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Biomedical subjects

Andrew Jackson

Publications and source records attributed to Andrew Jackson.

At least 19 recordsLinked to original sources

Reduced-order parameter optimization for simplifying prostate IMRT planning.

Intensity-modulated radiotherapy (IMRT) has become an effective tool for cancer treatment with radiation. However, even expert radiation planners still need to spend a substantial amount of time manually adjusting IMRT optimization parameters such as dose limits and costlet weights in order to obtain a clinically acceptable plan. In this paper, we describe two main advances that simplify the parameter adjustment process for five-field prostate IMRT planning. First, we report the results of a sensitivity analysis that quantifies the effect of each hand-tunable parameter of the IMRT cost function on each clinical objective and the overall quality of the resulting plan. Second, we show that a recursive random search over the six most sensitive parameters as an outer loop in IMRT planning can quickly and automatically determine parameters for the cost function that lead to a plan meeting the clinical requirements. Our experiments on a ten-patient dataset show that for 70% of the cases, we can automatically determine a plan in 10 min (on the average) that is either clinically acceptable or requires only minor adjustment by the planner. The outer-loop optimization can be easily integrated into a traditional IMRT planning system.

Algorithms↗

Long-term motor cortex plasticity induced by an electronic neural implant.

It has been proposed that the efficacy of neuronal connections is strengthened when there is a persistent causal relationship between presynaptic and postsynaptic activity. Such activity-dependent plasticity may underlie the reorganization of cortical representations during learning, although direct in vivo evidence is lacking. Here we show that stable reorganization of motor output can be induced by an artificial connection between two sites in the motor cortex of freely behaving primates. An autonomously operating electronic implant used action potentials recorded on one electrode to trigger electrical stimuli delivered at another location. Over one or more days of continuous operation, the output evoked from the recording site shifted to resemble the output from the corresponding stimulation site, in a manner consistent with the potentiation of synaptic connections between the artificially synchronized populations of neurons. Changes persisted in some cases for more than one week, whereas the output from sites not incorporated in the connection was unaffected. This method for inducing functional reorganization in vivo by using physiologically derived stimulus trains may have practical application in neurorehabilitation after injury.

Action Potentials↗

Correlations between the same motor cortex cells and arm muscles during a trained task, free behavior, and natural sleep in the macaque monkey.

Traditionally, the neural control of movement has been studied by recording cell activity in restrained animals performing repetitive, highly trained tasks within a restricted workspace. However, the degree to which results obtained under these conditions are valid during natural, unconstrained behavior remains unknown. Using an autonomous, implantable recording system, we examined the relationships between the firing of motor cortex cells and forearm muscle activity in primates under three behavioral conditions: performance of a conventional torque-tracking task, unrestrained behavior, and natural sleep. We found strong correlations over long periods of daytime activity, suggesting a consistent relationship between cortex and muscles across the repertoire of awake behavior. The range of correlation values was comparable during task performance, but many individual cells exhibited significant differences across conditions. During the night, phases of sleep were associated with a cyclical pattern of cell and muscle activity. Across the population, the strength of cell-muscle correlations was related to preferred direction for daytime but not nighttime activity. The relationship of cells to behavior remained consistent over periods of several weeks. These findings extend the interpretation of results obtained under constrained conditions and are relevant to the development of neural prostheses for restoring natural movements to patients with motor deficits.

Action Potentials↗

Principal component, Varimax rotation and cost analysis of volume effects in rectal bleeding in patients treated with 3D-CRT for prostate cancer.

We investigate the utility of principal component analysis as a tool for obtaining dose-volume combinations related to rectal bleeding after radiotherapy for prostate cancer. A direct implementation of principal component analysis reduces the number of degrees of freedom from the patient's dose-volume histograms that are associated with bleeding. However, when low-variance principal components are strongly correlated to outcome, their interpretation is problematic. A Varimax rotation is employed to aid in interpretability of the low-variance principal components. This procedure brings us closer to finding unique dose-volume combinations related to outcome but reintroduces correlation, requiring analysis of the overlap of information contained in such modes. Finally, we present examples of cost-benefit analyses for candidate dose-volume constraints for use in treatment planning.

Gastrointestinal Hemorrhage↗

Geometric factors influencing dosimetric sparing of the parotid glands using IMRT.

PURPOSE/OBJECTIVE: To determine the relationship between the parotid volume, parotid-planning target volume (PTV) overlap, and dosimetric sparing of the parotid with intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: Parotid data were collected retrospectively for 51 patients treated with simultaneous boost IMRT. Unresectable patients received 54 or 59.4 Gy to subclinical disease, 70 Gy to gross disease. Patients treated postoperatively received 54, 60, and 66 Gy to low-risk, high-risk, and tumor bed regions. Volume and mean dose of each gland and gland segments outside of and overlapping the PTV were collected. Proximity of each gland to each PTV was recorded. RESULTS: Dosimetric sparing (mean dose 21% overlap (p = <0.0001). Among spared glands, the median mean dose in the overlap region was 55.0 Gy in glands with < or =21% overlap, but only 45.4 Gy when overlap >21%. Median mean dose was 25.9 Gy to glands overlapping PTV(54) or PTV(59) alone and 30.0 Gy to those abutting PTV(70) (p < 0.001). Although proximity to PTV(70) was associated with higher parotid dose, satisfactory sparing was achieved in 24 of 43 ipsilateral glands. CONCLUSIONS: Dosimetric sparing of the parotid is feasible when the parotid-PTV overlap is less than approximately 20%. With more overlap, sparing may result in low doses within the overlap region, possibly leading to inadequate PTV coverage. Gland proximity to the high-dose PTV is associated with higher mean dose but does not always preclude dosimetric sparing.

Algorithms↗

The DNA sequence, annotation and analysis of human chromosome 3.

After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evolutionary history of the inversion.

Animals↗

CXCR4/SDF1 interaction inhibits the primordial to primary follicle transition in the neonatal mouse ovary.

The molecular mechanisms behind the entry of the primordial follicle into the growing follicle pool remain poorly understood. To investigate this process further, a microarray-based comparison was undertaken between 2-day postpartum mouse ovaries consisting of primordial follicles/naked oocytes only and those with both primordial follicles and newly activated follicles (7-day postpartum). Gene candidates identified included the chemoattractive cytokine stromal derived factor-1 (SDF1) and its receptor CXCR4. SDF1 and CXCR4 have been implicated in a variety of physiological processes including the migration of embryonic germ cells to the gonads. SDF1-alpha expression increased with the developmental stage of the follicle. Embryonic expression was found to be dichotomous post-germ cell migration, with low expression in the female. Immunohistochemical studies nonetheless indicate that the autocrine pattern of expression ligand and receptor begins during embryonic life. Addition of recombinant SDF1-alpha to neonatal mouse ovaries in vitro resulted in significantly higher follicle densities than for control ovaries. TUNEL analysis indicated no detectable difference in populations of apoptotic cells of treated or control ovaries. Treated ovaries also contained a significantly lower percentage of activated follicles as determined by measurement of oocyte diameter and morphological analysis. Treatment of cultured ovaries with an inhibitor of SDF1-alpha, AMD3100, ablated the effect of SDF1-alpha. By retaining follicles in an unactivated state, SDF1/CXCR4 signaling may play an important role in maintaining the size and longevity of the primordial follicle pool.

Animals↗

The finished DNA sequence of human chromosome 12.

Human chromosome 12 contains more than 1,400 coding genes and 487 loci that have been directly implicated in human disease. The q arm of chromosome 12 contains one of the largest blocks of linkage disequilibrium found in the human genome. Here we present the finished sequence of human chromosome 12, which has been finished to high quality and spans approximately 132 megabases, representing approximately 4.5% of the human genome. Alignment of the human chromosome 12 sequence across vertebrates reveals the origin of individual segments in chicken, and a unique history of rearrangement through rodent and primate lineages. The rate of base substitutions in recent evolutionary history shows an overall slowing in hominids compared with primates and rodents.

Animals↗

Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.

BACKGROUND: Combined modality therapy has become the standard of care for nasopharyngeal carcinoma, yet the combined ototoxic effects of radiation and cisplatin are poorly understood. The incidence and severity of sensorineural hearing loss (SNHL) with combined modality therapy was evaluated and the dose-response relation between radiation and hearing loss was investigated. METHODS: Patients with newly diagnosed AJCC Stage II-IVB nasopharynx carcinoma treated from 1994-2003 were identified. The records of 44 ears in 22 patients who received a preirradiation pure tone audiogram and followup audiograms 12+ months postirradiation were included in the analysis. All patients were treated with conformal radiotherapy to 70 Gy and received platinum-based chemotherapy similar to the Intergroup 0099 trial. Composite cochlear dose distributions were calculated. Ototoxicity was measured using intrasubject audiogram comparisons and SNHL was defined as per the American Speech and Hearing Association guidelines, with standard range of speech between 2000-4000 Hz. SNHL was analyzed using Fisher exact test and linear and logistic regression models. RESULTS PATIENT CHARACTERISTICS: median age, 45; 27% Asian; 68% male; 64% WHO III. Median audiologic followup was 29 months (range, 12-76 mos). Mean cochlear dose (Dmean) ranged from 28.4-70.0 Gy (median, 48.5 Gy). SNHL was detected in 25 of the 44 ears (57%) studied. There was an increased risk of SNHL for ears receiving Dmean > 48 Gy compared with those receiving < or = 48 Gy at all frequencies within the range of speech (P = 0.04). Using univariate logistic regression analysis, Dmean to the cochlea, cycles of cisplatin, and time postradiotherapy were independently significant factors in determining the incidence of SNHL (P = 0.02, P = 0.03, and P = 0.04, respectively). In univariate and multivariate linear regression analysis, Dmean was statistically significant at all frequencies in affecting degree of SNHL, whereas the significance of cisplatin and time was variable. CONCLUSIONS: There was a significant increase in risk of SNHL among patients receiving > 48 Gy, suggesting a threshold in cochlear radiation dose-response in the setting of combined modality therapy. This dose should serve as a Dmean constraint maximum for intensity-modulated radiotherapy treatment of nasopharynx carcinoma.

Adolescent↗

The atlas of complication incidence: a proposal for a new standard for reporting the results of radiotherapy protocols.

We present a new method of reporting the results of radiotherapy protocols. The dose-volume atlas of complication incidence is a comprehensive and unbiased summary of the dose-volume exposures and complications occurring in patients after treatment. This new tool provides clear and systematic information about the safety of regions of dose-volume exposure previously treated that can be used when considering new treatments. Actuarial and model-dependent versions of the atlas are described. By using the raw data in the appropriate forms of the atlas, logistic regression, Kaplan-Meier, and Cox proportional hazards analysis can be performed, allowing for the independent calculation of dose-volume response. The data required are simple enough that provided compatible definitions of dose, volume, and complications are used, atlases from different protocols are potentially additive, facilitating the meta-analysis of inter-interinstitutional data. If this method were adopted as a standard for reporting the outcome of treatment protocols, a potentially synergistic increase in the utility of each protocol could result.

Clinical Protocols↗

Learning the relationship between patient geometry and beam intensity in breast intensity-modulated radiotherapy.

Intensity modulated radiotherapy (IMRT) has become an effective tool for cancer treatment with radiation. However, even expert radiation planners still need to spend a substantial amount of time adjusting IMRT optimization parameters in order to get a clinically acceptable plan. We demonstrate that the relationship between patient geometry and radiation intensity distributions can be automatically inferred using a variety of machine learning techniques in the case of two-field breast IMRT. Our experiments show that given a small number of human-expert-generated clinically acceptable plans, the machine learning predictions produce equally acceptable plans in a matter of seconds. The machine learning approach has the potential for greater benefits in sites where the IMRT planning process is more challenging or tedious.

Artificial Intelligence↗

The Neurochip BCI: towards a neural prosthesis for upper limb function.

The Neurochip BCI is an autonomously operating interface between an implanted computer chip and recording and stimulating electrodes in the nervous system. By converting neural activity recorded in one brain area into electrical stimuli delivered to another site, the Neurochip BCI could form the basis for a simple, direct neural prosthetic. In tests with normal, unrestrained monkeys, the Neurochip continuously recorded activity of single neurons in primary motor cortex for several weeks at a time. Cortical activity was correlated with simultaneously-recorded electromyogram (EMG) activity from arm muscles during free behavior. In separate experiments with anesthetized monkeys, we found that microstimulation of the cervical spinal cord evoked movements of the arm and hand, often involving multiple muscles synergies. These observations suggest that spinal microstimulation controlled by cortical neurons could help compensate for damaged corticospinal projections.

Animals↗

Acupuncture for tinnitus: a series of six n = 1 controlled trials.

OBJECTIVE: To explore patient perceived benefits of acupuncture for tinnitus. DESIGN: Controlled n=1 trials, with two phases A and B. SUBJECTS: Six patients with tinnitus. OUTCOME MEASURES: Primary outcome was Daily Diary records related to four tinnitus symptoms: loudness of tinnitus; pitch of tinnitus; waking hours affected with tinnitus; quality of sleep. Secondary outcomes were the Tinnitus Handicap Inventory (THI) and Measure Your Medical Outcome Profile (MYMOP). METHODS: Patients received a course of 10 acupuncture treatments over a 2-week period. Daily Diary entries related to the four tinnitus symptoms were recorded by patients for 14 days pre-treatment (phase A) and 14 days post-treatment (phase B). A hierarchical Bayesian model was used to combine the results from the individual patients to obtain estimates of the population and individual patient treatment effects, incorporating random variations at both levels (between patients and within patient). Tinnitus Handicap Inventory (THI) and Measure Your Medical Outcome Profile (MYMOP) were recorded at assessment points pre-treatment and post-treatment. RESULTS: Six patients participated in the trials, each receiving 10 treatments and completing all Daily Diary entries and outcome measures. For the of symptoms of loudness and pitch, there were variable treatment effects between patients, with a trend for the median overall reduction for loudness of -2.49 (-5.04, 0.02) and for pitch -1.39 (-3.74, 0.89), 95% credibility intervals being shown in brackets. For the other two symptoms, the waking hours affected and quality of sleep, patients' responses were more consistent, with amore credible overall median reduction for affected waking hours of -2.76 (-3.94, -1.63) and for quality of sleep -2.72 (-3.45, -2.03). The THI and MYMOP measures showed a trend of improvement after treatment. CONCLUSION: The n=1 trial methodology, with an AB design and Bayesian analysis, can be considered of value in exploring treatment effects for small numbers of patients receiving individualised treatments, as is common within complementary medicine. When the treatment effects from six patients were synthesized, the results of this study suggest that acupuncture may have a beneficial role in the treatment of tinnitus.

Acupuncture Therapy↗

An autonomous implantable computer for neural recording and stimulation in unrestrained primates.

To perform neurobiological experiments on freely behaving primates, we have developed a miniature battery-powered implantable computer capable of recording and stimulating through chronic electrodes in the cortex. The device has: (1) an analog front end with a four-pole bandpass filter (500 Hz-5 kHz), programmable gain and offset nulling; (2) an analog-to-digital converter to sample the data at 11.7 ksps; (3) a programmable microcontroller to discriminate spikes in real time and perform computations; (4) a stimulator to deliver biphasic current pulses of up to 100 muA with variable pulse width and frequency; (5) a 4 Mbit non-volatile memory to store biological data; (6) a 57.6 kbps infrared data link for wireless communications with a hand-held or desktop computer. The device is enclosed in a 5.5 cm x 5 cm x 3 cm titanium casing on the monkey's head along with a 3.3 V lithium battery and an array of cortical electrodes. In in vivo tests, the device was able to record stable cell discharge continuously for time periods of a week or more. After downloading the parameters for recording, stimulation, discrimination, and other computations, the device is capable of operating autonomously, delivering stimuli to one electrode triggered by spikes recorded at a separate site.

Action Potentials↗

Correlation of dosimetric factors and radiation pneumonitis for non-small-cell lung cancer patients in a recently completed dose escalation study.

PURPOSE: To determine dosimetric factors for lung, lung subregions, and heart that correlate with radiation pneumonitis (Radiation Therapy Oncology Group Grade 3 or more) in the 78 evaluable patients from a Phase I dose escalation study (1991-2003) of three-dimensional conformal radiation therapy (3D-CRT) of non-small-cell lung cancer. METHODS AND MATERIALS: There were 10 > or = Grade 3 pneumonitis cases within 6 months after treatment. Dose-volume factors analyzed for univariate correlation with > or = Grade 3 pneumonitis were mean dose (MD), effective uniform dose (d(eff)), normal tissue complication probability (NTCP), parallel model f(dam) and V(D) for 5 < or = D < or = 60 Gy for whole, ipsilateral, contralateral, upper and lower halves of the lungs and heart D05, and mean and maximum doses. RESULTS: The most significant variables (0.005 < p < 0.006) were ipsilateral lung V(D) for D < 20 Gy. Also significant (p < 0.05) for ipsilateral lung were V(D) for D < 50 Gy, MD, f(dam) and d(eff); for total lung V(D) (D < 50 Gy), MD, f(dam), d(eff) and NTCP; for lower lung V(D) (D < 60 Gy), MD, f(dam) and d(eff). All variables for upper and contralateral lung were insignificant, as were heart variables. CONCLUSIONS: Previously reported correlations between severe pneumonitis and whole lung V13 and with other dose-volume factors of total lung and lower lung are confirmed. The most significant correlations were for (V05-V13) in ipsilateral lung.

Adult↗

Results of a phase I dose-escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma.

BACKGROUND: The objective of this study was to report the results of a Phase I dose-escalation study using three-dimensional conformal radiation therapy (3D-CRT) for the treatment of patients with nonsmall cell lung carcinoma (NSCLC). METHODS: Between 1991 and 2003, 104 patients were enrolled for 3D-CRT at Memorial Sloan-Kettering Cancer Center. The median patient age was 69 years. Twenty-eight percent of patients had Stage I-II NSCLC, 33% of patients had Stage IIIA NSCLC, 32% of patients had Stage IIIB NSCLC, and 6% of patients had recurrent NSCLC. Induction chemotherapy was received by 16% of patients. Radiation was delivered in daily fractions of 1.8 grays (Gy) for doses < or = 81.0 Gy and in daily fractions of 2.0 Gy for higher doses. Accrual at a dose level was complete when 10 patients received the intended dose without unacceptable acute morbidity. RESULTS: After an incident of fatal acute radiation pneumonitis at the starting dose of 70.2 Gy, the protocol was modified to limit normal tissue complication probabilities (NTCP) to < 25%. The dose was then escalated from 70.2 Gy, to 75.6 Gy, 81.0 Gy, and 84.0 Gy, with at least 10 patients treated at each dose level. Unacceptable pulmonary toxicity occurred at 90.0 Gy. Subsequently, another 10 patients were accrued at the 84.0 Gy level with acceptable toxicity. Thus, 84.0 Gy was the maximum tolerated dose (MTD). The crude late pulmonary toxicity rate was 7%, the 2-year local control rate was 52%, the disease-free survival rate was 33%, and the overall survival rate was 40%. The median survival was 21.1 months. Overall survival was improved significantly in patients who received > or = 80.0 Gy. CONCLUSIONS: The MTD of 3D-CRT for NSCLC with an NTCP constraint of 25% was 84.0 Gy in the current study. There was a suggestion of improved survival in patients who received 80.0 Gy.

Adult↗

Modulation of antitumor responses by dendritic cells.

The discovery that dendritic cells (DC) play a key role in regulating antitumor immunity has prompted considerable efforts in developing DC-based cancer vaccines for use in clinical oncology. Early translational trials using antigen-loaded DC have established clear evidence of vaccine safety, and demonstrated bioactivity by stimulating immunological and even clinical responses in selected subjects. Despite these encouraging results, the vaccine-induced immune responses achieved to date are not yet sufficient to attain a robust and durable therapeutic effect in the cancer patient. Therefore, further improvements are required to enhance vaccine potency and optimize the potential for clinical success. This article presents a set of emerging concepts that, together, form a framework for a multi-pronged approach that will further enhance the efficacy of DC-based vaccination by either directly improving DC-mediated T cell activation or by inhibiting mechanisms that suppress the induction of an effective antitumor response. The clinical translation of these concepts will result in new opportunities to successfully modulate immune responses in clinical settings.

Animals↗

The effect of paralogous lineages on the application of reconciliation analysis by cophylogeny mapping.

Paralogy defines similarity caused by duplication rather than common descent and is well known in the case of paralogous gene copies within a single genome. The term is here extended to paralogous lineages of associates within a single host. The phylogenies of four genera within the Herpesviridae were reconciled with host phylogenies using cophylogenetic mapping. The observed correspondence for each pair of phylogenies was evaluated through randomization of the viral phylogeny and demonstrated to be greater than expected by chance. A simulation study was then carried out to assess the influence of paralogous lineages on the efficacy of reconciliation analysis. Combining viral taxa from different genera that infected common hosts introduced incongruence into the cophylogenies and reduced both the minimum and maximum observed number of codivergence events relative to the initial analysis of orthologous clades. However, at an average sample size this did not alter the fundamental significance of observed correspondence. With smaller sample sizes, the number of orthologous taxa selected at random from the pool of taxa was reduced. False-negative results then increased in proportion from 0.02 to 0.33. These results demonstrated that reconciliation analysis is robust under conditions of paralogy at "normal" sample sizes but is adversely affected by a combination of paralogy and low sample size. Consideration of phylogenies for Papillomavirus, Atadenovirus, and Mastadenovirus suggest that paralogous lineages may be a widespread phenomenon among DNA viruses and that duplication irrespective of host speciation is an important cause of viral diversification.

Animals↗