Biomedical subjects

Michael D McClean

Publications and source records attributed to Michael D McClean.

14 recordsLinked to original sources

PubMed2007

Global DNA methylation level in whole blood as a biomarker in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol exposures, although dietary factors, particularly folate, and human papillomavirus, are also risk factors. Epigenetic alterations are increasingly implicated in the initiation and progression of cancer. Genome-wide (global) hypomethylation seems to occur in early neoplasia and is a feature of genomic DNA derived from solid tumor tissues, including HNSCC. This study aimed to determine whether global methylation in DNA derived from whole blood, a proxy tissue, is associated with HNSCC and to assess potential modification of this property by environmental or behavioral risk factors. METHODS: Global DNA methylation levels were assessed using a modified version of the combined bisulfite restriction analysis of the LRE1 sequence in a population-based case-control study of HNSCC from the Boston area. RESULTS: Hypomethylation lead to a significant 1.6-fold increased risk for disease (95% confidence interval, 1.1-2.4), in models controlled for other HNSCC risk factors. Smoking showed a significant differential effect (P < 0.03) on blood relative methylation between cases and controls. Furthermore, in cases, variant genotype in the MTHFR gene and low folate intake showed relationships with decreased global methylation, whereas in controls, antibody response to human papillomavirus 16 was associated with an increased global methylation level. DISCUSSION: DNA hypomethylation in nontarget tissue was independently associated with HNSCC and had a complex relationship with the known risk factors associated with the genesis of HNSCC.

Alcohol Drinking↗

PubMed2006

Epigenetic inactivation of the SFRP genes is associated with drinking, smoking and HPV in head and neck squamous cell carcinoma.

The soluble frizzled receptor protein (SFRP) family encodes antagonists of the WNT pathway, and silencing of these genes, through promoter hypermethylation, leads to constitutive WNT signaling. In bladder cancers, hypermethylation of the SFRP genes occurs more often in current and former smokers and is a strong predictor of poor patient survival. Hence, we examined methylation of these genes in another tobacco-related epithelial cancer, head and neck squamous cell carcinoma (HNSCC), to determine if the pattern of tobacco exposure again predicts the epigenetic alteration of these genes. Using methylation-specific PCR, the prevalence of methylation of SFRP1, SFRP2, SFRP4 and SFRP5 was 35, 32, 35 and 29%, respectively among 350 HNSCC cases. Promoter methylation of SFRP1 occurred more often in both heavy (OR 3.5, 95% CI 0.9-13.7) and light drinkers (OR 3.7, 95% CI 1.0-14.3) compared to nondrinkers. SFRP4 promoter methylation, on the other hand, occurred at a higher prevalence in never smokers and former smokers than in current smokers, and also was independently associated with HPV16 viral DNA. A joint effects model of SFRP4 promoter methylation demonstrated that smoking status and HPV virus significantly interacted (p < 0.04) such that never smokers with HPV16 had an OR of SFRP4 methylation of 9.0 (95% CI 2.1-38.6). These results suggest that epigenetic alterations of the SFRP genes are highly prevalent in HNSCC, and that the clonal selection for these alterations is complex and may be related to the carcinogenic exposures that are known risk factors for this disease.

Aged↗

PubMed2006

Dietary folate is associated with p16(INK4A) methylation in head and neck squamous cell carcinoma.

Inactivation of the p16(INK4A) (CDKN2A) gene in the Rb pathway is among the most common somatic alterations observed in tobacco-related solid tumors, including head and neck squamous cell carcinoma (HNSCC). In addition, a low folate diet is an important risk factor for HNSCC. Decreased dietary folate in an animal model of hepatocellular carcinoma has been associated with the induction of epigenetic silencing of the p16(INK4A) gene. In an ongoing population-based study of HNSCC, we sought to extend this observation to human disease testing the hypothesis that p16(INK4A) methylation is associated with decreased dietary folate. We also investigated the association of methylation silencing with functional polymorphisms in the folate metabolism enzyme methylene tetrahydrofolate reductase (MTHFR). In 169 HNSCCs, the odds ratio for p16(INK4A) methylation among those with low dietary folate intake was 2.3 (95% CI = 1.1-4.8) when compared with those with high folate intake. Furthermore, this increased risk for epigenetic silencing at p16(INK4A) was modified by the MTHFR alleles previously associated with diminished serum folate levels. Hence, in HNSCC low dietary intake of folate is associated with p16(INK4A) methylation, and this relationship is modified by the MTHFR genotype. Our data provides important evidence for a mechanism of action of folate deficiency in cancer.

Adult↗

PubMed2006

Duration but not intensity of alcohol and tobacco exposure predicts p16INK4A homozygous deletion in head and neck squamous cell carcinoma.

In tobacco-associated solid tumors, evidence suggests that the pattern of carcinogen exposure is related to the nature of somatic gene inactivation within crucial pathways, including the retinoblastoma (Rb) pathway. One somatic event in this pathway, homozygous deletion of the p16INK4A gene, is commonly observed in head and neck squamous cell carcinoma (HNSCC). Alcohol and tobacco are both well-established risk factors for HNSCC but there has been little characterization of the relationship of exposure to these carcinogens and inactivation of the p16INK4A gene. Hypothesizing that p16INK4A homozygous deletion is associated with tobacco and alcohol exposure, we investigated 330 consecutive HNSCC tumors. The odds ratio (OR) for p16INK4A homozygous deletion among alcohol consumers in the upper tertile (>43 years used) was 5.2 [95% confidence interval (95% CI), 2.1-12.8] as compared with those with < or = 43 years of alcohol consumption. Intensity of alcohol exposure, measured as average alcoholic drinks per week, was not associated with gene deletion. When we examined the distribution of duration of tobacco use, the OR for p16(INK4A) homozygous deletion was 1.3 (95% CI, 0.5-3.0) and 1.9 (95% CI, 0.9-4.0) for 29 to 39 years and >39 years of tobacco smoking, respectively, as compared with those that smoked < or = 28 years. As in the case of alcohol use, intensity of tobacco exposure (measured as packs per day) was not associated with gene deletion. Hence, the duration of alcohol use and duration of smoking, but not intensity of either, significantly predicted p16(INK4A) homozygous deletion in HNSCC.

Alcohol Drinking↗

PubMed2006

Glutathione S-transferase polymorphisms and the synergy of alcohol and tobacco in oral, pharyngeal, and laryngeal carcinoma.

Investigations of the ability of polymorphisms in the GSTM1, GSTT1, and GSTP1 genes to alter susceptibility to head and neck squamous cell carcinoma (HNSCC) have examined gene-environment interaction in their detoxification of tobacco-associated carcinogens. Little work has been done to ask if these variant genes also modify the interaction of tobacco and alcohol in the development of HNSCC. To test this hypothesis, we conducted a case-control study, enrolling 692 incident cases of HNSCC and 753 population controls. Information about lifetime tobacco and alcohol use was ascertained through questionnaires, and genotypes for GSTM1, GSTT1, and GSTP1 were determined from constitutional DNA. Genotype frequencies were compared among cases and controls, and the association between genotypes and tobacco use was evaluated on cancer risk through logistic regression. Deletion of GSTM1 was associated with an increased risk for HNSCC [odds ratio (OR), 1.3; 95% confidence interval (95% CI), 1.0-1.6]. GSTT1 deletion was associated with a slight decreased HNSCC risk (OR, 0.8; 95% CI, 0.6-1.0). Among those with GSTM1 present, the OR of cancer for heavy smoking was 2.6 (95% CI, 1.6-4.3) compared with 4.2 for those with the GSTM1 deleted (95% CI, 2.6-6.7). The combination of consuming 10 to 20 alcohol drinks weekly and smoking >45 pack-years was associated with a 13-fold elevated risk (OR, 12.6; 95% CI, 4.0-40.2) among the GSTM1 deleted subjects compared with an OR of 3.6 (95% CI, 1.5-8.7) among the GSTM1 present individuals. These data (showing that the GSTM1 deletion affects on the tobacco and alcohol synergy) suggest that the interaction of these carcinogens is, at least in part, driven by alcohol, enhancing the carcinogenic action of tobacco smoke.

Alcohol Drinking↗

PubMed2005

The ADH1C polymorphism modifies the risk of squamous cell carcinoma of the head and neck associated with alcohol and tobacco use.

Alcohol consumption interacts with tobacco use to increase the risk of head and neck squamous cell carcinoma (HNSCC). Alcohol is eliminated through oxidation by alcohol dehydrogenase (ADH). The ADH1C gene is polymorphic and the ADH1C*1 allele metabolizes ethanol to acetaldehyde at a higher rate than the variant ADH1C*2 allele. This polymorphism has been reported to alter the risk of HNSCC associated with alcohol use, although the literature differs in the estimates of both the magnitude and direction of this effect modification. We have investigated the association between the established risk factors for HNSCC and variant genotypes of ADH1C in a case-control study in the greater Boston area. ADH1C genotypes were determined from 521 cases and 599 population-based controls. The odds ratio (OR) for HNSCC associated with >26 drinks per week was 3.7 [95% confidence interval (95% CI), 2.4-5.7], whereas the OR for smoking >58 pack-years was 5.6 (95% CI, 3.8-8.4). The combination of heavy smoking and heavy drinking significantly interacted to produce an OR of 17.3 (95% CI, 7.8-38.3). In cases and controls, respectively, 16% and 14% were ADH1C*1-1, 46% and 46% were ADH1C*1-2 and 38% and 40% were ADH1C*2-2. There was a significant interaction of alcohol use and genotype (P = 0.05), with an estimated oral cancer risk in heavy drinkers of 7.1 (95% CI, 2.3-22.0) for homozygous variants compared with an OR of 2.3 (95% CI, 1.4-3.8) for ADH1C homozygous wild type or heterozygous individuals (controlling for smoking, age, race, and gender). These findings suggest that the ADH1C*2-2 genotype is associated with susceptibility to smoking and drinking-related HNSCC by modifying the biologically effective dose of alcohol.

Aged↗

PubMed2004

Correlation of orofacial speeds with voice acoustic measures in the fluent speech of persons who stutter.

Stuttering is often viewed as a problem in coordinating the movements of different muscle systems involved in speech production. From this perspective, it is logical that efforts be made to quantify and compare the strength of neural coupling between muscle systems in persons who stutter (PS) and those who do not stutter (NS). This problem was addressed by correlating the speeds of different orofacial structures with vowel fundamental frequency (F0) and intensity as subjects produced fluent repetitions of a simple nonsense phrase at habitual, high, and low intensity levels. It is assumed that resulting correlations indirectly reflect the strength of neural coupling between particular orofacial structures and the respiratory-laryngeal system. An electromagnetic system was employed to record movements of the upper lip, lower lip, tongue, and jaw in 43 NS and 39 PS. The acoustic speech signal was recorded and used to obtain measures of vowel F0 and intensity. For each subject, correlation measures were obtained relating peak orofacial speeds to F0 and intensity. Correlations were significantly reduced in PS compared to NS for the lower lip and tongue, although the magnitude of these group differences covaried with the correlation levels relating F0 and intensity. It is suggested that the group difference in correlation pattern reflects a reduced strength of neural coupling of the lower lip and tongue systems to the respiratory-laryngeal system in PS. Consideration is given to how this may contribute to temporal discoordination and stuttering.

Adult↗

PubMed2004

Variations in articulatory movement with changes in speech task.

Studies of normal and disordered articulatory movement often rely on the use of short, simple speech tasks. However, the severity of speech disorders can be observed to vary markedly with task. Understanding task-related variations in articulatory kinematic behavior may allow for an improved understanding of normal and disordered speech motor behavior in varying communication contexts. This study evaluated how orofacial kinematic behavior varies as a function of speaking task in a group of 15 healthy male speakers. The speech tasks included a nonsense phrase with a high frequency of stop consonants, a sentence, an oral reading passage, and a spontaneous monologue. In addition, rate and intensity conditions were varied for the nonsense phrase and sentence. The articulatory positions of the upper lip, lower lip, tongue blade, and mandible were recorded, and measures reflecting (a). average features of individual movements or strokes (i.e., peak speed, distance, and duration) and (b). overall spatial variability of the articulators for each task were extracted, derived, and analyzed. Results showed a number of task- and condition-related differences in speech kinematic behavior. The most prominent result from the task comparison was that the nonsense speech task exhibited larger, faster, and longer movement strokes than the other speech tasks. For some articulators (lower lip and tongue), there were task-related differences in spatial variability. Changes in loudness and rate revealed variation in kinematic measures that were often complicated by articulator identity and task type. The results suggest that an expanded range of speech tasks and conditions may aid in the study of normal and disordered speech motor behavior.

Adult↗

PubMed2004

Orofacial movements associated with fluent speech in persons who stutter.

This study was intended to replicate and extend previous findings that (a) during fluent speech persons who stutter (PS) and those who do not (NS) differ in their vocal tract closing movements (L. Max, A. J. Caruso, and V. L. Gracco, 2003) and (b) ratios relating lip and tongue speed to jaw speed increase with stuttering severity (M. D. McClean and C. R. Runyan, 2000). An electromagnetic system was used to record movements of the upper lip, lower lip, tongue, and jaw of 43 NS and 37 PS during productions of a nonsense phrase and a sentence. Measurement and analysis of movement speeds, durations, and ratios of lip and tongue speed to jaw speed were performed on fluent productions of a nonsense phrase and sentence. Statistical comparisons were made between PS with low and high stuttering severity levels (LPS and HPS) and NS. Significant variations across groups in movement speed and duration were observed, but the pattern of these effects was complex and did not replicate the results of the two earlier studies. In the nonsense phrase, significant reductions in lower lip closing duration, jaw closing duration, and jaw closing speed were seen in PS. In the sentence task, HPS showed elevated tongue opening and closing durations. For tongue opening in the sentence, LPS showed elevated speeds and HPS showed reduced speeds. The elevated speeds for LPS are interpreted as a contributing factor to speech disfluency, whereas the reduced speeds and increased durations in HPS are attributed to adaptive behavior intended to facilitate fluent speech. Significant group effects were not seen for the speed ratio measures. Results are discussed in relation to multivariate analyses intended to identify subgroups of PS.

Adult↗

PubMed2004

An unrecognized source of PCB contamination in schools and other buildings.

An investigation of 24 buildings in the Greater Boston Area revealed that one-third (8 of 24) contained caulking materials with polychlorinated biphenyl (PCB) content exceeding 50 ppm by weight, which is the U.S. Environmental Protection Agency (U.S. EPA) specified limit above which this material is considered to be PCB bulk product waste. These buildings included schools and other public buildings. In a university building where similar levels of PCB were found in caulking material, PCB levels in indoor air ranged from 111 to 393 ng/m3; and in dust taken from the building ventilation system, < 1 ppm to 81 ppm. In this building, the U.S. EPA mandated requirements for the removal and disposal of the PCB bulk product waste as well as for confirmatory sampling to ensure that the interior and exterior of the building were decontaminated. Although U.S. EPA regulations under the Toxic Substances Control Act stipulate procedures by which PCB-contaminated materials must be handled and disposed, the regulations apparently do not require that materials such as caulking be tested to determine its PCB content. This limited investigation strongly suggests that were this testing done, many buildings would be found to contain high levels of PCBs in the building materials and potentially in the building environment. The presence of PCBs in schools is of particular concern given evidence suggesting that PCBs are developmental toxins.

Boston↗

PubMed2003

Association of orofacial muscle activity and movement during changes in speech rate and intensity.

Understanding how orofacial muscle activity and movement covary across changes in speech rate and intensity has implications for the neural control of speech production and the use of clinical procedures that manipulate speech prosody. The present study involved a correlation analysis relating average lower-lip and jaw-muscle activity to lip and jaw movement distance, speed, and duration. Recordings were obtained on orofacial movement, muscle activity, and the acoustic signal in 3 normal speakers as they repeated a simple test utterance with targeted speech rates varying from 60% to 160% of their habitual rate and at targeted vocal intensities of -6 dB and +6 dB relative to their habitual intensity. Surface electromyographic (EMG) recordings were obtained with electrodes positioned to sample primarily the mentalis, depressor labii inferior, anterior belly of the digastric, and masseter muscles. Two-dimensional displacements of the lower lip and jaw in the midsagittal plane were recorded with an electromagnetic system. All participants produced linear changes in percent utterance duration relative to the auditory targets for speech rate variation. Intensity variations ranged from -10 dB to +8 dB. Average EMG levels for all 4 muscles were well correlated with specific parameters of movement. Across the intensity conditions, EMG level was positively correlated with movement speed and distance in all participants. Across the rate conditions, EMG level was negatively correlated with movement duration in all participants, while greater interparticipant variability was noted for correlations relating EMG to speed and distance. For intensity control, it is suggested that converging neural input to orofacial motoneurons varies monotonically with movement distance and speed. In contrast, rate control appears to be more strongly related to the temporal characteristics of neural input than activation level.

Acoustic Stimulation↗

PubMed2002

Association of orofacial with laryngeal and respiratory motor output during speech.

Speech motor coordination most likely involves synaptic coupling among neural systems that innervate orofacial, laryngeal, and respiratory muscles. The nature and strength of coupling of the orofacial with the respiratory and laryngeal systems was studied indirectly by correlating orofacial speeds with fundamental frequency, vocal intensity, and inspiratory volume during speech. Fourteen adult subjects repeated a simple test utterance at varying rates and vocal intensities while recordings were obtained of the acoustic signal and movements of the upper lip, lower lip, tongue, jaw, rib cage, and abdomen. Across subjects and orofacial speed measures (14 subjects x 4 structures), significant correlations were obtained for fundamental frequency in 42 of 56 cases, for intensity in 35 of 56 cases, and for inspiratory volume in 14 of 56 cases. These results suggest that during speech production there is significant neural coupling of orofacial muscle systems with the laryngeal and respiratory systems as they are involved in vocalization. Comparisons across the four orofacial structures revealed higher correlations for the jaw relative to other orofacial structures. This suggests stronger connectivity between neural systems linking the jaw with the laryngeal and respiratory systems. This finding may be relevant to the frame/content theory of speech production, which suggests that the neural circuitry involved in jaw motor control for speech has evolved to form relatively strong linkages with systems involved in vocalization.

Adolescent↗

PubMed2002

Tongues and lips without jaws: a comparison of methods for decoupling speech movements.

Speech-related motions of small markers attached to the tongue, lower lip, and lower jaw of 44 normal young adult talkers of American English were analyzed to estimate the relative accuracy of selected methods for decoupling tongue and lip motions from ongoing jaw motion when all movements are originally measured relative to a common reference frame (such as the head). In general, results of the analysis show that a common "simple subtraction" method that ignores pitching rotation of the jaw yields larger errors in positions and speeds of decoupled tongue and lip markers than methods that do not ignore rotation. When the jaw is widely opened, is moving quickly, and/or when any decoupled marker is relatively far from the origin of a local coordinate system fixed to the jaw, positional and speed errors associated with the subtraction method can exceed 5 mm and 25 mm/s, respectively. We propose a simple procedure for estimating the pitching rotation of the jaw that can be applied when pitch cannot be measured. We then show that decoupled motions of tongue and lower lip markers based on estimated jaw rotation involve less error than those derived from any other decoupling method considered. Careful attention to processing methods should yield more accurate inferences about the nature and degree of coordination between speech-related movements of the tongue and lower lip that are decoupled from, and hence independent of, concurrent movements of the lower jaw.

Adult↗

PubMedDate not supplied

Speech motor correlates of treatment-related changes in stuttering severity and speech naturalness.

Participants of stuttering treatment programs provide an opportunity to evaluate persons who stutter as they demonstrate varying levels of fluency. Identifying physiologic correlates of altered fluency levels may lead to insights about mechanisms of speech disfluency. This study examined respiratory, orofacial kinematic and acoustic measures in 35 persons who stutter prior to and as they were completing a 1-month intensive stuttering treatment program. Participants showed a marked reduction in stuttering severity as they completed the treatment program. Coincident with reduced stuttering severity, participants increased the amplitude and duration of speech breaths, reduced the rate of lung volume change during inspiration, reduced the amplitude and speed of lip movements early in the test utterance, increased lip and jaw movement durations, and reduced syllable rate. A multiple regression model that included two respiratory measures and one orofacial kinematic measure accounted for 62% of the variance in changes in stuttering severity. Finally, there was a weak but significant tendency for speech of participants with the largest reductions in stuttering severity to be rated as more unnatural as they completed the treatment program.

Adult↗