Biomedical subjects

J W Clark

Publications and source records attributed to J W Clark.

At least 19 recordsLinked to original sources

PubMed2006

Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome?

In this analysis of the safety and efficacy of BAY 43-9006 (sorafenib) -- a novel, oral multi-kinase inhibitor with effects on tumour and its vasculature -- pooled data were obtained from four phase I dose-escalation trials. Time to progression (TTP) was compared in patients with/without grade 2 skin toxicity/diarrhoea. Grade 3 hand-foot skin reactions (HFS; 8%) and diarrhoea (6%) were common. At the recommended 400mg bid dose for phase II/III trials (RDP), 15% of patients experienced grade 2/3 HFS, and 24% experienced grade 2/3 diarrhoea. Sorafenib induced stable disease for 6 months in 12% of patients (6% stabilized for 1 year). Patients receiving sorafenib doses at or close to the RDP, who experienced skin toxicity/diarrhoea, had a significantly increased TTP compared with patients without such toxicity (P < 0.05). Sorafenib was well tolerated at the RDP, and induced sustained disease stabilization, particularly in patients with skin toxicity/diarrhoea.

Administration, Oral↗

PubMed2005

Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle.

PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.

Adult↗

PubMed2005

A macrophage cell model for pH and volume regulation.

A whole-cell model of a macrophage (mphi) is developed to simulate pH and volume regulation during a NH4Cl prepulse challenge. The cell is assumed spherical, with a plasma membrane that separates the cytosolic and extracellular bathing media. The membrane contains background currents for Na+, K+ and Cl-, a Na(+)-K+ pump, a V-type H(+)-extruder (V-ATPase), and a leak pathway for NH4+. Cell volume is controlled by instantaneous osmotic balance between cytosolic and extracellular osmolytes. Simulations reveal that the mphi model can mimic alterations in measured pH(i) and cell volume (Vol(i)) data during and after delivery of an ammonia prepulse, which induces an acid load within the cell. Our analysis indicates that there are substantial problems in quantifying transporter-mediated H+ efflux solely from experimental observations of pH(i) recovery, as is commonly done in practice. Problems stemming from the separation of effects arise, since there is residual NH4+ dissociation to H+ inside the mphi during pH(i) recovery, as well as, proton extrusion via the V-ATPase. The core assumption of conventional measurement techniques used to estimate the H+ extrusion current (I(H)) is that the recovery phase is solely dependent on transporter-mediated H+ extrusion. However, our model predictions suggest that there are major problems in using this approach, due to the complex interactions between I(H), NH3/NH4+ buffering and NH3/NH4+ efflux during the active acid extrusion phase. That is, the conventional buffer capacity-based I(H) estimation must also take into account the perturbation that a prepulse challenge brings to the cytoplasmic acid buffer itself. The importance of this whole-cell model of mphipH(i) and volume regulation lies in its potential for extension to the characterization of several other types of non-excitable cells, such as the microglia (brain macrophage) and the T-lymphocyte.

Ammonium Chloride↗

PubMed2005

A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumours.

The goal of this phase I study was to develop a novel schedule using oral etoposide and infusional topotecan as a continually alternating schedule with potentially optimal reciprocal induction of the nontarget topoisomerase. The initial etoposide dose was 15 mg m(-2) b.i.d. days (D)1-5 weeks 1,3,5,7,9 and 11, escalated 5 mg per dose per dose level (DL). Topotecan in weeks 2,4,6,8,10 and 12 was administered by 96 h infusion at an initial dose of 0.2 mg m(-2) day(-1) with a dose escalation of 0.1, then at 0.05 mg m(-2) day(-1). Eligibility criteria required no organ dysfunction. Two dose reductions or delays were allowed. A total of 36 patients with a median age of 57 (22-78) years, received a median 8 (2-19) weeks of chemotherapy. At DL 6, dose-limiting toxicities consisted of grade 3 nausea, vomiting and intolerable fatigue. Three patients developed a line-related thrombosis or infection and one subsequently developed AML. There was no febrile neutropenia. There were six radiologically confirmed responses (18%) and 56% of patients demonstrated a response or stable disease, typically with only modest toxicity. Oral etoposide 35 mg m(-2) b.i.d. D1-5 and 1.8 mg m(-2) 96 h (total dose) infusional topotecan D8-11 can be administered on an alternating continual weekly schedule for at least 12 weeks, with promising clinical activity.

Adult↗

PubMed2004

Phase transitions in nucleonic matter and neutron-star cooling.

A new scenario for neutron-star cooling is suggested by the correspondence between pion condensation, induced by critical spin-isospin fluctuations, and the metal-insulator phase transition in a 2D electron gas. Above the threshold density for pion condensation, the neutron single-particle spectrum acquires an insulating gap that quenches neutron contributions to neutrino production. In the liquid phase just below the transition, the fluctuations play dual roles by (i) creating a multisheeted neutron Fermi surface that extends to low momenta and activates the normally forbidden direct Urca cooling mechanism, and (ii) amplifying the nodeless P-wave neutron superfluid gap while suppressing S-wave pairing. Lighter stars without a pion-condensed core undergo slow cooling, whereas enhanced cooling occurs in heavier stars via direct Urca emission from a thin shell of the interior.

Journal Article↗

PubMed2004

Motion-contrast computation without directionally selective motion sensors.

The detection of relative motion, i.e., motion contrast, has been reported for motion-sensitive neurons in several vertebrate systems, yet the mechanism underlying motion-contrast sensitivity remains unknown. An algorithm for computing motion contrast directly from the moving intensity distribution is proposed. In this algorithm, the time-dependent intensity distribution of the visual space is convolved with a periodic function. For coherent motion, the resulting convolution integral reduces to a traveling wave of fixed amplitude, while incoherent motion causes the amplitude to oscillate. The frequency of the amplitude oscillation provides a measure of motion contrast. The algorithm is successful in reproducing tuning curves derived from measurements of motion-contrast sensitivity in avian tectum and primate middle temporal area.

Algorithms↗

PubMed2003

Generating neural circuits that implement probabilistic reasoning.

We extend the hypothesis that neuronal populations represent and process analog variables in terms of probability density functions (PDFs). Aided by an intermediate representation of the probability density based on orthogonal functions spanning an underlying low-dimensional function space, it is shown how neural circuits may be generated from Bayesian belief networks. The ideas and the formalism of this PDF approach are illustrated and tested with several elementary examples, and in particular through a problem in which model-driven top-down information flow influences the processing of bottom-up sensory input.

Action Potentials↗

PubMed2003

Higher-order neural networks, Polyà polynomials, and Fermi cluster diagrams.

The problem of controlling higher-order interactions in neural networks is addressed with techniques commonly applied in the cluster analysis of quantum many-particle systems. For multineuron synaptic weights chosen according to a straightforward extension of the standard Hebbian learning rule, we show that higher-order contributions to the stimulus felt by a given neuron can be readily evaluated via Polyà's combinatoric group-theoretical approach or equivalently by exploiting a precise formal analogy with fermion diagrammatics.

Journal Article↗

PubMed2003

Cerebral autoregulation and gas exchange studied using a human cardiopulmonary model.

The goal of this work is to study the cerebral autoregulation, brain gas exchange, and their interaction by means of a mathematical model. We have previously developed a model of the human cardiopulmonary (CP) system, which included the whole body circulatory system, lung and peripheral tissue gas exchange, and the central nervous system control of arterial pressure and ventilation. In this study, we added a more detailed description of cerebral circulation, cerebrospinal fluid (CSF) dynamics, brain gas exchange, and cerebral blood flow (CBF) autoregulation. Two CBF regulatory mechanisms are included: autoregulation and CO(2) reactivity. Central chemoreceptor control of ventilation is also included. We first established nominal operating conditions for the cerebral model in an open-loop configuration using data generated by the CP model as inputs. The cerebral model was then integrated into the larger CP model to form a new integrated CP model, which was subsequently used to study cerebral hemodynamic and gas exchange responses to test protocols commonly used in the assessment of CBF autoregulation (e.g., carotid artery compression and the thigh-cuff deflation test). The model can closely mimic the experimental findings and provide biophysically based insights into the dynamics of cerebral autoregulation and brain tissue gas exchange as well as the mechanisms of their interaction during test protocols, which are aimed at assessing the degree of autoregulation. With further refinement, our CP model may be used on measured data associated with the clinical evaluation of the cerebral autoregulation and brain oxygenation in patients.

Baroreflex↗

PubMed2003

Neural representation of probabilistic information.

It has been proposed that populations of neurons process information in terms of probability density functions (PDFs) of analog variables. Such analog variables range, for example, from target luminance and depth on the sensory interface to eye position and joint angles on the motor output side. The requirement that analog variables must be processed leads inevitably to a probabilistic description, while the limited precision and lifetime of the neuronal processing units lead naturally to a population representation of information. We show how a time-dependent probability density rho(x; t) over variable x, residing in a specified function space of dimension D, may be decoded from the neuronal activities in a population as a linear combination of certain decoding functions phi(i)(x), with coefficients given by the N firing rates a(i)(t) (generally with D << N). We show how the neuronal encoding process may be described by projecting a set of complementary encoding functions phi;(i)(x) on the probability density rho(x; t), and passing the result through a rectifying nonlinear activation function. We show how both encoders phi;(i)(x) and decoders phi(i)(x) may be determined by minimizing cost functions that quantify the inaccuracy of the representation. Expressing a given computation in terms of manipulation and transformation of probabilities, we show how this representation leads to a neural circuit that can carry out the required computation within a consistent Bayesian framework, with the synaptic weights being explicitly generated in terms of encoders, decoders, conditional probabilities, and priors.

Models, Neurological↗

PubMed2001

Quality of informed consent in cancer clinical trials: a cross-sectional survey.

BACKGROUND: Investigators have to obtain informed consent before enrolling participants in clinical trials. We wanted to measure the quality of understanding among participants in clinical trials of cancer therapies, to identify correlates of increased understanding, and to assess providers' beliefs about clinical research. We also sought evidence of therapeutic misconceptions in participants and providers. METHODS: We sent a standard questionnaire to 287 adult patients with cancer who had recently enrolled in a clinical trial at one of three affiliated institutions, and surveyed the provider who obtained each patient's consent. FINDINGS: 207 of 287 (72%) patients responded. 90% (186) of these respondents were satisfied with the informed consent process and most considered themselves to be well informed. Nevertheless, many did not recognise non-standard treatment (74%), the potential for incremental risk from participation (63%), the unproven nature of the treatment (70%), the uncertainty of benefits to self (29%), or that trials are done mainly to benefit future patients (25%). In multivariate analysis, increased knowledge was associated with college education, speaking only English at home, use of the US National Cancer Institute consent form template, not signing the consent form at initial discussion, presence of a nurse, and careful reading of the consent form. Only 28 of 61 providers (46%) recognised that the main reason for clinical trials is benefit to future patients. INTERPRETATION: Misconceptions about cancer clinical trials are frequent among trial participants, and physician/investigators might share some of these misconceptions. Efforts to educate providers and participants about the underlying goals of clinical trials are needed.

Adult↗

PubMed2001

Superfluid phase transitions in dense neutron matter.

The phase transitions in a realistic system with triplet pairing, dense neutron matter, have been investigated. The spectrum of phases of the 3P2-3F2 model, which adequately describes pairing in this system, is analytically constructed with the aid of a separation method for solving BCS gap equations in states of arbitrary angular momentum. In addition to solutions involving a single value of the magnetic quantum number (and its negative), there exist ten real multicomponent solutions. Five of the corresponding angle-dependent order parameters have nodes, and five do not. In contrast to the case of superfluid 3He, transitions occur between phases with nodeless order parameters.

Journal Article↗

PubMed2001

Coevolution between a cockroach and its bacterial endosymbiont: a biogeographical perspective.

Cryptocercus are subsocial, xylophagous cockroaches that live in temperate forests. Like other cockroaches, Cryptocercus harbour endosymbiotic bacteria in their fat bodies. Two species of Cryptocercus occur in the palaearctic, one each in eastern Russia and south-central China. In the USA, there are five species: one in the north-west and four in the south-east. Little is known about the relationship between the Eurasian and North American Cryptocercus or the causes of the disjunct distribution. Here, a molecular phylogeny for six out of the seven Cryptocercus species and their endosymbionts is inferred in an attempt to understand the evolution and biogeography of the genus. Our analysis showed that the North American Cryptocercus are monophyletic, suggesting that a single colonization event was followed by vicariance. There was complete concordance between the host and endosymbiont phylogenetic trees. Divergence estimates based on endosymbiont DNA sequences suggested that the palaearctic and nearctic Cryptocercus diverged 70-115 million years (Myr) ago and the eastern- and western-USA species diverged 53-88 Myr ago. These divergence estimates were correlated with biogeographical events, and a hypothesis is presented to explain the current distribution of Cryptocercus. Our findings suggest that Cryptocercus has had a long evolutionary history, dating back to the Jurassic.

Animals↗

PubMed2001

Quality of informed consent: a new measure of understanding among research subjects.

BACKGROUND: The informed consent of participants is ethically and legally required for most research involving human subjects. However, standardized methods for assessing the adequacy of informed consent to research are lacking. METHODS AND RESULTS: We designed a brief questionnaire, the Quality of Informed Consent (QuIC), to measure subjects' actual (objective) and perceived (subjective) understanding of cancer clinical trials. The QuIC incorporates the basic elements of informed consent specified in federal regulations, assesses the therapeutic misconception (the belief that all aspects of a clinical trial are designed to directly benefit the subject), and employs the language and structure of the new National Cancer Institute template for informed consent documents. We modified the QuIC after receiving feedback from pilot tests with cancer research subjects, as well as validation from two independent expert panels. We then sent the QuIC to 287 adult cancer patients enrolled on phase I, II, or III clinical trials. Two hundred seven subjects (72%) completed the QuIC. To assess test-retest reliability, a random sample of 32 respondents was selected, of whom 17 (53%) completed the questionnaire a second time. The test-retest reliability was good with intraclass correlation coefficients of.66 for tests of objective understanding and.77 for tests of subjective understanding. The current version of the QuIC, which consists of 20 questions for objective understanding and 14 questions for subjective understanding, was tested for time and ease of administration in a sample of nine adult cancer patients. The QuIC required an average of 7.2 minutes to complete. CONCLUSIONS: The QuIC is a brief, reliable, and valid questionnaire that holds promise as a standardized way to assess the outcome of the informed consent process in cancer clinical trials.

Adult↗

PubMed2001

Phase I clinical trial of 7-cyanoquinocarcinol (DX-52-1) in adult patients with refractory solid malignancies.

PURPOSE: A phase I study of the antitumor antibiotic 7-cyanoquinocarcinol, DX-52-1, was conducted in patients with refractory solid malignancies. This study sought to determine the maximum tolerated dose and principal toxicities of this agent and to characterize its pharmacokinetic behavior. METHODS: Patients were required to have adequate bone marrow, renal and hepatic function. DX-52-1 was administered by i.v. continuous infusion over a 6-h period each week for four consecutive weeks followed by a 2-week rest period, which constituted one cycle of treatment. RESULTS: Initial dose levels were 3, 6, and 10 mg/m2. An intermediate dose level of 8 mg/m2 was added after acceptable toxicity was observed at the 6 mg/m2 dose level, but dose-limiting toxicities, including life-threatening ones, were seen at the 10 mg/m2 dose level in all three patients. The maximum tolerated dose (MTD) was subsequently determined to be 6 mg/m2. Because a clear pattern of toxicities was not initially evident, a larger than usual number of additional patients (16) were enrolled at the MTD to better distinguish toxicities due to the study drug from those secondary to the patients' underlying malignancies. Even at the MTD, the drug was poorly tolerated, with gastrointestinal toxicities (abdominal pain, nausea, vomiting and increased liver function tests) predominating and dose-limiting. Pharmacokinetic studies revealed that the mean maximum plasma concentration of DX-52-1 in patients evaluated at the MTD (138.8 +/- 59.3 ng/ml, n = 19) was considerably lower than the concentrations required for cytostatic or cytotoxic activity against sensitive human tumor cell lines in vitro. Further, the weekly dose intensity of the most efficacious treatment schedule identified during in vivo antitumor efficacy studies was 60 times greater than the 6 mg/m2 weekly dose tolerated by cancer patients. None of the 33 patients participating in this study, including the 22 patients evaluated at the MTD, had any response to treatment. CONCLUSION: Given the poor tolerability, the inability to achieve drug levels necessary to inhibit in vitro or in vivo tumor growth, and the lack of any responses in our study, DX-52-1, as given by this schedule, does not appear to warrant further investigation in phase II studies.

Adult↗

PubMed2001

Double bond in the side chain of 1alpha,25-dihydroxy-22-ene-vitamin D(3) is reduced during its metabolism: studies in chronic myeloid leukemia (RWLeu-4) cells and rat kidney.

1alpha,25-Dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] is mainly metabolized via the C-24 oxidation pathway and undergoes several side chain modifications which include C-24 hydroxylation, C-24 ketonization, C-23 hydroxylation and side chain cleavage between C-23 and C-24 to form the final product, calcitroic acid. In a recent study we reported that 1alpha,25-dihydroxyvitamin D(2) [1alpha,25(OH)(2)D(2)] like 1alpha,25(OH)(2)D(3), is also converted into the same final product, calcitroic acid. This finding indicated that 1alpha,25(OH)(2)D(2) also undergoes side chain cleavage between C-23 and C-24. As the side chain of 1alpha,25(OH)(2)D(2) when compared to the side chain of 1alpha,25(OH)(2)D(3), has a double bond between C-22 and C-23 and an extra methyl group at C-24 position, it opens the possibility for both (a) double bond reduction and (b) demethylation to occur during the metabolism of 1alpha,25(OH)(2)D(2). We undertook the present study to establish firmly the possibility of double bond reduction in the metabolism of vitamin D(2) related compounds. We compared the metabolism of 1alpha,25-dihydroxy-22-ene-vitamin D(3) [1alpha,25(OH)(2)-22-ene-D(3)], a synthetic vitamin D analog whose side chain differs from that of 1alpha,25(OH)(2)D(3) only through a single modification namely the presence of a double bond between C-22 and C-23. Metabolism studies were performed in the chronic myeloid leukemic cell line (RWLeu-4) and in the isolated perfused rat kidney. Our results indicate that both 1alpha,25(OH)(2)-22-ene-D(3) and 1alpha,25(OH)(2)D(3) are converted into common metabolites namely, 1alpha,24(R),25-trihydroxyvitamin D(3) [1alpha,24(R),25(OH)(3)D(3)], 1alpha,25-dihydroxy-24-oxovitamin D(3) [1alpha,25(OH)(2)-24-oxo-D(3)], 1alpha,23(S),25-trihydroxy-24-oxovitamin D(3) and 1alpha,23-dihydroxy-24,25,26,27-tetranorvitamin D(3). This finding indicates that the double bond in the side chain of 1alpha,25(OH)(2)-22-ene-D(3) is reduced during its metabolism. Along with the aforementioned metabolites, 1alpha,25(OH)(2)-22-ene-D(3) is also converted into two additional metabolites namely, 1alpha,24,25(OH)(3)-22-ene-D(3) and 1alpha,25(OH)(2)-24-oxo-22-ene-D(3). Furthermore, we did not observe direct conversion of 1alpha,25(OH)(2)-22-ene-D(3) into 1alpha,25(OH)(2)D(3). These findings indicate that 1alpha,25(OH)(2)-22-ene-D(3) is first converted into 1alpha,24,25(OH)(3)-22-ene-D(3) and 1alpha,25(OH)(2)-24-oxo-22-ene-D(3). Then the double bonds in the side chains of 1alpha,24,25(OH)(3)-22-ene-D(3) and 1alpha,25(OH)(2)-24-oxo-22-ene-D(3) undergo reduction to form 1alpha,24(R),25(OH)(3)D(3) and 1alpha,25(OH)(2)-24-oxo-D(3), respectively. Thus, our study indicates that the double bond in 1alpha,25(OH)(2)-22-ene-D(3) is reduced during its metabolism. Furthermore, it appears that the double bond reduction occurs only during the second or the third step of 1alpha,25(OH)(2)-22-ene-D(3) metabolism indicating that prior C-24 hydroxylation of 1alpha,25(OH)(2)-22-ene-D(3) is required for the double bond reduction to occur.

Animals↗

PubMed2001

Pancreatic cancer: cost-effectiveness of imaging technologies for assessing resectability.

PURPOSE: To evaluate the cost-effectiveness of imaging strategies for the assessment of resectability in patients with pancreatic cancer. MATERIALS AND METHODS: A decision model was developed to calculate costs and benefits (survival) accruing to hypothetical cohorts of patients with known or suspected pancreatic cancer. Results are presented as cost per life-year gained under various scenarios and assumptions of diagnostic test characteristics, surgical mortality, disease characteristics, and costs. RESULTS: With best estimates for all data inputs, the strategy of computed tomography (CT) followed by laparoscopy and laparoscopic ultrasonography (US) had an incremental cost-effectiveness ratio of $87,502 per life-year gained, compared with best supportive care. This strategy was significantly more cost-effective than CT followed by magnetic resonance (MR) imaging and was significantly less expensive than other imaging strategies while providing a statistically and clinically insignificant difference in life-year gains. A strategy involving no imaging (immediate surgery) was more expensive but less effective than all imaging strategies. A hypothetical perfect test with cost equal to that of CT followed by MR had an incremental cost-effectiveness ratio of $64,401 per life-year gained, compared to best supportive care. CONCLUSION: Most available imaging tests for assessing resectability of pancreatic cancer do not differ in effectiveness, but a strategy of CT, laparoscopy, and laparoscopic US would consistently result in significantly lower costs than other imaging tests under a wide range of scenarios.

Cost-Benefit Analysis↗

PubMed2001

A human cardiopulmonary system model applied to the analysis of the Valsalva maneuver.

Previous models combining the human cardiovascular and pulmonary systems have not addressed their strong dynamic interaction. They are primarily cardiovascular or pulmonary in their orientation and do not permit a full exploration of how the combined cardiopulmonary system responds to large amplitude forcing (e.g., by the Valsalva maneuver). To address this issue, we developed a new model that represents the important components of the cardiopulmonary system and their coupled interaction. Included in the model are descriptions of atrial and ventricular mechanics, hemodynamics of the systemic and pulmonic circulations, baroreflex control of arterial pressure, airway and lung mechanics, and gas transport at the alveolar-capillary membrane. Parameters of this combined model were adjusted to fit nominal data, yielding accurate and realistic pressure, volume, and flow waveforms. With the same set of parameters, the nominal model predicted the hemodynamic responses to the markedly increased intrathoracic (pleural) pressures during the Valsalva maneuver. In summary, this model accurately represents the cardiopulmonary system and can explain how the heart, lung, and autonomic tone interact during the Valsalva maneuver. It is likely that with further refinement it could describe various physiological states and help investigators to better understand the biophysics of cardiopulmonary disease.

Baroreflex↗