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E Hanna

Publications and source records attributed to E Hanna.

At least 19 recordsLinked to original sources

Temperature effects on the allosteric transition of ATP sulfurylase from Penicillium chrysogenum.

The effects of temperature on the initial velocity kinetics of allosteric ATP sulfurylase from Penicillium chrysogenum were measured. The experiments were prompted by the structural similarity between the C-terminal regulatory domain of fungal ATP sulfurylase and fungal APS kinase, a homodimer that undergoes a temperature-dependent, reversible dissociation of subunits over a narrow temperature range. Wild-type ATP sulfurylase yielded hyperbolic velocity curves between 18 and 30 degrees C. Increasing the assay temperature above 30 degrees C at a constant pH of 8.0 increased the cooperativity of the velocity curves. Hill coefficients (n(H)) up to 1.8 were observed at 42 degrees C. The bireactant kinetics at 42 degrees C were the same as those observed at 30 degrees C in the presence of PAPS, the allosteric inhibitor. In contrast, yeast ATP sulfurylase yielded hyperbolic plots at 42 degrees C. The P. chrysogenum mutant enzyme, C509S, which is intrinsically cooperative (n(H) = 1.8) at 30 degrees C, became more cooperative as the temperature was increased yielding n(H) values up to 2.9 at 42 degrees C. As the temperature was decreased, the cooperativity of C509S decreased; n(H) was 1.0 at 18 degrees C. The cumulative results indicate that increasing the temperature increases the allosteric constant, L, i.e., promotes a shift in the base-level distribution of enzyme molecules from the high MgATP affinity R state toward the low MgATP affinity T state. As a result, the enzyme displays a true "temperature optimum" at subsaturating MgATP. The reversible temperature-dependent transitions of fungal ATP sulfurylase and APS kinase may play a role in energy conservation at high temperatures where the organism can survive but not grow optimally.

Allosteric Regulation↗

A novel alternative approach for prediction of radiation response of squamous cell carcinoma of head and neck.

Accurate prediction of human tumor response to radiation therapy and concomitant chemoradiation would be an important tool to assist the physician in making recommendations for tumor treatment. Most of the studies that define the molecular markers for prediction of radiation response are based on the observation of gene expression using immunostaining, Northern blot, or Western blot analysis of a single or several genes. The results vary among different studies, and some results are contradictory. However, the studies agree that the change in expression of the tumor-related gene affects the radiation response. In this study, we explored a novel approach to predict the radiation response of human tumor using Atlas human cancer 1.2 cDNA array to analyze the expression profile of 1187 tumor-related genes in radiation-resistant and radiation-sensitive tissues. Sixty tumor-related genes were selected as predictors of radiation response of squamous cell carcinoma of the head and neck. Using the expression intensity of these 60 tumor-related genes, in combination with cluster analysis, we successfully predicted the radiation identity of two tumor samples.

Carcinoma, Squamous Cell↗

Thriving in a changing environment.

Undeniably, working in an environment that challenges the status quo is not without its problems. Members of the service redesign teams who participated in the West Ottawa Valley Network experience confess that many times during the process they felt a threat to their own job security along with uncertainty about their future roles and responsibilities. June Merkley points out that "working outside one's "normal comfort level" in a non-traditional leadership role has it's own set of difficulties, and dealing with multiple network members adds a dimension of complexity not encountered at the single site level." But she believes that "the challenges encountered within the network are helping to broaden the scope of job knowledge and communication skills. This can only have a direct and positive impact on the day-to-day tasks, while providing value to both the employee and employer". As a career management strategy, healthcare managers should seek out opportunities beyond their normal range of accountability, participate in activities that encourage the growth of new skills or hone skills that are a bit rusty. Often these projects will cause some anxiety or discomfort but the rewards, both short and long term, far outweigh the short-term pain.

Career Mobility↗

Intramuscular electroporation delivery of IL-12 gene for treatment of squamous cell carcinoma located at distant site.

Gene therapy with IL-12 has been shown to elicit potent systemic antitumor response in a variety of tumors. Although direct intratumoral injection is the most commonly used delivery route for gene therapy of solid tumors, the skeletal muscle has been shown to be an ideal tissue for gene delivery to produce systemic gene expression. We have previously demonstrated that electroporation delivery of a reporter gene to muscle enhances the transfection efficiency and the level of gene expression by two to three logs. We report here that intramuscular (i.m.) injection of as little as 10 microg of the IL-12 DNA plasmid followed by electroporation prevents squamous cell carcinoma (SCCVII) tumor establishment in up to 40% of experimental animals and reduces the volume of established tumors by 75% compared to controls (P<.05). By comparison, there was no difference in tumor growth observed between IL-12 injection alone and injection of empty vector with or without electroporation. The induction of antitumor activity by i.m. electroporation delivery of the IL-12 gene is associated with an increase in IL-12 expression in muscle and serum. The level of IL-12 expression in muscle and serum was 1500 pg/tibialias muscle and 170 pg/mL serum, respectively, at day 6, after the gene was delivered by electroporation. In contrast, the level of IL-12 when the gene was injected without electroporation was hardly detectable after subtracting the background level of IL-12 detected in naïve mice. The high level of IL-12 expression led to a 170-fold induction of IFN-gamma expression in serum at day 6 after i.m. electroporation delivery of IL-12 DNA plasmid, which was equal to 1450 pg/mL in the serum. The induction of antitumor activity by i.m. electroporation delivery of the IL-12 gene also correlates with increased CD8+ T-cell population in peripheral blood but not in spleen. Our findings suggest that i.m. delivery of IL-12 gene using electroporation is an effective method of inducing a systemic antitumor response against SCC.

Animals↗

Intramuscular electroporation delivery of IFN-alpha gene therapy for inhibition of tumor growth located at a distant site.

Although electroporation has been shown in recent years to be a powerful method for delivering genes to muscle, no gene therapy via electro-injection has been studied for the treatment of tumors. In an immunocompetent tumor-bearing murine model, we have found that delivery of a low dose of reporter gene DNA (10 microg) to muscle via electroporation under specific pulse conditions (two 25-ms pulses of 375 V/cm) increased the level of gene expression by two logs of magnitude. Moreover, administration of 10 microg of interferon (IFN)-alpha DNA plasmid using these parameters once a week for 3 weeks increased the survival time and reduced squamous cell carcinoma (SCC) growth at a distant site in the C3H/HeJ-immunocompetent mouse. IFN-alpha gene therapy delivered to muscle using electroporation demonstrated statistically significant (P < 0.05) therapeutic efficacy for treating SCC located at a distant site, compared with interleukin (IL)-2 or endostatin gene, also delivered by electro-injection. The increased therapeutic efficacy was associated with a high level and extended duration of IFN-alpha expression in muscle and serum. We also discovered that the high level of IFN-alpha expression correlated with increased expression levels of the antiangiogenic genes IP-10 and Mig in local tumor tissue, which may have led to the reduction of blood vessels observed at the local tumor site. Delivery of increasing doses (10-100 microg) of IFN-alpha plasmid DNA by injection alone did not increase antitumor activity, whereas electroporation delivery of increasing doses (10-40 microg) of IFN-alpha plasmid DNA did increase the survival time. Our data clearly demonstrate the potential utility of electroporation for delivery of gene therapy to muscle for the treatment of residual or disseminated tumors.

Animals↗

Clinical experience with HLA-B7 plasmid DNA/lipid complex in advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: To investigate the safety and efficacy of alloantigen plasmid DNA therapy in patients with advanced head and neck squamous cell carcinoma using Allovectin-7 (Vical Inc, San Diego, Calif), a DNA/lipid complex designed to express the class I major histocompatibility complex antigen HLA-B7. DESIGN: Multi-institutional prospective trial. SETTING: Academic medical setting. PATIENTS: A total of 69 patients were enrolled in 3 sequential clinical trials: a single-center phase 1 trial and 2 multicenter phase 2 trials. Eligibility criteria included unresectable squamous cell carcinoma that failed conventional therapy, Karnofsky performance status score of 70 or greater, and no concurrent anticancer or immunosuppressive therapies. INTERVENTION: Patients received 2 biweekly intratumoral injections of 10 microg (phase 1 and first phase 2 trials) or 100 microg (second phase 2 trial) of Allovectin-7 followed by 4 weeks of observation. Patients with stable or responding disease after the observation period were given a second treatment cycle identical to the first. MAIN OUTCOME MEASURES: Patients were assessed for toxic effects, and tumor size was measured after cycles 1 (at 6 weeks) and 2 (at 16 weeks). RESULTS: Allovectin-7 treatment was well tolerated, with no grade 3 or 4 drug-related toxic effects. Of 69 patients treated, 23 (33%) had stable disease or a partial response after the first cycle of treatment and proceeded to the second cycle. After the second cycle, 6 patients had stable disease, 4 had a partial response, and 1 had a complete response. Responses persisted for 21 to 106 weeks. CONCLUSIONS: Intratumoral plasmid DNA immunotherapy for head and neck cancer with Allovectin-7 is safe, and further investigations are planned in patients with less advanced disease, where it could potentially improve patient survival and reduce the need for radical high-morbidity treatments.

Adult↗

Induction of positive cooperativity by amino acid replacements within the C-terminal domain of Penicillium chrysogenum ATP sulfurylase.

ATP sulfurylase from Penicillium chrysogenum is an allosteric enzyme in which Cys-509 is critical for maintaining the R state. Cys-509 is located in a C-terminal domain that is 42% identical to the conserved core of adenosine 5'-phosphosulfate (adenylylsulfate) (APS) kinase. This domain is believed to provide the binding site for the allosteric effector, 3'-phosphoadenosine 5'-phosphosulfate (PAPS). Replacement of Cys-509 with either Tyr or Ser destabilizes the R state, resulting in an enzyme that is intrinsically cooperative at pH 8 in the absence of PAPS. The kinetics of C509Y resemble those of the wild type enzyme in which Cys-509 has been covalently modified. The kinetics of C509S resemble those of the wild type enzyme in the presence of PAPS. It is likely that the negative charge on the Cys-509 side chain helps to stabilize the R state. Treatment of the enzyme with a low level of trypsin results in cleavage at Lys-527, a residue that lies in a region analogous to a PAPS motif-containing mobile loop of true APS kinase. Both mutant enzymes were cleaved more rapidly than the wild type enzyme, suggesting that movement of the mobile loop occurs during the R to T transition.

Allosteric Regulation↗

Assessing quality of life in patients with head and neck cancer: cross-validation of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Head and Neck module (QLQ-H&N35).

OBJECTIVE: To evaluate the reliability and validity of a new, disease-specific quality-of-life measure for patients with head and neck cancer: the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire--QLQ-H&N35. DESIGN: Cross-sectional study using questionnaire data and medical chart review. SETTING: Academic tertiary care otolaryngology clinic. PARTICIPANTS: One hundred twenty ambulatory patients, including 30 patients with advanced head and neck cancer in each of the following stages of treatment: (1) prior to treatment, (2) during active treatment, (3) within 6 months of completing treatment, and (4) more than 6 months after completing treatment. In addition, (5) a comparison group of 40 patients without malignant disease was included (total sample, N = 160). MAIN OUTCOME MEASURES: Scores on EORTC Quality of Life Core Questionnaire (QLQ-C30) and head and neck module (QLQ-H&N35), Profile of Mood States, and Impact of Events Scale. RESULTS: The QLQ-H&N35 demonstrated acceptable reliability (internal consistency). It successfully discriminated between cancer patients and the comparison group, and among subgroups of cancer patients at different phases of treatment (construct validity). The instrument was sensitive to the effects of radiation treatment and to site of disease. Its low-to-moderate correlations with the EORTC core questionnaire indicated that the QLQ-H&N35 provided unique information (discriminant validity). Scores were significantly associated with a number of demographic variables. CONCLUSION: Results support the use of this disease-specific measure to assess quality of life among patients with advanced head and neck cancer.

Activities of Daily Living↗

Peripheral primitive neuroectodermal tumor of the parotid gland region: report of a case with fine-needle aspiration findings.

A case of peripheral primitive neuroectodermal tumor of the parotid gland region in a 38-yr-old woman is reported. She had a 1-yr history of a large, firm, and slightly tender left parotid-region mass. CT scan showed an invasive tumor involving the parotid gland, mandible, infratemporal fossa, and parapharyngeal space. Fine-needle aspiration cytology of the mass showed a highly cellular, poorly cohesive smear pattern exhibiting small cuboidal cells, with fibrillary cytoplasm forming occasional rosette-like structures. Numerous intact single cells with fragile cytoplasm, finely granular chromatin, and inconspicuous nucleoli were present together with free-lying nuclei in the background. Histologic, immunohistochemical, and ultrastructural findings confirmed the diagnosis. Diagn. Cytopathol. 2000;22:161-166. Published 2000 Wiley-Liss, Inc.

Adult↗

Coping with head and neck cancer during different phases of treatment.

BACKGROUND: Little is known about how patients cope with head and neck cancer despite its devastating impact on basic functioning. This study examined coping patterns among patients at different phases of illness. METHODS: Participants were 120 patients with advanced disease, who were grouped according to the following phases of illness: (1) pretreatment, (2) on treatment, (3) <6 months after treatment, and (4) >6 months after treatment. Coping was assessed with the COPE questionnaire, and outcome measures assessed general distress (Profile of Mood States) and illness-specific distress (Impact of Events Scale). RESULTS: Use of specific coping responses differed among the groups. Denial (p <.05), behavioral disengagement (ie, giving up or withdrawing, p <.05), suppression of competing activities (ie, focusing exclusively on the illness, p <.01), and emotional ventilation (p <.10) were most characteristic of patients who were receiving or had recently completed treatment. There were no differences in flexibility of coping or overall effort expended, but patients who were on treatment or who had recently completed treatment used the greatest number of strategies. Generally, denial, behavioral disengagement, and emotional ventilation were associated with greater distress. CONCLUSIONS: Results suggest that phase of illness may be important in shaping patients' responses to life-threatening illness.

Adaptation, Physiological↗

Correlation of neural cell adhesion molecules with perineural spread of squamous cell carcinoma of the head and neck.

Perineural spread (PNS) is a poor prognostic factor associated with increased risk of local recurrence and nodal metastasis and reduced survival of patients with squamous cell carcinoma of the head and neck (SCCHN). There is some evidence to indicate that neural cell adhesion molecules (NCAMs) may play a role in PNS of a variety of tumor types. We performed this study to investigate whether NCAM expression can be used as a predictor of PNS in SCCHN. The surgical specimens of 66 patients with SCCHN were evaluated with monoclonal IgG antibody immunoperoxidase staining for NCAM. Of the 41 specimens with PNS, 38 (93%) showed evidence of NCAM expression. In contrast, only 9 specimens (36%) without PNS expressed NCAMs. The difference in NCAM expression between the study and control groups was statistically significant (P < 0.01).

Adult↗

Extended lateral rhinotomy incision for total maxillectomy.

An extended lateral rhinotomy incision for total maxillectomy, which avoids postoperative lower eyelid complications, is described. Advantages of the extended lateral rhinotomy incision for total maxillectomy are discussed in comparison with the classic Weber-Fergusson incision.

Esthetics↗

Results of remedial continuing medical education in dyscompetent physicians.

PURPOSE: Noticing that moderately to severely incompetent physicians (as measured by a standardized assessment of physician competence) did not improve after traditional remedial continuing medical education (CME), the authors investigated the effects of a polyvalent, intensive, prolonged educational intervention on five physicians' competence. METHOD: The five physicians participated in a CME program that lasted three years and consisted of individualized review, ongoing small-group and evidence-based discussions, simulated patients and role playing, formal chart review, and peer review. At the end of the program, the physicians were reassessed. RESULTS: Only one physician improved; another remained the same, and three deteriorated. CONCLUSION: Successful remediation of severely incompetent physicians is uncertain at best, even with prolonged, intensive CME that incorporates modalities thought to be effective in changing physicians' behaviors. Alternative educational techniques may need to be developed for this select population. Conversely, there may be reasons that preclude improvement even with optimal techniques.

Aged↗

Cognitive difficulty in physicians.

PURPOSE: Remediation of some incompetent physicians has proven difficult or impossible. The authors sought to determine whether physicians with impaired competency had neuropsychological impairment sufficient to explain their incompetence and their failure to improve with remedial continuing medical education (CME). METHOD: During a one-year period, 1996-97, all 27 participants in the Physician Review Program (PREP) conducted at McMaster University, a physician competency assessment program, undertook a detailed neuropsychological screening battery. RESULTS: Nearly all physicians assessed as competent also performed well on the neuropsychological testing. However, a significant number (about one third) of the physicians who performed poorly on the competency assessment had neuropsychological impairments sufficient to explain their poor performances. The difficulties were more marked in elderly physicians. CONCLUSION: A significant minority of incompetent physicians have cognitive impairments sufficient to explain both their incompetence and, probably, their failure to improve with remedial CME. Testing physicians for these impairments is important: to detect and treat reversible conditions, to manage irreversible conditions that preclude successful educational intervention, and to facilitate compensation in this instance. Serious consideration should be given to the incorporation of neuropsychological screening in all intensive physician review programs.

Adult↗

Neural cell adhesion molecule expression in adenoid cystic carcinoma of the head and neck.

OBJECTIVE: To investigate whether there is a correlation between neural cell adhesion molecule (NCAM) expression and perineural spread in patients with adenoid cystic carcinoma of the head and neck (ACCHN). STUDY DESIGN: Retrospective review of medical records and immunohistochemical staining of specimens from 37 patients treated at the University of Arkansas in Little Rock from 1987 to 1997. METHODS: Sections from paraffin-embedded specimens were examined for the presence of NCAM using monoclonal anti-NCAM antibody by avidin-biotin-peroxidase immunohistochemical staining. NCAM staining was scored in each specimen and correlated with the data obtained from patient charts. RESULTS: Twenty-five of 37 specimens (68%) showed histopathological evidence of perineural spread. All 37 specimens (100%) stained positive for NCAM, regardless of perineural spread status. CONCLUSION: Our results suggested that the use of NCAM expression as a predictor of perineural spread is highly unlikely.

Adult↗

Development and implementation of a clinical pathway for patients undergoing total laryngectomy: impact on cost and quality of care.

BACKGROUND: The current health care climate demands the provision of quality patient care in a cost-effective manner. Clinical pathways define the essential components of care that are provided to patients with a specific diagnosis to achieve a desired outcome within a predetermined period. Development and implementation of clinical pathways streamline the provision of quality care in the most cost-effective manner. OBJECTIVES: To develop a clinical pathway for patients undergoing total laryngectomy and to evaluate its impact on the cost and quality of care provided to these patients. SETTING: A tertiary care academic medical center. PATIENTS AND METHODS: A total of 45 patients were included in the study. The clinical pathway was implemented for 15 patients, while the other 30 patients were treated without the implementation of the pathway guidelines. MAIN OUTCOME MEASURES: Length of hospital stay, readmission rate, and hospital variable costs. RESULTS: The clinical pathway affected all cost outcome measures. Length of stay decreased by 2.4 days (29%; P=.001), and the average hospital variable cost decreased from $3992 to $3419 per case. This represents a 14.4% reduction in cost associated with pathway implementation (P=.02). The standardization of care eliminated unnecessary variation and repetition in resource usage, resulting in overall cost reduction. Pathway implementation resulted in a lower readmission rate (7% [1/15]) than that of patients treated prior to protocol implementation (23% [7/30]). CONCLUSION: Implementing a carefully developed clinical pathway may reduce cost without compromising the quality of care for patients undergoing total laryngectomy.

Cost Control↗