose of MPH. Compared with the on-MPH condition, the off-MPH condition was associated with relative increases in rCBF bilaterally in the precentral gyri, left caudate nucleus, and right claustrum. The on-MPH condition was associated with relative increases in rCBF in the cerebellar vermis. A correlational analysis measured the relation between rCBF in the off-medication condition to change in ADHD ratings between the off- and on-MPH condition to identify brain regions associated with treatment response. The degree of change in the ratings was negatively correlated with rCBF increases in the midbrain, cerebellar vermis, and the precentral and middle frontal gyri in the off-MPH condition. The majority of these brain regions are involved in the planning and execution of motor behavior. These data suggest that MPH modulates brain regions associated with motor function to achieve a reduction in ADHD symptoms.

Adult↗
PubMed2003

Dissociable neural pathways are involved in the recognition of emotion in static and dynamic facial expressions.

Facial expressions of emotion powerfully influence social behavior. The distributed network of brain regions thought to decode these social signals has been empirically defined using static, usually photographic, displays of such expressions. Facial emotional expressions are however highly dynamic signals that encode the emotion message in facial action patterns. This study sought to determine whether the encoding of facial expressions of emotion by static or dynamic displays is associated with different neural correlates for their decoding. We used positron emission tomography to compare patterns of brain activity in healthy men and women during the explicit judgment of emotion intensity in static and dynamic facial expressions of anger and happiness. Compared to judgments of spatial orientation for moving neutral facial expressions, the judgment of anger in dynamic expressions was associated with increased right-lateralized activity in the medial, superior, middle, and inferior frontal cortex and cerebellum, while judgments of happiness were associated with relative activation of the cuneus, temporal cortex, and the middle, medial, and superior frontal cortex. In contrast, the perception of anger or happiness in static facial expressions activated a motor, prefrontal, and parietal cortical network previously shown to be involved in motor imagery. The direct contrast of dynamic and static expressions indicated differential activation of visual area V5, superior temporal sulcus, periamygdaloid cortex, and cerebellum for dynamic angry expressions and differential activation of area V5, extrastriate cortex, brain stem, and middle temporal cortical activations for dynamic happy expressions. Thus, a distribution of neural activations is related to the analysis of emotion messages in the nearly constant biological motion of the face and differ for angry and happy expressions. Static displays of facial emotional expression may represent noncanonical stimuli that are processed for emotion content by mental strategies and neural events distinct from their more ecologically relevant dynamic counterparts.

Adult↗
PubMed2003

The functional anatomy of parkinsonian bradykinesia.

To investigate the difficulty that patients with Parkinson's disease (PD) have in performing fast movements, we used H(2)(15)O PET to study regional cerebral blood flow (rCBF) associated with performance of a simple predictive visuomanual tracking task at three different velocities. Tracking movements in PD patients (versus tracking with the eyes alone) were associated with a general underactivation of the areas normally activated by the task (sensorimotor cortex contralateral to the moving arm, bilateral dorsal premotor cortices, and ipsilateral cerebellum). Presupplementary motor cortex (pre-SMA) ipsilateral to the moving arm had greater than normal movement-related activations. Increasing movement velocity led to increased rCBF in multiple premotor and parietal cortical areas and basal ganglia in the patients as opposed to the few cerebral locations that are normally velocity-related. The functional correlates of PD bradykinesia are: (1) impaired recruitment of cortical and subcortical systems that normally regulate kinematic parameters of movement such as velocity; and (2) increased recruitment of multiple premotor areas including both regions specialized for visuomotor control (ventral premotor and parietal cortices) and some that are not (pre-SMA). The overactivation of cortical regions observed in patients may be functional correlates of compensatory mechanisms and/or impaired suppression as a facet of the primary pathophysiology of PD.

Brain↗
PubMed2003

Initial human PET imaging studies with the dopamine transporter ligand 18F-FECNT.

UNLABELLED: The aim of this study was to do an initial assessment of the usefulness of 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-(18)F-fluoroethyl)nortropane ((18)F-FECNT) PET scanning in determining in vivo brain dopamine transporter (DAT) density in healthy humans and subjects with Parkinson's disease (PD). METHODS: We investigated 6 neurologically healthy subjects and 5 PD patients: 2 with mild unilateral disease, 1 with mild-to-moderate bilateral disease, and 2 with moderately severe bilateral disease. The healthy subjects underwent a 3-h PET scan (26 frames) and the PD subjects underwent a 2-h PET scan (23 frames) while (18)F-FECNT was being injected over the first 5 min of the scan. Arterial blood samples were taken throughout scanning for well-counter and metabolite analysis to determine the presence of possible active metabolites. The scans were reconstructed; then we placed spheric regions of interest in the caudate nuclei, putamena, thalami, brain stem, cerebellum, and occipital cortex of each subject. The radioactivity level in each region was calculated for each frame of a subject's PET scan. Then we calculated target tissue-to-cerebellum ratios for each time frame. RESULTS: The analysis of arterial blood samples revealed that metabolism of the tracer was rapid. The ether-extractable component of the arterial input was >98% pure (18)F-FECNT. The caudate nucleus and putamen exhibited the highest uptake and prolonged retention of the radioligand. They both attained maximum uptake at approximately 90 min, with the healthy subjects' average caudate- and putamen-to-cerebellum ratios (+/-SD) at that time being 9.0 +/- 1.2 and 7.8 +/- 0.7, respectively. The maximal caudate-to-cerebellum ratios for the healthy subjects ranged from 7.6 to 10.5 and their maximal putamen-to-cerebellum ratios ranged from 7.1 to 9.3. The 2 early-stage, unilateral PD patients had, at 90 min, an average right caudate-to-cerebellum ratio of 5.3 +/- 1.1 and a left ratio of 5.9 +/- 0.7 and an average right putamen-to cerebellum ratio of 2.8 +/- 0.1 and a left ratio of 3.0 +/- 0.6. The late-stage PD patients had, at 90 min, an average right caudate-to-cerebellum ratio of 3.7 +/- 0.4 and a left ratio of 3.9 +/- 0 and an average right putamen-to cerebellum ratio of 1.8 +/- 0.1 and a left ratio of 1.8 +/- 0. CONCLUSION: These results indicate that (18)F-FECNT is an excellent candidate radioligand for in vivo imaging of the DAT system in humans. It has a much higher affinity for DAT than for the serotonin transporter and yields the highest peak striatum-to-cerebellum ratios and has among the most favorable kinetics of (18)F-radiolabeled DAT ligands. Having picked up presymptomatic changes in the hemisphere opposite the unaffected side of the body in our early-stage (unilateral) PD patients, it appears that, like other DAT radioligands, it may be able to identify presymptomatic PD.

Adult↗
PubMed2002

Measurement of dopamine transporter occupancy for multiple injections of cocaine using a single injection of [F-18]FECNT.

The fraction of transporters occupied following injection of specific inhibitors is an important parameter for defining and comparing the molecular mechanisms of different drugs. This work generalizes the reference tissue method to estimate dopamine transporter occupancy for two levels of cocaine administration using only a single injection of [(18)F]FECNT. The results are validated by comparison with literature values. Five rhesus monkeys were studied. On each animal, a baseline scan was collected following [(18)F]FECNT injection (phase a). At 120 min postinjection, 0.1 mg/kg cocaine was injected and the animal was scanned for 50 additional min (phase b). Then 1.0 mg/kg cocaine was injected and another 50-min scan sequence was collected (phase c). Time-activity curves (encompassing all three phases) were generated for each animal from regions drawn over the putamen and cerebellum. The putamen curve was modeled using the cerebellum as the input function. Percent DAT occupancy following the cocaine injections was determined by comparing k(3)/k(4) = B(max)/k(D) for the three phases. The 0.1 and 1.0 mg/kg cocaine doses occupied 53% +/- 5% and 87% +/- 5% of the transporters, respectively. The measured occupancies are consistent with literature values that maintain self-administration in animals and produce a "high" in human subjects. This work demonstrates that a single injection of [(18)F]FECNT can be used to measure the effects of multiple cocaine challenges. Two advantages of this technique are: reduced variability in dose-response curves because the subject is his/her own control, and the (18)F label allows evaluation of longer-acting drugs.

Algorithms↗
PubMed2002

Cerebral blood flow during propofol induced sedation.

PURPOSE: This work determined if 2, 6-diisopropylphenol (propofol) selectively affects cerebral blood flow in regions associated with wakefulness. PROCEDURES: Cerebral blood flow (CBF) was measured with positron emission tomography (PET) using the 15O-water bolus technique in 10 subjects while awake and during light and deep sedation. Arterial blood was sampled for CBF estimation, blood gases and propofol plasma concentrations. RESULTS: Global CBF decreased under deep sedation. A regression analysis of CBF vs. propofol concentration showed significant decreases in CBF in the thalamus and posterior cingulate and increases in the hippocampus and cerebellum. An ANCOVA analysis on condition (controlling for pCO(2) levels) showed mean CBF decreased in the thalamus and posterior cingulate cortex and increased in the primary motor and hippocampal areas during the light and deep sedation compared to awake conditions. CONCLUSIONS: These data support the hypothesis that propofol preferentially alters CBF in specific brain regions necessary to maintain wakefulness.

Journal Article↗
PubMed2002

Ecstasy and agony: activation of the human amygdala in positive and negative emotion.

Considerable evidence indicates that the amygdala plays a critical role in negative, aversive human emotions. Although researchers have speculated that the amygdala plays a role in positive emotion, little relevant evidence exists. We examined the neural correlates of positive and negative emotion using positron emission tomography (PET), focusing on the amygdala. Participants viewed positive and negative photographs, as well as interesting and uninteresting neutral photographs, during PET scanning. The left amygdala and ventromedial prefrontal cortex were activated during positive emotion, and bilateral amygdala activation occurred during negative emotion. High-interest, unusual photographs also elicited left-amygdala activation, a finding consistent with suggestions that the amygdala is involved in vigilance reactions to associatively ambiguous stimuli. The current results constitute the first neuroimaging evidence for a role of the amygdala in positive emotional reactions elicited by visual stimuli. Although the amygdala appears to play a more extensive role in negative emotion, it is involved in positive emotion as well.

Adult↗
PubMed2001

Cocaine-induced brain activation determined by positron emission tomography neuroimaging in conscious rhesus monkeys.

RATIONALE: Cerebral blood flow can provide a useful dependent measure to characterize cocaine-induced changes in brain function. The acute effects of cocaine administration on cerebral blood flow may have direct relevance to the etiology of cocaine addiction. OBJECTIVES: The present study used positron emission tomography (PET) neuroimaging techniques to characterize the acute effects of cocaine administration on cerebral blood flow in conscious rhesus monkeys. METHODS: Functional changes in cerebral blood flow were determined in four drug-naive subjects with the positron-emitting tracer 15O water following acute i.v. administration of cocaine (0.3 and 1.0 mg/kg). Specific attention was devoted to the development of an effective and comfortable head restraint device to use in the imaging of conscious monkeys. Experimental sessions comprised eight consecutive i.v. injections of 15O water at 10-min intervals. PET scans of 90 s duration occurred 10 s after each injection. RESULTS: Repeated baseline determinations of cerebral blood flow prior to drug administration were reliable. Cocaine had significant, dose-related effects on cerebral blood flow at 5 min postinjection that diminished relative to control (saline) conditions by 15 min postinjection. Brain activation maps normalized to global flow showed prominent cocaine-induced activation of prefrontal cortex localized primarily to dorsolateral regions. Importantly, cocaine-induced brain activation was blocked by pretreatment with the selective serotonin uptake inhibitor, alaproclate (3.0 and 10.0 mg/kg). The results document a distinct pattern of cocaine-induced brain activation that is sensitive to pharmacological manipulation. CONCLUSION: The pattern of brain activation induced by acute administration of cocaine may provide a useful means to evaluate medication effectiveness for treating cocaine addiction.

Animals↗
PubMedDate not supplied

Meeting report: high-throughput technologies for in vivo imaging agents.

Combinatorial chemistry and high-throughput screening have become standard tools for discovering new drug candidates with suitable pharmacological properties. Now, those same technologies are starting to be applied to the problem of discovering novel in vivo imaging agents. Important differences in the biological and pharmacological properties needed for imaging agents, compared to those for a therapeutic agent, require new screening methods that emphasize those characteristics, such as optimized residence time and tissue specificity, that make for a good imaging agent candidate.

Animals↗
PubMedDate not supplied

Donepezil HCl (E2020) maintains functional brain activity in patients with Alzheimer disease: results of a 24-week, double-blind, placebo-controlled study.

OBJECTIVE: The authors evaluated the effects of donepezil (10 mg/day) versus placebo on brain glucose metabolism. METHODS: This was a randomized, double-blind, parallel-group, 24-week pilot study in 28 patients with mild-to-moderate Alzheimer disease (AD). Functional brain activity was quantified by measuring average glucose metabolism in an axial brain slice and regional brain glucose metabolism using positron emission tomography. RESULTS: At Week 24, relative to the pons metabolic rate, mean brain glucose metabolism in an axial slice at the level of the striatum was maintained within 0.5% of mean baseline levels for donepezil-treated patients, whereas it declined by an average of 10.4% in placebo-treated patients. This observation was confirmed by an analysis of differences in the mean slopes of glucose metabolism in the striatal slice in donepezil- and placebo-treated patients during the 24-week period. Significant treatment differences at Week 24 favoring donepezil for the mean percentage change from baseline in regional brain glucose metabolism were observed in four predefined regions of interest: the right parietal lobe 1, left temporal lobe 2, right frontal lobe 2, and left frontal lobe 2. CONCLUSION: Placebo-treated patients with AD show a decline in functional brain activity, relative to the pons, in several regions, and treatment with donepezil may slow this decline.

Aged↗