Measuring patient acuity and nursing care needs in South Korea: application of a new patient classification system.

BACKGROUND: An accurate and reliable patient classification system (PCS) can help inform decisions regarding adequate assignments for nurse staffing. This study aimed to evaluate the criterion validity of the Asan Patient Classification System (APCS), a new tertiary hospital-specific PCS, by comparing its rating and total scores with those of KPCS-1 and KPCS-GW for measuring patient activity and nursing needs. METHODS: We performed a retrospective analysis of the medical records of 50,314 inpatients admitted to the general wards of a tertiary teaching hospital in Seoul, South Korea in March, June, September, and December 2019. Spearman's correlation and Kappa statistics according to quartiles were calculated to examine the criterion validity of the APCS compared with the KPCS-1 and KPCS-GW. RESULTS: The average patient classification score was 28.3 points for APCS, 25.7 points for KPCS-1, and 21.6 points for KPCS-GW. The kappa value between APCS and KPCS-1 was 0.91 (95% CI:0.9072, 0.9119) and that between APCS and KPCS-GW was 0.88 (95% CI:0.8757, 0.8810). Additionally, Spearman's correlation coefficients among APCS, KPCS-1, and KPCS-GW showed a very strong correlation. However, 10.8% of the participants' results were inconsistent, and KPCS-1 tended to classify patients into groups with lower nursing needs compared to APCS. CONCLUSION: This study showed that electronic health record-generated APCS can provide useful information on patients' severity and nursing activities to measure workload estimation. Additional research is needed to develop and implement a real-world EHR-based PCS system to accommodate for direct and indirect nursing care while considering diverse population and dynamic healthcare system.

Predicting Responsiveness to Biofeedback Therapy Using High-resolution Anorectal Manometry With Integrated Pressurized Volume.

Background/Aims: Biofeedback therapy is widely used to treat patients with chronic constipation, especially those with dyssynergic defecation. Yet, the utility of high-resolution manometry with novel parameters in the prediction of biofeedback response has not been reported. Thus, we constructed a model for predicting biofeedback therapy responders by applying the concept of integrated pressurized volume in patients undergoing high-resolution anorectal manometry. Methods: Seventy-one female patients (age: 48-68 years) with dyssynergic defecation who underwent initial high-resolution anorectal manometry and subsequent biofeedback therapy were enrolled. The manometry profiles were used to calculate the 3-dimensional integrated pressurized volumes by multiplying the distance, time, and amplitude during simulated evacuation. Partial least squares regression was performed to generate a predictive model for responders to biofeedback therapy by using the integrated pressurized volume parameters. Results: Fifty-five (77.5%) patients responded to biofeedback therapy. The responders and non-responders did not show significant differences in the conventional manometric parameters. The partial least squares regression model used a linear combination of eight integrated pressurized volume parameters and generated an area under the curve of 0.84 (95% confidence interval: 0.76-0.95, P < 0.01), with 85.5% sensitivity and 62.1% specificity. Conclusions: Integrated pressurized volume parameters were better than conventional parameters in predicting the responsiveness to biofeedback therapy, and the combination of these parameters and partial least squares regression was particularly promising. Integrated pressurized volume parameters can more effectively explain the physiology of the anorectal canal compared with conventional parameters.

New parameter for quantifying bolus transit with high-resolution impedance manometry: A comparison with simultaneous esophagogram.

BACKGROUND: Esophageal bolus transit can be assessed using esophagogram or high-resolution impedance manometry (HRIM). The three-dimensional volume of inverted impedance (VII) has been developed to quantify the residual bolus between each swallow through spatiotemporal analysis. However, this novel metric has not been validated against simultaneous esophagogram. METHODS: A total of nine healthy volunteers (Seven males, aged 19-45 years) were prospectively evaluated with HRIM and barium esophagogram. In addition, 21 symptomatic patients (12 males, aged 20-85 years) without major motility disorder were also included. The VII was estimated from HRIM data using MATLAB program and was compared with residual bolus volume in the esophagus estimated from simultaneous esophagogram. KEY RESULTS: A total of 80 swallows (24 in controls and 56 in patients) were analyzed. Results from the VII method were concordant with the bolus transit pattern estimated from the esophagogram in 91.3% (73/80) of swallows. The correlation between quantitative data from VII and the volume of residual bolus estimated from esophagogram was strong in both groups with a Pearson's correlation coefficient of 0.805 for healthy volunteers and 0.730 for symptomatic patients. The intraclass correlation coefficient of VII between the three swallows within a subject was 0.901 in healthy subjects and 0.705 in patients, indicating a modest reliability of this method. CONCLUSIONS AND INFERENCES: The newly developed VII method is a reliable method in assessing residual bolus volume in the esophagus based on comparison with bolus volume estimated from simultaneous esophagogram.

Prevalence of Fructose Malabsorption in Patients With Irritable Bowel Syndrome After Excluding Small Intestinal Bacterial Overgrowth.

BACKGROUND/AIMS: Fructose malabsorption (FM) mimics symptoms of irritable bowel syndrome (IBS), and its prevalence has increased. Diagnosing FM in IBS is challenging because of its overlap with small intestinal bacterial overgrowth (SIBO). We assessed the prevalence of FM by comparing patients with IBS with asymptomatic control individuals after excluding SIBO using the glucose hydrogen breath test (HBT). METHODS: Patients diagnosed with IBS and asymptomatic control individuals were enrolled prospectively. Dietary habits were assessed with the Food Frequency Questionnaire. After excluding SIBO, participants underwent HBTs with both 15 g and 25 g of fructose. RESULTS: Thirty-five patients with IBS and 35 age- and sex-matched asymptomatic control individuals were enrolled. The 15-g fructose HBT yielded positive results in 7 of the 35 (20.0%) patients with IBS and in 2 of 35 (5.7%) controls (P = 0.070). The 25-g fructose HBT was positive in 16 of the 35 (45.7%) patients with IBS and in 8 of the 35 (22.9%) controls (P = 0.040). Analysis of the Food Frequency Questionnaire responses showed no significant differences between the 2 groups in dietary intake, although patients with IBS showed a significantly higher mean fiber intake than controls (21.24 ± 11.35 g vs 15.87 ± 7.07 g, respectively, P = 0.040). CONCLUSIONS: The 25-g fructose HBT identified FM in a significantly higher percentage of SIBO-negative patients with IBS than in asymptomatic control individuals, suggesting that FM may correlate with IBS. Education regarding dietary control of foods containing fructose may be useful for the management of patients with IBS.

Metastatic uterine cancer looking as cervical fibroid in recurrent breast cancer woman: a case report.

Metastasis to the female genital tract from extragenital primary cancer is uncommon. In this case, a 46-year-old woman was diagnosed with invasive lobular carcinoma of the left breast in 2011. She had left breast conserving surgery, chemotherapy, radiation, and hormonal therapy (gosereline and tamoxifen). However, she developed menorrhagia after interruption of hormonal therapy and incidentally, the ultrasonogram of her pelvis showed a solid, large mass in the cervix. It looked like leiomyoma. Because of massive vaginal bleeding requiring multiple blood transfusions, she underwent total hysterectomy with bilateral salpingo-oophorectomy. Unexpectedly, however, histopathological examination revealed metastatic carcinoma, consistent with breast origin.The metastatic tumor involved the uterine corpus with spreading to the endocervix, left ovary, and multiple lymphovascular invasion was present. We described the rarity and risk of metastatic uterine cancer in patient with history of malignant tumor treatment.

The diagnostic value of a digital rectal examination compared with high-resolution anorectal manometry in patients with chronic constipation and fecal incontinence.

OBJECTIVES: Digital rectal examination (DRE) is a simple clinical method to diagnose anorectal disorders. High-resolution antorectal manometry (HRAM) based on a spatiotemporal plot is expected to promote improved diagnostic accuracy. However, there are no reports comparing the effectiveness of DRE and HRAM. The aim of our study was therefore to evaluate the diagnostic value of DRE compared with HRAM. METHODS: A total of 309 consecutive patients with chronic constipation (n=268) or fecal incontinence (n=41) who underwent a standardized DRE, HRAM, and balloon expulsion test were enrolled in this study. The diagnostic yield of DRE compared with HRAM was determined, and agreement between DRE and HRAM data was evaluated. RESULTS: Of the constipated patients, 207 (77.2%) were diagnosed with dyssynergia using HRAM. The sensitivity, specificity, and positive predictive value of DRE in the diagnosis of dyssynergia were 93.2%, 58.7%, and 91.0%, respectively, and moderate agreement was seen between the two modalities (κ-coefficient =0.542, P<0.001). In patients with fecal incontinence, there was moderate agreement in terms of anal squeeze pressure between the two modalities (κ-coefficient =0.418, P=0.006); however, there was poor agreement for anal resting tone (κ-coefficient =0.079, P=0.368). CONCLUSIONS: DRE shows high sensitivity and positive predictive value in detecting dyssynergia compared with HRAM, and could therefore be used as a bedside screening test for the diagnosis of this disorder. Further studies are warranted to evaluate the correlation between DRE and HRAM in assessing anal sphincter pressure.

A novel high-resolution anorectal manometry parameter based on a three-dimensional integrated pressurized volume of a spatiotemporal plot, for predicting balloon expulsion in asymptomatic normal individuals.

BACKGROUND: Anorectal manometry with simulated evacuation (SE) has limited applicability in predicting balloon expulsion (BE) test results. The newly developed high-resolution anorectal manometry (HRAM) technique can yield spatiotemporal plots with three-dimensional pressurization. We aimed to define new parameters based on three-dimensional integrated pressurized volume (IPV) for predicting the BE test results in asymptomatic normal individuals. METHODS: Fifty-four asymptomatic healthy individuals were prospectively enrolled. BE tests were performed using 50 mL of water, and a requirement of more than 1 min was considered as delayed BE. HRAM profiles were converted into ASCII files and analyzed using a MATLAB program. A three-dimensional IPV was plotted after transforming the data to a cubic spline interpolation followed by resampling the manometry position at 0.1-cm intervals. KEY RESULTS: Eight of the 54 (15%) individuals demonstrated delayed BE. Conventional manometric profiles did not differ significantly between cases of early and delayed BE. Receiver-operator characteristic curve analysis revealed that the ratio of the IPVs of the upper 1 cm to the lower 4 cm of the anorectal canal with balloon distension was more predictable of the BE results (area under curve, 0.73: 95% confidence interval, 0.53-0.92; p = 0.04) than the other IPVs or their ratios. CONCLUSIONS & INFERENCES: The newly developed IPV methods could predict delayed BE tests during SE better than the conventional parameters defined on the basis of linear waves. Well-designed prospective trials on a large number of subjects are warranted to validate the clinical application of this novel parameter.

Electrical stimulation therapy in chronic functional constipation: five years' experience in patients refractory to biofeedback therapy and with rectal hyposensitivity.

BACKGROUND/AIMS: Biofeedback therapy (BFT) can be unsuccessful in constipated patients, even those with pelvic floor dysfunction. Electrical stimulation therapy (EST) has been introduced as a novel therapeutic modality in patients with chronic constipation, especially those who have rectal hyposensitivity. We evaluated the efficacy of EST based on five years' clinical experience. METHODS: From January 2002 to February 2007, 159 patients underwent EST. After exclusion of 12 drop-outs, 147 (M:F = 61:86, 49 ± 17 years) finished all treatment sessions. Among them, 88 (M:F = 29:59, 49 ± 17 years) were refractory to BFT without rectal hyposensitivity (RH), and 59 (M:F = 32:27, 54 ± 17 years) were those with RH. RESULTS: The overall response to EST was 59.2% (87/147) by per-protocol analysis. In the EST-responsive group, overall satisfaction improved significantly (from 7.3 ± 3.0 to 4.3 ± 2.5, P < 0.05). Subgroup analysis showed that the response rate was 64.8% (57/88) in patients refractory to BFT without RH, and 50.8% (30/59) in those with RH. CONCLUSIONS: EST may have additional therapeutic efficacy in patients who are refractory to BFT. EST may also be effective in patients with RH, including restoration of rectal sensation. Therefore, EST could be considered as an alternative choice in patients refractory to BFT and with or without RH.

Effect of biofeedback therapy in constipation according to rectal sensation.

BACKGROUND/AIMS: The pathophysiologic mechanism of rectal hyposensitivity (RH) is not well documented, and the significance of RH in biofeedback therapy (BFT) has not been evaluated. Thus, we aimed to assess the effect of BFT in constipated patients according to the presence of RH. METHODS: Five hundred and ninety constipated patients (238 males and 352 females) underwent anorectal physiologic assessments. Of these, anorectal manometry was performed before and after BFT in 244 patients (63 RH and 181 non-RH patients). RESULTS: The success rate of BFT was 56% in the RH and 61% in the non-RH group (p=0.604). The measurements of resting pressure, squeezing pressure, desire to defecate volume, urge to defecate volume, and maximum volume were decreased after BFT in the RH group (p<0.05), whereas only resting and squeezing pressures were decreased in the non-RH group (p<0.05). Among the RH group, individuals who responded to BFT showed decreased resting pressure, squeezing pressure, desire to defecate, urge to defecate, and maximum volume and increased balloon expulsion rate; among those who did not respond to BFT, only desire to defecate volume was improved. CONCLUSIONS: In constipated patients with RH, changes of anorectal manometric findings differed in comparison to patients without RH. The responses to BFT showed both anorectal muscle relaxation and restoration of rectal sensation.

Biofeedback therapy for female patients with constipation caused by radical hysterectomy or vaginal delivery.

BACKGROUND AND AIM: Chronic constipation is frequently seen in women who have undergone hysterectomy or delivery. However, reports regarding anorectal physiologic features in those patients are rare. Patients with constipation associated with either radical hysterectomy or vaginal delivery were analyzed in order to clarify the anorectal physiologic features and the effectiveness of biofeedback therapy. METHODS: Of the constipated patients, a hysterectomy group (n = 40), delivery group (n = 41), and a control group (n = 89), who had no history of either surgery or delivery before developing functional constipation were included. Their anorectal physiological tests and the effectiveness of biofeedback therapy were investigated. RESULTS: The volume of desire to defecate was greater in the hysterectomy group than in the control group (86.5 ± 55.0 mL vs 62.9 ± 33.7 mL; P = 0.03), and more than 240 mL of maximal volume of toleration was more frequently noted in the hysterectomy group (32.5%) than in the delivery group (14.6%) and control group (13.5%) (P = 0.02).The failure of balloon expulsion was more frequently noted in the delivery group (44.0%) than in the hysterectomy group (15.0%) and control group (25.0%) (P = 0.01). The defecation satisfaction score was significantly increased after biofeedback therapy in the hysterectomy group (2.0 ± 2.7 vs 7.8 ± 1.5, P < 0.001), the delivery group (1.6 ± 2.1 vs 6.7 ± 2.0, P < 0.001), and the control group (2.5 ± 2.7 vs 6.9 ± 2.1, P < 0.001). CONCLUSIONS: Rectal hyposensitivity could have been the characteristic mechanism in the hysterectomy group, whereas dyssynergic defecation could have been the cause in the delivery group. Biofeedback therapy was effective for both groups.

Epstein-Barr Virus latent membrane protein 1 overcomes all-trans retinoic acid-induced apoptosis by inhibiting retinoic acid receptor-ß2 expression.

Nasopharyngeal carcinoma is closely associated with infection with Epstein-Barr Virus (EBV); however, the mechanism is still unclear. Here, we report that the EBV oncoprotein, latent membrane protein 1 (LMP1), suppresses apoptotic cell death provoked by all-trans retinoic acid (ATRA) in NPC cells. For this purpose, LMP1 downregulated levels of Bak whilst it upregulated levels of Bcl2, lowering the ratio of Bak to Bcl2. In addition, LMP1 suppressed ATRA-mediated activation of Caspase 9, Caspase 3, and PARP but not Caspase 8 in Ad-AH cells, suggesting that LMP1 acts by blocking the activation of intrinsic apoptosis pathway by ATRA. These effects were almost completely abolished when levels of retinoic acid receptor-ß(2) (RAR-ß(2)) in the LMP1-expressing cells were recovered by either exogenous gene expression or treatment with a universal DNMT inhibitor, 5-Aza-2'dC, indicating that LMP1 executes its antiapoptotic effects by downregulating levels of RAR-ß(2) via DNA methylation.

Pulmonary thromboembolism in a patient with myotonic dystrophy type 1.

Thromboembolism is a rare complication in patients with myotonic dystrophy. While immobilization of patients with advanced disease predisposes to high risk for venous thromboembolism, hypercoagulability could account for venous thromboembolism in patients without impaired mobilization. We report a patient with myotonic dystrophy type 1 who developed pulmonary thromboembolism unrelated to immobilization.

Burden of ischemic stroke in Korea: analysis of disability-adjusted life years lost.

BACKGROUND AND PURPOSE: Disability-adjusted life years (DALY), incorporating both disability and mortality, has been widely employed to measure regional and global burdens of stroke. Thus far, the DALY lost to stroke in a population has been estimated using only the crude population-level data; no previous study has incorporated refined data from stroke registries. The aim of this study was to integrate the stroke registry data and the population-level incidence data to project the nationwide DALY lost to ischemic stroke. METHODS: from the data of two large ischemic stroke registries, we derived an average daly lost due to ischemic stroke for each of the following age groups: <45, 45-54, 55-64, 65-74, 75-84, and ≥85 years. The nationwide ischemic stroke incidence for each age group was extracted from a cardiovascular and cerebrovascular surveillance study that analyzed the 2004 Korean Health Insurance database. RESULTS: The average DALY lost due to ischemic stroke for the age groups <45, 45-54, 55-64, 65-74, 75-84, and ≥85 years was 5.07, 4.63, 4.35, 3.88, 2.88, and 1.73, respectively. By multiplying the incidence and the average DALY lost, the nationwide DALY lost was determined to be 9,952 for those <45 years, 24,608 for 45-54 years, 50,682 for 55-64 years, 88,875 for 65-74 years, 52,089 for 75-84 years, and 8,192 for ≥85 years, respectively. The projected nationwide DALY lost due to 64,688 ischemic strokes in 2004 was 234,399 (121,482 for men and 113,244 for women), and the DALY lost per 100,000 person-years was 483 (500 for men and 469 for women). CONCLUSIONS: Incidence data from a population study and DALY values derived from stroke registries can be integrated to provide a more refined projection of the nationwide burden of ischemic stroke. In Korea, more than 230,000 years of healthy life are being lost annually due to ischemic stroke, and hence prompt action is imperative.

Anorectal function and the effect of biofeedback therapy in ambulatory spinal cord disease patients having constipation.

OBJECTIVE: Constipation in patients with mild spinal cord disease is not well investigated yet. We aimed to investigate anorectal function and the effect of biofeedback therapy in constipated patients with mild spinal cord diseases. MATERIAL AND METHODS: A total of 14 constipated patients with myelopathy and 32 with radiculopathy were enrolled retrospectively. All patients were able to walk independently. The control group comprised of 100 constipated patients without any neurologic problem. Colonic transit time and the presence of dyssynergia were assessed before biofeedback therapy. All patients answered structured questionnaires on constipation, before and after biofeedback therapy. RESULTS: The mean rectosigmoid colonic transit time of the myelopathy group was significantly delayed (myelopathy, 18.6 ± 14.6 h; radiculopathy, 12.8 ± 11.9 h; control, 9.6 ± 11.2 h; p = 0.032). Delay in total colonic transit time was more frequent in the myelopathy group (myelopathy, 57.1%; radiculopathy, 23.3%; control, 18.5%; p = 0.004). On anorectal manometry, the squeezing pressure of the anal sphincter was decreased in the myelopathy group (myelopathy, 132.3 ± 73.3 mmHg; radiculopathy, 179.9 ± 86.1 mmHg; control 200.4 ± 82.4 mmHg; p < 0.05). The success rate of biofeedback therapy was lower in the myelopathy group (28.6% for myelopathy vs. 62.0% for control group; p = 0.034). The response rate to biofeedback therapy was similar between radiculopathy and control group (62.5% for radiculopathy vs. 62.0% for control group; p = 1.000). CONCLUSIONS: In constipation associated with mild myelopathy, delayed colonic transit and dyssynergic defecation were major pathophysiologic abnormalities and biofeedback was less effective compared with control group. However, in the radiculopathy group, biofeedback was as effective as in the control group.

Mutations at codons 178, 200-129, and 232 contributed to the inherited prion diseases in Korean patients.

BACKGROUND: Polymorphisms of the human prion protein gene (PRNP) contribute to the genetic determinants of Creutzfeldt-Jakob disease (CJD). Numerous polymorphisms in the promoter regions as well as the open reading frame of PRNP were investigated. Greater than 90% of Korean, Chinese, and Japanese carry the homozygote 129 MM codon. In Korea, polymorphisms have not been comprehensively studied, except codons 129 and 219 in PRNP among Korean CJD cases. Although polymorphisms at codons 129 and 219 play an important role in susceptibility to sporadic CJD, patients with other polymorphisms in PRNP exhibited critical distinctions of clinical symptoms. METHODS: The genetic analyses of PRNP were carried out among probable CJD patients in comparison with the results from magnetic resonance imaging (MRI) and electroencephalogram (EEG). RESULTS: The molecular analyses revealed that three mutations at codons D178N, E200K, and M232R in heterozygosity. Patients with the D178N and M232R mutations had a 129MM codon, whereas the patient with the E200K mutation showed 129MV heterozygosity. They all revealed strong 14-3-3 positive signals. The 67-year-old patient with the D178N-129M mutation showed progressive gait disturbance and dysarthria was in progress. The 58-year-old patient with the E200K mutation coupled to the 129MV codon had gait disturbance, dysarthria, agitation, and ataxic gait, and progressed rapidly to death 3 months from the first onset of symptoms. The 65-year-old patient with the M232R mutation showed rapidly progressive memory decline and gait disturbance, and died within 16 months after onset of symptoms. CONCLUSION: Despite differences in ethnicity, the clinical and pathological outcomes were similar to the respective mutations around the world, except absence of insomnia in D178N-129M subject.

Nonmotor symptoms in de novo Parkinson disease before and after dopaminergic treatment.

BACKGROUND: Nonmotor symptoms (NMSs) are common in patients with Parkinson disease (PD), but little is known about the burden of the full range of NMSs in de novo PD patients. OBJECTIVES: NMSs in untreated de novo PD patients were evaluated both quantitatively and qualitatively using the Non-Motor Symptoms Assessment Scale (NMSS); the findings were compared to those of control subjects. The effects of dopaminergic treatment on NMSs were also determined. METHODS: NMSs were evaluated in 23 patients with untreated de novo PD and 23 healthy controls. The motor section of the Unified Parkinson Disease Rating Scale (mUPDRS) and the Hoehn and Yahr (HY) stage were also checked in the PD patients. The number of NMSs and the NMSS scores of the PD patients were compared with those of the controls. Three months after the start of dopaminergic medication, 16 PD patients were reevaluated with respect to the NMSS and mUPDRS, and the HY stage. RESULTS: The number of NMSs and the NMSS scores were significantly higher in the PD patients than in the controls. The three most prevalent NMSs among the PD patients were 'nocturia,' 'forget things or events,' and 'restless legs.' In the PD group, the number of NMSs was correlated with the HY stage but not with age, disease duration, or mUPDRS score. Follow-up of 16 patients at 3months after commencing PD medication revealed no changes in either the number of NMSs or the NMSS score, despite improvement in motor symptoms. CONCLUSIONS: Untreated de novo PD patients have more nonmotor problems than controls, and these NMSs are not ameliorated by dopaminergic medication.

Intravenous recombinant tissue plasminogen activator thrombolysis in a patient with acute ischemic stroke secondary to aortic dissection.

BACKGROUND: Acute ischemic stroke secondary to aortic dissection (AoD) is challenging in the era of thrombolysis owing to the diagnostic difficulty within a narrow time window and the high risk of complications. CASE REPORT: A 64-year-old woman with middle cerebral artery occlusion syndrome admitted to the emergency room within intravenous recombinant tissue plasminogen activator (rt-PA) time window. Her neurological symptoms improved during thrombolysis, but chest and abdominal pain developed. Repeated history-taking, physical examination, and imaging studies led to the timely diagnosis and surgical treatment of AoD, which produced a successful outcome. CONCLUSIONS: Clinical suspicion is invaluable for the diagnosis of this rare cause of stroke. Considering the stroke mechanism and complications, the risks of thrombolysis might outweigh its benefits.

Recurrent emotion-triggered headache following primary headache associated with sexual activity.

We present a 44-year-old woman who was admitted to our hospital after three episodes of coital headache. Magnetic resonance imaging (MRI) and angiography (MRA) revealed no vascular abnormality. She was discharged with a diagnosis of primary headache associated with sexual activity (PHSA). Although she abstained from sexual activity after discharge, she experienced recurrent headaches several times a day, whenever there was a change in her emotional state. This case implies that emotional changes can trigger headache attacks during headache-prone state in PHSA.

Epstein-Barr virus latent membrane protein 1 suppresses the growth-inhibitory effect of retinoic acid by inhibiting retinoic acid receptor-beta2 expression via DNA methylation.

Epigenetic alteration through DNA methylation in retinoic acid receptor-beta2 (RAR-beta2) is common in human tumors including nasopharyngeal carcinoma (NPC); however, the mechanism and its biological significance are unknown. Here, we report that the Epstein-Barr virus (EBV) oncogene product, latent membrane protein 1 (LMP1), induces promoter hypermethylation of RAR-beta2 via up-regulation of DNA methyltransferases 1, 3a, and 3b, leading to decrease in RAR-beta2 expression in NPC cells. In addition, LMP1 abolished the potentials of retinoic acid (RA) to down-regulate Cdk2 and Cdk4 and to up-regulate p16, p21, and p27, resulting in activation of E2F1 in the presence of RA. As a consequence, LMP1 could abrogate the growth-inhibitory effect of RA by releasing cell cycle arrest at G1 phase. Considering that RAR-beta2 is a major executor of the anti-tumor potentials of retinoids, its down-regulation by LMP1 might play an important role during EBV-mediated tumorigenesis.

EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1alpha through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells.

Hypoxia-inducible factor 1 (HIF1) is up-regulated in most malignant tumors usually via interruption of ubiquitination and proteasomal degradation of its subunit alpha. Recently, we have shown that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), activates HIF1alpha and subsequently expression of HIF1-responsive genes in epithelial cells. Here, we explore the mechanism for HIF1alpha activation by LMP1 in nasopharyngeal epithelial cells: LMP1 up-regulates the level of Siah1 E3 ubiquitin ligase by enhancing its stability, which subsequently induces proteasomal degradation of prolyl HIF-hydroxylases 1 and 3 that normally mark HIF1alpha for degradation. As a result, LMP1 prevents formation of von Hippel-Lindau/HIF1alpha complex, as shown by coimmunoprecipitation analyses. Thus, Siah1 is implicated in the regulation of HIF1alpha and is involved in a recently appreciated aspect of EBV-mediated tumorigenesis, namely, the angiogenesis process triggered by LMP1.