Concomitant obstructive sleep apnea and chronic obstructive pulmonary disease: study design--the OLIN OSAS-COPD study.

BACKGROUND: Obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) are both common disorders. Concomitant disease, overlap syndrome, is reported to cause a more severe condition. AIM: To describe a study designed to evaluate the prevalence of overlap syndrome in the general population, and further, to assess the impact of overlap syndrome on cardiovascular morbidity and health-related quality of life. A secondary aim is to evaluate screening oxygen saturation (Sa02) by pulse oxymetry. MATERIAL AND METHOD: From the last examination of the OLIN-studies (Obstructive Lung Disease in Northern Sweden), cohorts I-IV all subjects with FEV1 < or = 50 percent predicted or Sa02 < or = 93 percent predicted were identified (Phase 1). They are invited to a program including lab tests, spirometry, arterial blood gases, chest x-ray, echocardiography, sleep studies and health-related quality of life (HRQL) questionnaires. In Phase 2, a random sample of subjects reporting snoring as a problem (n = 100) will be invited to a limited program above all including sleep studies and HRQL questionnaires; and in Phase 3, a random sample (n = 100) will be invited to a similar program. SUMMARY: The collection of data in Phase 1 is in progress and will be completed by the end of year 2007. Phase 2 will start year 2008.

Randomized clinical trial comparing 5-year recurrence rate after laparoscopic versus Shouldice repair of primary inguinal hernia.

BACKGROUND: The Shouldice technique is the 'gold standard' of open non-mesh hernia repair. The aim of this study was to compare 5-year recurrence rates after Shouldice and laparoscopic transabdominal preperitoneal patch (TAPP) repair for primary inguinal hernia. METHOD: Men with a primary unilateral inguinal hernia were randomized to either Shouldice or TAPP operation. An independent observer scored the surgeons' performance. Follow-up comprised clinical examination after 1 year, a questionnaire after 2 and 3 years, and a clinical examination after 5 years. RESULTS: Between February 1993 and March 1996, 1183 patients were included. Nine hundred and twenty patients were followed for 5 years, 454 in the TAPP group and 466 in the Shouldice group. Recurrences were evenly distributed between groups throughout the follow-up period. The cumulative recurrence rate after 5 years was 6.6 per cent in the TAPP group and 6.7 per cent in the Shouldice group. Postoperative pain was a risk factor for recurrence after Shouldice operation but not after TAPP repair. There was a correlation between a low surgeon's performance score and recurrence. CONCLUSION: The 5-year recurrence rate is acceptable, with no difference between TAPP and Shouldice repair. Poor operative performance resulted in a higher recurrence rate. The TAPP operation represents an excellent alternative for primary inguinal hernia repair.

Epidemiological aspects and early detection of chronic obstructive airway diseases in the elderly.

The burdens of chronic obstructive airway diseases among the elderly in Europe, and worldwide, are increasing. Although asthma is common in all ages, the main airway disease affecting the elderly is chronic obstructive pulmonary disease (COPD). The aim of this paper is to review the prevalence and incidence of COPD on the basis of population studies. As the prevalence estimates of asthma are probably well known, only the incidence and remission of asthma will be discussed. The underdiagnosis of obstructive airway diseases is huge. A Dutch programme for early detection of obstructive airway disease among the elderly has, thus, been included in the presentation. A prerequisite for fighting COPD is to acquire data on illnesses and death. COPD has only recently been defined by cut-off points of spirometric outcomes, which is why measures of the prevalence of COPD have been distorted by use of a large number of different diagnostic terms and lung function criteria. The prevalence of clinically-relevant COPD has been estimated in several community studies to 4-6% in adult population samples, with a considerable increase by age, particularly among smokers. The incidence of COPD not only increases heavily with age and smoking, but also occupational exposure to dust, gas and damp. Precise estimates of the incidence of COPD or spirometric airflow limitation are not available. Demographic changes will result in a further substantial increase of chronic obstructive airway disorders, mainly chronic obstructive pulmonary disease, among the elderly. The increasing burden of chronic obstructive pulmonary disease has to come to the awareness of the public, governments, health authorities, and industry.

Not 15 but 50% of smokers develop COPD?--Report from the Obstructive Lung Disease in Northern Sweden Studies.

BACKGROUND: The prevalence of chronic obstructive pulmonary disease (COPD) according to guidelines of today seems considerably higher than has been reported also in recent literature. AIM: To estimate the prevalence of COPD as defined by British Thoracic Society (BTS) criteria and the recent global initiative for chronic obstructive lung disease (GOLD) criteria. Further aims were to assess the proportion of underdiagnosis and of symptoms in subjects with COPD, and to study risk factors for COPD. METHODS: In 1996, 5892 of the Obstructive Lung Disease in Northern Sweden (OLIN) Study's first cohort could be traced to a third follow-up survey, and 5189 completed responses (88%) were received corresponding to 79% of the original cohort from December 1985. Of the responders, a random sample of 1500 subjects were invited to a structured interview and a lung function test, and 1237 of the invited completed a lung function test with acceptable quality. RESULTS: In ages >45 years, the prevalence of COPD according to the BTS guidelines was 8%, while it was 14% according to the GOLD criteria. The absolutely dominating risk factors were increasing age and smoking, and approximately a half of elderly smokers fulfilled the criteria for COPD according to both the BTS and the GOLD criteria. Family history of obstructive airway disease was also a risk factor, while gender was not. Of those fulfilling the BTS criteria for COPD, 94% were symptomatics, 69% had chronic productive cough, but only 31% had prior to the study been diagnosed as having either chronic bronchitis, emphysema, or COPD. The corresponding figures for COPD according GOLD were 88, 51, and 18%. CONCLUSIONS: In ages >45 years, the prevalence of COPD according to the BTS guidelines was 8%, and it was 14% according to the GOLD criteria. Fifty percent of elderly smokers had developed COPD. The large majority of subjects having COPD were symptomatic, while the proportion of those diagnosed as having COPD or similar diagnoses was small.

Low-dose bupivacaine plus fentanyl for spinal anesthesia during ambulatory inguinal herniorrhaphy: a comparison between 6 mg and 7. 5 mg of bupivacaine.

BACKGROUND: Inguinal herniorrhaphy is commonly performed as an outpatient procedure. Spinal anesthesia offers some advantages over general anesthesia in this setting. METHODS: Forty patients were randomly divided into two groups according to a double-blind protocol: Group L had spinal anesthesia with bupivacaine 6.0 mg and Group H with bupivacaine 7.5 mg; in both groups, fentanyl 25 micro g was added to the spinal anesthetic. The sensory block was measured by 'pin-prick' and the motor block was evaluated by a modified Bromage scale. RESULTS: No differences were seen in the spread, duration and regression of sensory block between the groups on the operated side. A greater number of patients required analgesics during the operation in Group L (6) compared with Group H (1) (P<0.05). The return of the modified Bromage scale to grade 0 was earlier in Group L than in Group H (P<0.05) but the time to mobilization and discharge was similar. Seven patients (17%) needed to be catheterized and two had the catheter retained overnight. Times to home discharge (median) were 350 and 445 min, respectively, in Groups L and H. Postoperatively and during the first week, visual analog pain scores, analgesic requirements and side-effects were similar between the groups. In Group H, 95% of the patients and in Group L 85% would have the same anesthetic again if operated upon for a similar procedure. CONCLUSIONS: Spinal anesthesia with bupivacaine 7.5 mg and fentanyl offers an alternative to general or local anesthesia for ambulatory inguinal herniorrhaphy. However, the long discharge times and risk for urinary retention restrict its routine use in all patients.

Perioperative gastric emptying is not a predictor of early postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy.

UNLABELLED: It is not known whether patients with postoperative nausea and vomiting (PONV) have delayed gastric emptying compared with patients without PONV. We compared the perioperative rate of gastric emptying in patients experiencing PONV with the rate in those without PONV immediately after laparoscopic cholecystectomy. Gastric emptying was studied by the acetaminophen method. Acetaminophen is not absorbed from the stomach but is rapidly absorbed from the small intestine, and the rate of gastric emptying therefore determines the rate of absorption of acetaminophen administered into the stomach. Forty patients (ASA physical status I and II) were included in the study. After the induction of anesthesia, a gastric tube was positioned in the stomach and 1.5 g of acetaminophen dissolved in 200 mL of water was administered. Venous blood samples for the determination of serum acetaminophen concentrations were taken before and at 15-min intervals during a period of 180 min after the administration of acetaminophen. Twenty-six patients experienced nausea during the first 4 h postoperatively. The other 14 patients had no nausea. There were no statistically significant differences in the maximal acetaminophen concentration, the time taken to reach the maximal concentration, or the area under the serum acetaminophen concentration time curves from 0 to 60, 0-120, and 0-180 min between the groups of patients with or without PONV. We did not find any relationship between postoperative gastric emptying and PONV, and therefore gastric emptying is not a predictor of PONV. IMPLICATIONS: The incidence of postoperative nausea and vomiting is frequent after laparoscopic cholecystectomy. This study has shown that perioperative gastric emptying is not a predictor of early postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy.

The pharmacological profile of (R)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide, a selective 5-hydroxytryptamine(1A) receptor agonist.

The pharmacological properties of the 5-hydroxytryptamine (HT)(1A) receptor agonist (R)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide (NAE-086) were examined with in vitro and in vivo techniques. Receptor binding studies demonstrated that NAE-086 was a high-affinity and selective 5-HT(1A) receptor ligand with a K(i) value of 4.5 nM in membranes from rat hippocampus. Of 32 other receptors examined NAE-086 had a modest affinity only for the 5-HT(7) receptor (K(i) = 240 nM). NAE-086 inhibited VIP-stimulated adenylyl cyclase activity in GH(4)ZD10 cells with 79% of the efficacy of 5-HT. This inhibition was blocked by the 5-HT(1A) receptor (and beta-adrenoceptor) antagonist (-)alprenolol. A minor metabolite of NAE-086 in rats, (R)-3,4-dihydro-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide had a similar receptor profile but had 17 times higher affinity for the 5-HT(1A) receptor (K(i) = 0.26 nM). In vivo, NAE-086 induced all the typical effects of a 5-HT(1A) receptor agonist in rats: it decreased 5-HT synthesis (5-HTP accumulation) and 5-HT turnover (measured as the ratio of 5-hydroxyindoleacetic acid/5-HT), increased corticosterone secretion, induced the 5-HT(1A) syndrome (flat body posture and forepaw treading), inhibited the cage-leaving response, and caused hypothermia. All the responses mediated by postsynaptic 5-HT(1A) receptors were attenuated after single or repeated treatment of the rats with NAE-086. Simultaneously with the development of the tolerance to 5-HT(1A) receptor-mediated responses, 5-HT(2A) receptor-mediated responses were enhanced, as judged from the increased number of spontaneous and/or agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-induced wet-dog shake responses. The significance of this behavioral effect in relation to clinical observations is discussed.

Interferon-gamma cooperates with retinoic acid and phorbol ester to induce differentiation and growth inhibition of human neuroblastoma cells.

The prognosis of patients with advanced stages of neuroblastoma with N-myc amplification remains poor despite escalated therapy, a situation that has called for alternative therapeutic approaches. Neuroblastoma cells, which represent immature peripheral neuronal cells, treated with certain physiologic and nonphysiologic agents such as retinoic acid (RA), phorbol esters and interferons (IFN) in vitro undergo cellular differentiation and stop to divide, a process that mimics normal neuronal development. Such "differentiation therapy" using RA after autologous bone marrow transplantation has recently given encouraging results in neuroblastoma patients with advanced disease. Considering approaches for improved differentiation therapy, we investigated possible synergistic effects of combining agents known to influence neuroblastoma growth and differentiation in vitro. Our results show that combined treatment with IFN-gamma and RA or the phorbol ester 12-O-tetradecanoyl-phorbol acetate (TPA) had synergistic or enhancing effects on morphologic differentiation and neurite outgrowth in 5 of 5 neuroblastoma cell lines, 3 of which expressed very high levels of N-myc mRNA due to N-myc amplification. The combinations RA+IFN-gamma or TPA+IFN-gamma also enhanced induced growth inhibition in all 5 cell lines, in several cases resulting in complete growth arrest under conditions where cells stimulated with either agent alone continued to grow. The phenotypic effects of the combined RA+IFN-gamma or TPA+IFN-gamma treatments were in most, but not all, investigated cases accompanied by moderate reductions in N-myc expression, suggesting that the cooperative signals may counteract N-Myc activity at several levels. The cooperativity between IFN-gamma and other differentiation signals may be relevant for approaches to improve the therapy for high-risk neuroblastoma with N-myc-amplification.

Symptoms related to obstructive sleep apnoea are common in subjects with asthma, chronic bronchitis and rhinitis in a general population.

The purpose of this study was to examine the prevalence of self-reported snoring, apnoeas and daytime sleepiness in relation to chronic bronchitis, recurrent wheeze, physician-diagnosed asthma and rhinitis. This was a questionnaire study in a representative sample of a general population. The study was a part of the Obstructive Lung Disease in Northern Sweden Studies (OLIN). A total of 5424 subjects aged 20-69 years, born on the 15th day of each month, participated in the study. Eligible answers were obtained from 4648 subjects (85.7%). Having snoring as a problem was reported by 10.7%. Among subjects with chronic bronchitis it was reported by 25.9%, with recurrent wheeze by 21.3%, with physician-diagnosed asthma by 17.9%, and with rhinitis by 14.7%. Relatives' concerns of witnessed apnoea was reported by 6.8% of all subjects, while among subjects with chronic bronchitis it was reported by 18.1%, with recurrent wheeze by 17.1%, with physician-diagnosed asthma by 14.3%, and with rhinitis by 9.1%. After correction for age, gender and smoking habits, chronic bronchitis, rhinitis, asthma, and current smoking were significantly related, with snoring as a problem and with relatives' concern of witnessed apnoeas. Symptoms of daytime sleepiness were significantly related with concern of witnessed apnoeas, chronic bronchitis, snoring as a problem, recurrent wheeze and age 50-59 years. In conclusion, respiratory symptoms and conditions affecting mainly the lower respiratory tract, such as chronic bronchitis and asthma, were related with symptoms common in obstructive sleep apnoea.

Obstructive sleep apnoea syndrome is common in subjects with chronic bronchitis. Report from the Obstructive Lung Disease in Northern Sweden studies.

BACKGROUND: In previous studies we have found that subjects with bronchitis have a higher prevalence of 'snoring as a problem' than respiratory healthy subjects. OBJECTIVES: We aimed to study whether the high prevalence of snoring among subjects with bronchitis also represents a high prevalence of obstructive sleep apnoea (OSA). METHOD: Subjects in three age groups born 1919-1920, 1934-1935 and 1949-1950 had been identified as bronchitic in an earlier study (n = 471) and without respiratory symptoms (n = 108). Of the 91 subjects reporting snoring to be a problem, 70 were invited to participate in the study. Sleep investigation was performed in 52 of these 70 subjects. RESULTS: 'Snoring as a problem', predicted OSA to a similar degree in both bronchitic and respiratory healthy subjects. The estimated prevalence for obstructive sleep apnoea with an apnoea/hypopnoea index (AHI) 10 as the cut-off point and concomitant daytime symptoms such as daytime sleepiness or liability to nodding off during breaks in activity in the daytime, was 5.4% for bronchitic subjects and 2.3% for respiratory healthy subjects. Apnoea in addition to snoring predicted OSA better than did snoring alone. Age correlated significantly with AHI, and OSA was most common in the middle-aged group, 61-62 years old. CONCLUSION: OSA is twice as common in subjects with chronic bronchitis as in subjects free of pulmonary disease or symptoms.

Cytokine-induced restoration of differentiation and cell cycle arrest in v-Myc transformed U-937 monoblasts correlates with reduced Myc activity.

Deregulated expression of the myc-family of oncogenes in hematopoietic and other cell types plays an important role in tumorigenesis, and results in increased proliferative potential and block of cellular differentiation. We have previously shown that IFN-gamma restores phorbol ester-induced differentiation and cell cycle arrest in v-myc transformed human U-937 monoblasts. To investigate whether other cytokine signals could also abrogate such a block, IL-1, IL-3, IL-4, IL-6, IL-7, IL-10, IL-11, LIF, oncostatin M, M-CSF, G-CSF and GM-CSF, and TGFbeta1, TNF-alpha, IFN-alpha were examined. We show that GM-CSF and IL-6, in combination with the phorbol ester 12-O-tetradecanoyl-phorbol acetate (TPA), restored differentiation and cell cycle arrest. In contrast, treatment by TGFbeta1 +/- TPA resulted in an efficient G1/G0 arrest, but did not appear to induce terminal differentiation. Restoration of differentiation and cell cycle arrest was accomplished despite maintained expression of the v-Myc protein. Our results show that the cytokine-induced signals reduced Myc-dependent transcription of an artificial target promoter/reporter gene construct, correlating in most, but not all, cases with decreased association of v- and c-Myc with its essential partner, Max. Thus, cytokine-induced signals may counteract the activity of deregulated Myc, and contribute to the normalization of differentiation, arrest in the G1/G0 phase of the cell cycle, or both.

Effect of HER2/neu expression on survival in non-small-cell lung cancer.

Major prognostic factors for early-stage non-small-cell lung cancer (NSCLC) are tumor size and nodal status. It has been suggested that HER2/neu overexpression may be related to poor prognosis in NSCLC. We evaluated the significance of HER2/neu overexpression on survival in patients with NSCLC. Data were collected on 239 patients treated surgically for stage I/II NSCLC between 1987 and 1996. None of the patients received adjuvant chemotherapy or radiation. Formalin-fixed, paraffin-embedded tumor tissue samples were stained with p185/HER2 receptor antibody. Results were reported as positive (2+, 3+) or negative (0, 1+) (Group A). A separate analysis considered only 3+ as positive (Group B). HER2/neu overexpression was seen in 18% in Group A (43 of 239) and 6% in Group B (15 of 239). HER2/neu overexpression was highest in bronchoalveolar cell carcinoma and adenocarcinoma. More stage I tumors were positive than stage II in both groups, but this was significant only in Group A (21% vs. 7%, P = 0.02). No difference was seen with age, gender, or grade for either group. In Group A, the relapse rate was 55% for HER2/neu-overexpressing tumors and 31% for HER2/neu-negative tumors (P = 0.003). Median time to relapse in patients with HER2/neu-positive tumors was 2.9 years; it was not reached in patients with HER2/neu-negative tumors. Median survival of patients with HER2/neu-positive tumors was 3.6 years compared to 5 years in patients with HER2/neu-negative tumors (P = 0.66). In Group B, the relapse rate was 60% for HER2/neu-overexpressing tumors and 33% for negative tumors (P = 0.036). Median time to relapse was 3.4 years in HER2/neu positive and had not been reached in negative tumors. There was no difference in 5-year survival rates for both groups (47% for HER2/neu positive and 50% for negative, P = 0.66).

Estrogen and progesterone receptors in non-small cell lung cancer in 248 consecutive patients who underwent surgical resection.

CONTEXT: Different authors have reported estrogen receptor (ER) expression between 0% and 96.8% and progesterone receptor (PR) expression between 21.8% and 34.7%. OBJECTIVE: To examine the discrepancies in the literature regarding the expression of ERs and PRs in non-small cell lung cancer. DESIGN: Retrospective analysis. SETTING: A referral tertiary care center. PATIENTS: We reviewed 248 consecutive cases of stage I and II non-small cell lung cancers. METHODS AND RESULTS: Sections of formalin-fixed and paraffin-embedded tumor tissue were stained with ER and PR monoclonal antibodies using the avidin-biotin complex detection system with antigen retrieval. Men represented 66.1% of the patients, and women represented 33.9%. Large cell (undifferentiated) carcinoma constituted 10.4% of the entire population; squamous cell carcinoma, 39.1%; adenocarcinoma, 33.0%; and bronchoalveolar carcinoma, 17.3%. Patients with stage I disease represented 77.0% of the population. In this patient population, we found no nuclear or cytoplasmic expression of either ERs or PRs (95% confidence interval, 0%-1.2%). CONCLUSIONS: The absence of expression of ERs and PRs differs from previous articles, which use a variety of techniques, impairing a meaningful comparison of data. In addition, the presence of ER and PR expression in a lung carcinoma is supportive of a nonpulmonary primary tumor metastatic to the lung. The absence of their expression in non-small cell lung cancer does not support a role of these transcription factors in initiating and maintaining this neoplastic process.

Brachial plexopathy after postoperative radiotherapy of breast cancer patients--a long-term follow-up.

In 1963-1965 a group of 71 patients operated on for breast cancer with total mastectomy and axillary clearance were given aggressive postoperative telecobalt therapy to the axillary, supraclavicular and parasternal lymph node regions. The prescribed dose to these lymph node regions was 44 Gy in 11 fractions. Only two of the three fields were treated per day. Retrospective dose calculations showed that the total dose in the brachial plexus from the axillary and supraclavicular fields was c. 57 Gy in 16-17 fractions over 3-4 weeks. After a few years, symptoms and signs of brachial plexus injury appeared in many patients, which was reported in some early papers. The cohort has now been followed-up to 34 years. As expected, there was progression of both prevalence and severity of the late effects between 5 and 34 years and 11 of 12 patients who are still alive have paralysis of their arms. The neuropathy seems to be closely linked to fibrosis around the nerve trunks. The use of large daily fractions, in some cases combined with hot spots from overlapping fields, was certainly the cause of the complication.

Acute intravascular hemolysis secondaryto out-of-group platelet transfusion.

BACKGROUND: Acute intravascular hemolysis is rarely associated with platelet transfusion. Out-of-group single-donor platelets may cause hemolysis if the donor has high-titer ABO hemagglutinins. CASE REPORT: A 44-year-old woman, blood group A, was recently diagnosed with acute myeloid leukemia and was receiving chemotherapy. After the transfusion of apheresis platelets from a group O donor, back pain, hemoglobinuria, and hemoglobinemia developed, and her Hb dropped by 2.3 g per dL, despite the transfusion of 2 units of RBCs. RESULTS: Investigation revealed acute intravascular hemolysis with a positive DAT due to anti-A(1) on her RBCs. The donor's titer of anti-A(1) was greater than 16,000. CONCLUSION: Review of published cases raises the possibility that hemolytic reactions to out-of-group platelets may be more frequent since the use of apheresis platelets has increased.

c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover.

The c-myc proto-oncogene encodes a short-lived transcription factor that plays an important role in cell cycle regulation, differentiation and apoptosis. c-myc is often rearranged in tumors resulting in deregulated expression. In addition, mutations in the coding region of c-myc are frequently found in human lymphomas, a hot spot being the Thr58 phosphorylation site, a mutation shown to enhance the transforming capacity of c-Myc. It is, however, still unclear in what way this mutation affects c-Myc activity. Our results show that proteasome-mediated turnover of c-Myc is substantially impaired in Burkitt's lymphoma cells with mutated Thr58 or other mutations that abolish Thr58 phosphorylation, whereas endogenous or ectopically expressed wild type c-Myc proteins turn over at normal rates in these cells. Myc Thr58 mutants expressed ectopically in other cell types also exhibit reduced proteasome-mediated degradation, which correlates with a substantial decrease in their ubiquitination. These results suggest that ubiquitin/proteasome-mediated degradation of c-Myc is triggered by Thr58 phosphorylation revealing a new important level of control of c-Myc activity. Mutation of Thr58 in lymphoma thus escapes this regulation resulting in accumulation of c-Myc protein, likely as part of the tumor progression. (Blood. 2000;95:2104-2110)

The basic region/helix-loop-helix/leucine zipper domain of Myc proto-oncoproteins: function and regulation.

A large body of evidence has been accumulated that demonstrates dominant effects of Myc proto-oncoproteins on different aspects of cellular growth. Myc is one of the few proteins that is sufficient to drive resting cells into the cell cycle and promote DNA synthesis. In line with this finding is that the constitutive expression of Myc in cells blocks their differentiation. These growth stimulating properties are most likely responsible for Myc's ability to initiate and promote tumor formation. Interestingly Myc can also sensitize cells to apoptosis, suggesting that this protein is part of a life-and-death switch. Molecularly Myc functions as a transcriptional regulator that needs to heterodimerize with Max to exert the biological activities described above and to regulate gene transcription. Myc and Max are just two members of a growing family of proteins referred to as the Myc/Max/Mad network. A hallmark of these proteins is that they possess a C-terminal basic region/helix-loop-helix/leucine zipper domain (bHLHZip). The bHLHZip domain specifies dimerization within the network and determines sequence specific DNA binding. Importantly this domain together with the N-terminal transactivation domain is essential for Myc biology. Here we have summarized the structural, functional, and regulatory aspects of the bHLHZip domain of Myc proteins.

Posttranslational regulation of Myc function in response to phorbol ester/interferon-gamma-induced differentiation of v-Myc-transformed U-937 monoblasts.

The transcription factors of the Myc/Max/Mad network are important regulators of cell growth, differentiation, and apoptosis and are frequently involved in tumor development. Constitutive expression of v-Myc blocks phorbol ester (TPA)-induced differentiation of human U-937 monoblasts. However, costimulation with interferon-gamma (IFN-gamma) and TPA restores terminal differentiation and G1 cell-cycle arrest despite continuous expression of v-Myc. The mechanism by which TPA + IFN-gamma counteract v-Myc activity has not been unravelled. Our results show that TPA + IFN-gamma treatment led to an inhibition of v-Myc- and c-Myc-dependent transcription, and a specific reduction of v-Myc:Max complexes and associated DNA-binding activity, whereas the steady state level of the v-Myc protein was only marginally affected. In contrast, TPA + IFN-gamma costimulation neither increased the expression of Mad1 or other mad/mnt family genes nor altered heterodimerization or DNA-binding activity of Mad1. The reduced amount of v-Myc:Max heterodimers in response to treatment was accompanied by partial dephosphorylation of v-Myc and c-Myc. Phosphatase treatment of Myc:Max complexes lead to their dissociation, thus mimicking the effect of TPA + IFN-gamma. In addition to modulation of the expression of Myc/Max/Mad network proteins, posttranslational negative regulation of Myc by external signals may, therefore, be an alternative biologically important level of control with potential therapeutic relevance for hematopoietic and other tumors with deregulated Myc expression.