Biomedical subjects
Publications and source records attributed to J H Ho.
[figure: see text] Photochemical reaction pathways during direct irradiation of stilbene analogues (1a-1d) can be switched completely by adjusting the concentration of hydrochloric acids. Competitive ring opening and acid-catalyzed hydrolysis processes are responsible for this novel selectivity.
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Nineteen consecutive patients with metastatic or recurrent nasopharyngeal cancer (NPC) receiving combination chemotherapy were monitored for EBV DNA in their serum. EBV DNA (EBER-1) concentration in serum was measured before, during, and after chemotherapy. Thirteen patients had additional multiple prechemotherapy readings. There was a significant lead time from first detection of serum EBER-1 to clinical recurrence in 62% of patients by a mean of 17.4 weeks (range: 8-74.5 weeks; mean = 28.2 weeks if confined to the 8 patients with significant lead time). The median EBER-1 concentration was significantly higher in those with distant metastasis as compared to those with loco-regional recurrence only (17,468 vs. 684 pg/mL serum; p = 0.046, Mann-Whitney U test). Among the 13 patients who responded to chemotherapy, 4 exhibited clinical complete remission (CR) who were only found in the group with EBER-1 DNA drop to background level, while the magnitude of EBER-1 drop did not discriminate partial remission (PR) and stable disease (SD) patients clearly. Subsequent profile of EBER-1 DNA showed concordance with clinical course of either continuous remission or later progression. EBER-1 DNA in serum can become a useful adjunctive surrogate marker to monitor chemotherapeutic response in NPC patients with distant metastasis or advanced local recurrence.
In eukaryotic cells, nuclear export of nascent ribosomal subunits through the nuclear pore complex depends on the small GTPase Ran. However, neither the nuclear export signals (NESs) for the ribosomal subunits nor the receptor proteins, which recognize the NESs and mediate export of the subunits, have been identified. We showed previously that Nmd3p is an essential protein from yeast that is required for a late step in biogenesis of the large (60S) ribosomal subunit. Here, we show that Nmd3p shuttles and that deletion of the NES from Nmd3p leads to nuclear accumulation of the mutant protein, inhibition of the 60S subunit biogenesis, and inhibition of the nuclear export of 60S subunits. Moreover, the 60S subunits that accumulate in the nucleus can be coimmunoprecipitated with the NES-deficient Nmd3p. 60S subunit biogenesis and export of truncated Nmd3p were restored by the addition of an exogenous NES. To identify the export receptor for Nmd3p we show that Nmd3p shuttling and 60S export is blocked by the Crm1p-specific inhibitor leptomycin B. These results identify Crm1p as the receptor for Nmd3p export. Thus, export of the 60S subunit is mediated by the adapter protein Nmd3p in a Crm1p-dependent pathway.
PURPOSE: To assess the additional damage of normal tissues attributable to reirradiation and the magnitude of partial recovery following the initial course. METHODS AND MATERIALS: Symptomatic late complication rates (excluding xerostomia) in 3635 patients receiving one course (Group 1) and 487 patients receiving two courses of external radiotherapy (Group 2) for nasopharyngeal carcinoma were retrospectively analyzed and compared. RESULTS: Group 2 had significantly lower actuarial complication-free survival rates than Group 1: 48% versus 81% at 5 years. The post-retreatment incidence was significantly affected by biologically effective dose (BED) (assuming an alpha/beta ratio of 3 Gy) of the first course: hazard ratio (HR) = 1.04 per Gy(3) (p = 0.01), but only marginally by that of the second course: HR = 1.01 per Gy(3) (p = 0.06). If the summated BED was taken as the dose unit, it was estimated that a total BED of 143 Gy(3) would induce a 20% incidence at 5 years, while the corresponding dose projected from Group 1 was 111 Gy(3). The gap effect was insignificant in the overall analyses, but a trend of decreasing risk with increasing interval was observed in patients with gap > or = 2 years: HR = 0.86 per year (p = 0.07). CONCLUSION: The major determinant of post-retreatment complication is the severity of damage during the initial course. The sum of total doses tolerated is higher than that expected with a single-course treatment, suggesting occurrence of partial recovery (particularly in those reirradiated after an interval of 2 years or more).
Nmd3p from yeast is required for the export of the large (60S) ribosomal subunit from the nucleus (Ho et al., 2000). Here, we show that Nmd3p forms a stable complex with free 60S subunits. Using an epitope-tagged Nmd3p, we show that free 60S subunits can be coimmunoprecipitated with Nmd3p. The interaction was specific for 60S subunits; 40S subunits were not coimmunoprecipitated. Using this coprecipitation technique and pulse-chase labeling of ribosomal subunit proteins we showed that Nmd3p bound nascent subunits, consistent with its role in export. However, under conditions in which ribosome biogenesis was inhibited (e.g., inhibition of transcription with thiolutin, inhibition of transcription of ribosomal protein and RNA genes in a sly1-1 mutant at nonpermissive temperature, and inhibition of translation in a conditional prt1 mutant), Nmd3p remained associated with 60S subunits. In addition, Nmd3delta120, a truncated protein that lacked a nuclear localization signal, retained 60S binding. These results suggest that Nmd3p recruits nascent 60S subunits into the pool of free 60S subunits and exchanges on 60S subunits as they recycle during translation.
The independent significance of different tumor factors in 4,514 patients with undifferentiated or non-keratinizing carcinoma of the nasopharynx irradiated at the Queen Elizabeth Hospital during 1976-1985 were analyzed retrospectively. Multivariate analyses showed that the most significant primary factors included cranial nerve palsy, erosion of base of skull and oropharynx. For tumors within the nasopharynx, there was no difference in survival between those with involvement of 1 site vs. more than 1 sites. Patients with cranial nerve palsy had significantly worse prognosis than those with bony erosion alone. Although the nodal characteristics (size, level of extension, fixation, laterality and multiplicity) were inter-related, their independent impact all reached statistical significance. However, the criteria used currently could be simplified: laterality should be revised to unilateral vs. bilateral, level to upper-mid vs. lower neck, and size to < or =6 cm vs. >6 cm. Grouping of N2 together with N3 into Stage IV was inappropriate as the former had significantly better prognosis. Our findings, together with review of the publications, provided clinical data for developing the current UICC staging system for nasopharyngeal carcinoma. Such major revision resulted not only in better distinction of hazards, but also more even distribution of cases between different stages.
PURPOSE: To study the peculiar characteristics of relapses with long latency following radical treatment for nasopharyngeal carcinoma. METHODS AND MATERIALS: 847 patients with nasopharyngeal recurrence were retrospectively studied, focusing on the independent effects of latency on different outcome aspects and its relationship with other prognostic factors. RESULTS: The proportion of recurrence with latency <2 years (Group A), 2-<5 years (Group B), and 25 years (Group C) were 52%, 39%, and 9%, respectively. A higher proportion of Group C originated from patients with node-negative early primary, but fewer of them were still confined within the nasopharynx at detection of recurrence. There was no significant difference in the choice of salvage modality, but among those reirradiated, more of Group C were treated with external beams to a higher dose. The difference in local salvage rate was not statistically significant, but the 5-year distant failure-free rates of the 3 groups were 57%, 67%, and 83%, respectively; and the corresponding disease-specific survival (DSS) were 14%, 20%, and 35%. Multivariate analysis confirmed the independent significance of latency in predicting distant failure (hazard ratio = 0.81 per year, p < 0.01) and cancer deaths (hazard ratio = 0.90 per year, p < 0.01). CONCLUSIONS: Nasopharyngeal recurrence with long latency showed different natural behavior: the prognosis was significantly better due to lower risk of distant failure.
A mutation in NMD3 was found to be lethal in the absence of XRN1, which encodes the major cytoplasmic exoribonuclease responsible for mRNA turnover. Molecular genetic analysis of NMD3 revealed that it is an essential gene required for stable 60S ribosomal subunits. Cells bearing a temperature-sensitive allele of NMD3 had decreased levels of 60S subunits at the nonpermissive temperature which resulted in the formation of half-mer polysomes. Pulse-chase analysis of rRNA biogenesis indicated that 25S rRNA was made and processed with kinetics similar to wild-type kinetics. However, the mature RNA was rapidly degraded, with a half-life of 4 min. Nmd3p fractionated as a cytoplasmic protein and sedimented in the position of free 60S subunits in sucrose gradients. These results suggest that Nmd3p is a cytoplasmic factor required for a late cytoplasmic assembly step of the 60S subunit but is not a ribosomal protein. Putative orthologs of Nmd3p exist in Drosophila, in nematodes, and in archaebacteria but not in eubacteria. The Nmd3 protein sequence does not contain readily recognizable motifs of known function. However, these proteins all have an amino-terminal domain containing four repeats of Cx2C, reminiscent of zinc-binding proteins, implicated in nucleic acid binding or protein oligomerization.
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a prevalent malignant tumor among Southern Chinese. Previously, the authors described the prognostic significance of a serum antibody assay to a recombinant Epstein-Barr virus Bam HI-Z replication activator protein (ZEBRA) in NPC patients with long term follow-up. In this study, the authors further reported the use of DNA flow cytometry (DNA-FCM) as an additional technique for determining the prognosis of NPC patients in the same series. METHODS: One hundred and forty-three archival biopsies from 110 NPC patients were deparaffinized and subjected to DNA-FCM analysis. DNA ploidy state and various proliferative indices (PI) of the tumors were correlated with patient survival and frequency of recurrence. RESULTS: Among the biopsies analyzed, 119 were histologically positive NPC and 24 were negative. Fifty-one tumor biopsies that fulfilled the guideline criteria of the DNA Cytometry Consensus Conference were correlated with the clinical manifestations of the patients. Among them, 43 tumors (84%) were DNA diploid and 8 (16%) were aneuploid. Two PI, S-phase fraction (SPF) and proliferation fraction (PF), appear to be potentially useful prognostic indicators. For example, PF in patients who developed locoregional recurrence (15.1%) and distant recurrence (16.4%) after radiation therapy both were significantly higher than PF in patients who were in complete remission (8.2%) (P = 0.0005 and P = 0.004, respectively). Significant differences in SPF between patients with distant recurrence (10.6%) and those in remission (5.7%) also was found (P = 0.005). Using Kaplan-Meier analysis, patients with high PF, high SPF, and aneuploid tumors had significantly poorer 12-year survival rates (35%, 26%, and 28%, respectively) than those patients with low PF, low SPF, and diploid tumors (77%, 67%, and 59%, respectively) (P < 0.0009, P < 0.004, and P < 0.01, respectively). CONCLUSIONS: Determination of tumor PI and DNA ploidy state by DNA-FCM at diagnosis of NPC can be potentially useful in selecting a poor prognostic subgroup of NPC patients. These parameters may enable oncologists to plan for more stringent treatment strategies such as hyperfractionated and accelerated radiation therapy or concomitant chemoradiotherapy for these patients.
PURPOSE: To study the relative effects of different radiation factors on temporal lobe necrosis (TLN) and predictive accuracy of different biological equivalent models. METHODS AND MATERIALS: Consecutive patients (1008) treated radically with four different fractionation schedules during 1976-1985 for T1 nasopharyngeal carcinoma were retrospectively analyzed. All were irradiated by megavoltage photons using the same technique. Their age ranged from 18-84 years, and 92% of patients had complete follow-up. The fractional dose to inferomedial parts of both temporal lobes ranged from 2.5-4.2 Gy, total dose 45.6-60 Gy, and overall time 38-75 days. RESULTS: Despite a lower total dose of 50.4 Gy, the 621 patients irradiated with 4.2 Gy per fraction had a significantly higher incidence of temporal lobe necrosis than the 320 patients treated to 60 Gy with 2.5 Gy per fraction: the 10-year actuarial incidence being 18.6% vs. 4.6%, p < 0.001. Multivariate survival analysis showed that fractional effect (product of total dose and fractional dose) was the most significant factor: p = 0.0022, hazard ratio (HR) = 1.044 per Gy2. Overall time and age were both insignificant. The alpha/beta ratio calculated from our data was 2.9 Gy (95% CI: -1.8, 7.6 Gy). Biological effective dose (BED(Gy3)), neuret, and brain tolerance unit all showed strongly significant correlation with the necrotic rate (p < 0.001), and gave similar predictions. The hazard of TLN increased by 14% per Gy3, and it was estimated that 64 Gy (at conventional fractionation of 2 Gy daily) would lead to a 5% necrotic rate at 10 years. Not only did the nominal standard dose (NSD) show the lowest value in terms of log likelihood and standardized HR, but its predictions on TLN deviated markedly from clinically observed rates. CONCLUSION: Fractional effect is the most significant factor affecting cerebral necrosis, and overall time has little protective effect. The BED formula, assuming an alpha/beta ratio of 3 Gy, is an appropriate model for predicting late effects on the temporal lobe, and NSD could give seriously misleading predictions.
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From epidemiologic studies in several countries, passive smoking has been associated with increased risk for lung cancer, respiratory diseases, and coronary heart disease. Since the relative risks derived from those studies are weak, i.e. relative risk less than two, we investigated whether poorer diets and less healthy lifestyles might act as confounders and be correlated with having a smoking husband on a cross-cultural basis. Characteristics of never-smoked wives with or without smoking husbands were compared between 530 women from Hong Kong, 13,047 from Japan, 87 from Sweden, and 144 from the U.S. In all four sites, wives with smoking husbands generally ate less healthy diets. They had a tendency to eat more fried food but less fruit than wives with nonsmoking husbands. Other healthy traits, e.g. avoiding obesity, dietary cholesterol and alcohol, or taking vitamins and participating in preventive screening were also less prevalent among wives with smoking husbands. These patterns suggest that never-smoked wives with smoking husbands tend to share the same less healthy dietary traits characteristic of smokers, and to have dietary habits associated with increased risk for lung cancer and heart disease in their societies. These results emphasize the need to take into account the potential confounding effects of diet and lifestyle in studies evaluating the health effects of passive smoking, especially since it is known that the current prevalence rates of smoking among men is indirectly associated with social class and education in affluent urban societies.
Cancer incidence rates from the Hong Kong Cancer Registry show significant increases in lung and colon cancers and decreases in nasopharyngeal cancer in both sexes from 1973 to 1992. Moreover, cervical cancer and male esophageal cancer have declined significantly, and changes in the trends of cancer of the following sites were of borderline significance: decreasing male laryngeal and female esophageal cancers and increasing prostate and female breast cancers. These changes have occurred along with dietary shifts in the population, from a diet predominantly of rice and small portions of meat, vegetables, and fish to one with larger portions of all foods but rice and eggs. The latter data were gathered from six government household surveys from 1963-64 to 1994-95. By combining the two data sets, correlation coefficients were calculated for per capita consumption patterns of eight foods (rice, pork, beef, poultry, saltwater fish, freshwater fish, fresh vegetables, and eggs) and cancer incidence data of the same year or 10 years later. Higher meat intakes were significantly and positively correlated with cancers of the colon, rectum, prostate, and female breast. The correlations also suggested that current diets were more influential than diets a decade before for cancers of the lung, esophagus, rectum, and prostate. Cancers of the nasopharynx and colon were significantly correlated with current and past diets. These results support the hypothesis that intakes of meat and its associated fat are risk factors for colon, rectal, prostate, and female breast cancers.
BACKGROUND: Few studies have addressed ocular disorders among the homeless and nonhomeless poor. METHODS: To better understand the health problems of the homeless, ophthalmic disorders were analyzed among 512 homeless and 413 nonhomeless poor individuals receiving vision-screening examinations in Los Angeles. RESULTS: Significantly, more 4- to 17-year-old nonhomeless poor were diagnosed with uncorrected visual acuity worse than or equal to 20/50 without correction (p = 0.001), total refractive errors (p < 0.0005), astigmatism (p = 0.001), and myopia (p < 0.0005) than were a control group of 4- to 17-year-old homeless individuals. More homeless individuals had extraocular muscle imbalance (p < 0.040), but fewer had external eye diseases (p2 = 0.016) than the nonhomeless poor, when age adjusted. In addition, higher rates of glaucoma and cataracts were observed in both homeless and poor nonhomeless populations than in the general population. CONCLUSIONS: Health care professionals should provide vision screenings intended to detect these ocular disorders. Screening and correction of myopia and glaucoma, in particular, can greatly improve the quality of life for those treated.
Chinese females in Hong Kong, where only about a third of the lung cancer cases can be attributed to a history of active smoking, have a world age-standardized lung cancer incidence rate of 32.6 per 100 000, which is among the highest in the world. Trends in Hong Kong's female lung cancer mortality also indicate a tripling in mortality rates from 1961 to 1990. The characteristically high Chinese female lung cancer incidence among nonsmokers is also found among overseas Chinese communities in Singapore and Hawaii. To help elucidate the role of ingested and inhaled substances in the etiology of lung cancer, four epidemiological studies have been conducted in Hong Kong over the last 15 years: (1) a retrospective study of 200 cases and 200 neighbourhood controls, (2) a cross-sectional study measuring personal exposures to nitrogen dioxide among 362 children and their mothers, (3) a site monitoring study of 33 homes measuring airborne carcinogens, and (4) a telephone survey of 500 women on their dietary habits and exposure to air pollutants. Selected data from each study were drawn to evaluate exposures to three major air pollutants (environmental tobacco smoke, incense, and cooking fumes), their relationship with lung cancer risk, and their association with dietary habits. Generally in this population, nutritionally poorer diets were characterized by higher consumption of alcohol and preserved/cured foods, whereas better diets were characterized by higher intakes of fresh fruits, vegetables, and fish. For environmental tobacco smoke, exposure was only moderately high in Hong Kong (36% have current smokers at home), lung cancer risk was equivocal with exposure, and it was associated with poorer diets among wives with smoking husbands. Incense was identified as a major source of exposure to nitrogen dioxide and airborne carcinogens, but it had no effect on lung cancer risk among nonsmokers and significantly reduced risk (trend, P-value = 0.01) among smokers, even after adjusting for smoking. The last finding may be explained by the relatively better diets among smoking women who burned incense versus those who did not. Although about 94% of the Chinese women cook on a regular basis, and the cooking fires were associated with increased airborne carcinogens, nonsmoking women who cooked for more than 25 years had a 60% reduction in lung cancer risk and the trend was highly significant (P < 0.001). Again, this unexpected finding may be due to the confounding effects of diet. Female controls who cooked for more than 25 years had a poorer diet than those who cooked for shorter durations. These three examples were chosen to illustrate the complexities of assessing air pollution exposure, and understanding the behavioral and dietary dynamics underlying lung cancer risk assessments. Our conclusion is that diet can be an important confounding factor affecting lung cancer risk estimates from air pollution exposures among Chinese women living in an affluent urban environment.
To evaluate the prognostic accuracy of N-staging by Ho's and the UICC/AJCC systems, 5020 patients with undifferentiated or poorly differentiated squamous cell carcinoma of the nasopharynx treated at the Queen Elizabeth Hospital, Hong Kong in the period 1976-1985 were analysed retrospectively. They were initially staged with Ho's system, but detailed records of nodal involvement allowed accurate retrospective restaging with the UICC/ AJCC (1988) system. Staging assessment depended almost entirely on physical examination; only 14% of patients had additional investigations with computed tomography. To evaluate the independent significance of different nodal parameters, T-stage adjusted analyses of the 4730 patients presenting without distant metastases were performed. Both N-staging systems showed a strongly significant overall correlation with distant failures and cancer-specific deaths. A significant trend was also shown for nodal failures in node-positive patients. Ho's system was superior in predicting distant failures, while the UICC/AJCC system was superior for nodal failures. However, even with due adjustment for level, the independent significance of nodal size, laterality and fixity could be demonstrated. After adjustment for UICC/AJCC N-stage, both level and fixity were also significant. Furthermore, when adjusted for all other meaningful parameters, there were no significant differences between ipsilateral and contralateral involvement, upper and mid-level extent, and nodal size < or = 3 cm or > 3- < or = 6 cm. N-staging can be further optimized by a newly proposed system incorporating fixity (movable versus fixed), level (upper-mid versus lower), size (greatest diameter < or = 6 cm versus > 6 cm), and laterality (unilateral versus bilateral) as staging criteria.