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PubMed1998

Molecular bases of coronary heart disease in Koreans.

Coronary heart disease (CHD) has been considered as a multifactorial disorder with the involvement of both environmental and genetic factors. The advent of tools to investigate individual variability of DNA has allowed us to perform the association studies of candidate genes. However, an association between genetic trait and phenotypic variations is not easy to demonstrate and several reported association between genetic markers and risk factors or overt CHD have gone unconfirmed. It should not be assumed that for a given genetic trait, the impact on risk will be similar in all populations. In particular, most studies of the molecular bases of CHD have involved Caucasian subjects, so much more work with the Korean population is needed before genetic testing for susceptibility to CHD can be offered to Koreans as a clinical service. In this review, we discuss two aspects of the molecular bases of CHD: i) Molecular bases of the candidate gene related to lipoprotein metabolism including apolipoprotein AI-CIII-AIV gene duster, apolipoprotein B, apolipoprotein E-CI-CII gene cluster, apolipoprotein(a), LDL receptors, lipoprotein lipase, cholesteryl ester transfer protein, and apo B editing protein; ii) Molecular bases of the candidate gene related to thrombotic and other factors including fibrinogen, factor VII, plasminogen activator inhibitor 1, homocysteine, stromelysin, paraoxonase, and angiotensin converting enzyme. Studies involving the Korean population, especially those performed by our teams, are also summarized.

Coronary Disease↗
PubMed2006

Validation of the deCODE Migraine Questionnaire (DMQ3) for use in genetic studies.

We assessed the reliability of the diagnosis of migraine with aura (MA) and migraine without aura (MO) based on the third edition of the deCODE Migraine Questionnaire (DMQ3) using a physician-conducted interview as an empirical index of validity. Amongst Danish migraine families recruited from specialist practice we selected 200 cases diagnosed according to the International Classification of Headache Disorders 2nd Edition in a validated physician-conducted telephone interview: 50 patients with exclusively MA, 50 with both MA and MO, 50 with exclusively MO and 50 controls. A written copy of the DMQ3 was mailed to the participant. The DMQ3-based diagnosis was compared with the interview-based diagnosis. Overall, the DMQ3 diagnosed migraine (MA, MO or both) with a sensitivity of 99% (109/110), a specificity of 86% (32/37) and a kappa statistic of 0.89. The most reliable subtype of migraine was MA (with or without co-occurring attacks of MO) which was diagnosed with a sensitivity of 92% (71/77), a specificity of 93% (65/70) and a kappa statistic of 0.85. Exclusively MO was diagnosed with a sensitivity of 91% (30/33), a specificity of 93% (106/114) and a kappa statistic of 0.80. Weakest was the diagnosis of both MO and MA which was diagnosed with a sensitivity of 63% (24/38), a specificity of 92% (100/109) and a kappa statistic of 0.57. In conclusion, the DMQ3 is a valid tool for diagnosing patients with migraine for genetic studies.

Adult↗
PubMed2026

Next-generation macrophage engineering in cancer therapy: From TAM reprogramming to CAR-macrophages.

Macrophages are central regulators of the tumor microenvironment (TME), shaping immune suppression, angiogenesis, metabolism, and therapeutic resistance in solid cancers. While early strategies sought to deplete tumor-associated macrophages (TAMs) or block monocyte recruitment, limited efficacy and compensatory mechanisms revealed the need for functional reprogramming rather than elimination. Recent advances in viral vectors, CRISPR-Cas genome editing, and RNA-based delivery platforms have enabled precise genetic modification of macrophages, giving rise to chimeric antigen receptor macrophages (CAR-Ms) and related engineered products. Beyond antigen targeting, effective macrophage engineering requires stabilization of pro-inflammatory identity, resistance to tumor-induced repolarization, metabolic reinforcement, and integration of checkpoint modulation pathways. This review synthesizes current strategies across DNA, mRNA, and siRNA-based platforms, highlighting convergent design principles that connect TAM reprogramming with CAR-M development. We discuss reshaping phagocytosis checkpoints, metabolic and transcriptional stabilization, cytokine augmentation, and synthetic receptor architecture, emphasizing combinatorial and context-aware engineering, while proposing new candidate gene targets. Engineered macrophages are thus evolving from simple effector cells into programmable immune coordinators capable of converting immunologically "cold" tumors into inflamed, therapy-responsive niches.

CAR-M↗
PubMed2004

Simple statistical models predict C-to-U edited sites in plant mitochondrial RNA.

BACKGROUND: RNA editing is the process whereby an RNA sequence is modified from the sequence of the corresponding DNA template. In the mitochondria of land plants, some cytidines are converted to uridines before translation. Despite substantial study, the molecular biological mechanism by which C-to-U RNA editing proceeds remains relatively obscure, although several experimental studies have implicated a role for cis-recognition. A highly non-random distribution of nucleotides is observed in the immediate vicinity of edited sites (within 20 nucleotides 5' and 3'), but no precise consensus motif has been identified. RESULTS: Data for analysis were derived from the the complete mitochondrial genomes of Arabidopsis thaliana, Brassica napus, and Oryza sativa; additionally, a combined data set of observations across all three genomes was generated. We selected datasets based on the 20 nucleotides 5' and the 20 nucleotides 3' of edited sites and an equivalently sized and appropriately constructed null-set of non-edited sites. We used tree-based statistical methods and random forests to generate models of C-to-U RNA editing based on the nucleotides surrounding the edited/non-edited sites and on the estimated folding energies of those regions. Tree-based statistical methods based on primary sequence data surrounding edited/non-edited sites and estimates of free energy of folding yield models with optimistic re-substitution-based estimates of approximately 0.71 accuracy, approximately 0.64 sensitivity, and approximately 0.88 specificity. Random forest analysis yielded better models and more exact performance estimates with approximately 0.74 accuracy, approximately 0.72 sensitivity, and approximately 0.81 specificity for the combined observations. CONCLUSIONS: Simple models do moderately well in predicting which cytidines will be edited to uridines, and provide the first quantitative predictive models for RNA edited sites in plant mitochondria. Our analysis shows that the identity of the nucleotide -1 to the edited C and the estimated free energy of folding for a 41 nt region surrounding the edited C are the most important variables that distinguish most edited from non-edited sites. However, the results suggest that primary sequence data and simple free energy of folding calculations alone are insufficient to make highly accurate predictions.

Arabidopsis↗
PubMed1996

Characterization of the radish mitochondrial nad3/rps12 locus: analysis of recombination repeats and RNA editing.

In order to further investigate sequences that are responsible for low-frequency recombination in plant mitochondrial DNAs and RNA editing in radish mitochondria, the nad3/rps12 locus has been isolated and characterized from a normal cultivar of radish and the male-sterile Ogura cytoplasm. A repeated sequence that has been implicated in other radish mitochondrial DNA rearrangements was identified at the breakpoint between the two loci indicating that it was also involved in the nad3/rps12 rearrangement. Similar to some other radish mitochondrial genes, nad3/rps12 genomic sequences already contain several, but not all, of the bases that are typically edited in plant mitochondrial nad3 and rps12 genes. Analysis of nad3/rps12 cDNAs indicated that the mRNAs are not edited. One partially edited transcript was identified out of the twenty two that were examined. This finding, along with the observation that nad3/rps12 RNAs are present at very low levels, raises the possibility that radish mitochondria may not encode functional copies of these genes. Consistent with this hypothesis, DNA-blot analysis detects nad3/rps12 sequences in the nucleus.

Amino Acid Sequence↗
PubMed1997

[TNM classification of carcinoma of the esophagus].

TNM classification of esophageal carcinoma was first described in the supplement to the first edition of the TNM classification in 1973. In the second edition, the classification was changed based on the data of 1,000 cases from the Task Force on Esophagus of American Joint Committee. In this edition, only the clinical classification was described, but the third edition included both clinical and post-surgical histopathological classification. But the criteria for T and pT classification differed. Before the fourth edition, specialists from Japan and the United States met in Hawaii in 1984. Data of the Japanese Nationwide Registration, including 7,742 patients from 1969 to 1978, were presented. After discussion based on these data, T was classified according to the depth of invasion, and perigastric lymph nodes were included in Regional Nodes in the fourth edition. Then, the TNM Research Committee of ISDE collected patient data of esophageal carcinoma from seven countries, and they were studied according to many factors. Based on these data, two proposals were made to the UICC TNM Committee. First, T1 should be divided into two categories: T1a, Tumor invasion of lamina propria; and T1b, Tumor invasion of submucosa. Second, metastases to distant lymph nodes should be grouped into the N classification instead of M classification. The first was accepted in the TNM Supplement of 1993, and the second will be accepted in the Fifth Edition, which will appear in 1997. It is important to accumulate data on many patients using the uniform registration form and to follow these patients very closely in the discussion of revisions to the TNM classification.

Esophageal Neoplasms↗
PubMed2006

American Joint Committee on Cancer clinical stage as a selection criterion for sentinel lymph node biopsy in thin melanoma.

BACKGROUND: A significant proportion of newly diagnosed melanomas are thin lesions (< or = 1.00 mm). Because tumor thickness correlates with the risk for nodal metastases, sentinel lymph node (SLN) biopsy in this subset is controversial. Incorporating other prognostic factors (Clark level and ulceration), we evaluated the 6th edition American Joint Committee on Cancer (AJCC) clinical stage as a simple and widely applicable guideline for offering SLN biopsy for thin melanoma. METHODS: This study was a review of a prospective melanoma SLN database from 1993 to 2003 with emphasis on SLN positivity rates based on the 6th edition AJCC primary tumor thickness intervals and clinical stage. RESULTS: Three hundred five patients underwent SLN biopsy, with an overall positivity rate of 17.7%. By the 6th edition AJCC, lesions < or = 1.00 mm had an SLN positivity rate of 6.6%. By 6th edition clinical stage, SLN positivity rates were 4.9% for stage IA and 10.4% for stage IB. By using stage IA as the criterion for not offering SLN biopsy, this procedure would have been avoided in 46% (39 of 85) of < or = 1.00-mm melanoma patients with a negative SLN. CONCLUSIONS: Sixth edition AJCC clinical stage IB as a selection criterion for performing SLN biopsy in thin melanoma identifies most patients with a positive SLN while also avoiding a negative SLN biopsy in many patients. Until additional widely accepted and validated selection criteria are available, SLN biopsy for clinical stage IB, but not stage IA, thin melanomas is a reasonable approach.

Adult↗
PubMed1998

Respiratory infections in the community. A concise update.

BACKGROUND: The decision to institute antibiotic therapy is often empirical and based on historical precedent. As respiratory tract infections are the commonest reason for prescribing antibiotics and bacterial resistance to many drugs is increasing, it is important to look at the evidence for using antibiotics. OBJECTIVE: This article reviews the various components of the respiratory tree addressing the indications for instituting antibiotic therapy and the most appropriate antibiotic. DISCUSSION: The information contained in this article is based on the 10th edition of the Therapeutic Guidelines: Antibiotics. It is acknowledged that the decision of when and which antibiotics to prescribe must be made on an individual basis, however, by considering the broader ramifications of antibiotic use and the evidence of outcome studies, the decision can be based on a more rational approach.

Adult↗
PubMed2004

Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial [ISRCTN45683816].

BACKGROUND: The morbidity and mortality associated with depression are considerable and continue to increase. Depression currently ranks fourth among the major causes of disability worldwide, after lower respiratory infections, prenatal conditions, and HIV/AIDS. Crocus sativus L. is used to treat depression. Many medicinal plants textbooks refer to this indication whereas there is no evidence-based document. Our objective was to compare the efficacy of stigmas of Crocus sativus (saffron) with imipramine in the treatment of mild to moderate depression in a 6-week pilot double-blind randomized trial. METHODS: Thirty adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition for major depression based on the structured clinical interview for DSM IV participated in the trial. Patients have a baseline Hamilton Rating Scale for Depression score of at least 18. In this double-blind, single-center trial, patients were randomly assigned to receive capsule of saffron 30 mg/day (TDS) (Group 1) and capsule of imipramine 100 mg/day (TDS) (Group 2) for a 6-week study. RESULTS: Saffron at this dose was found to be effective similar to imipramine in the treatment of mild to moderate depression (F = 2.91, d.f. = 1, P = 0.09). In the imipramine group anticholinergic effects such as dry mouth and also sedation were observed more often that was predictable. CONCLUSION: The main overall finding from this study is that saffron may be of therapeutic benefit in the treatment of mild to moderate depression. To the best of our knowledge this is the first clinical trial that supports this indication for saffron. A large-scale trial with placebo control is warranted.

Adult↗
PubMed2003

Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression: a double-blind, randomized trial.

Depression is a major health problem and is not only underrecognized and undertreated but is associated with significant morbidity and mortality. Lavandula angustifolia Mill. (Lamiacae) is used to treat depression. Many medicinal plant textbooks refer to this indication, whereas there is no evidence-based document. Our objective was to compare the efficacy of tincture of L. angustifolia with imipramine in the treatment of mild to moderate depression and to evaluate the possible adjuvant effect of this tincture in a 4 week double-blind, randomized trial. Forty-five adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, for major depression based on the structured clinical interview for DSM IV participated in the trial. Patients have a baseline Hamilton Rating Scale for Depression score of at least 18. In this double-blind, single-center trial, patients were randomly assigned to receive lavandula tincture (1:5 in 50% alcohol ) 60 drops/day plus placebo tablet (Group A), tablet imipramine 100 mg/day plus placebo drop (Group B) and tablet imipramine 100 mg/day plus lavandula tincture 60 drops/day (Group C) for a 4-week study. In this small preliminary double-blind and randomized trial, lavandula tincture at this concentration was found to be less effective than imipramine in the treatment of mild to moderate depression (F=13.16, df=1, P=.001). In the imipramine group, anticholinergic effects such as dry mouth and urinary retention were observed more often that was predictable, whereas headache was observed more in the lavandula tincture group. A combination of imipramine and lavandula tincture was more effective than imipramine alone (F=20.83, df=1, P<.0001). As this study indicates, one of the advantages of this combination is a better and earlier improvement. The main overall finding from this study is that lavandula tincture may be of therapeutic benefit in the management of mild to moderate depression as adjuvant therapy. A large-scale trial is justified.

Adult↗
PubMed2005

Reversible neurobehavioral performance with reductions in blood lead levels--a prospective study on lead workers.

Lead poisoning remains an occupational hazard in Taiwan. Many studies, based on crossed-section design, have focused on changes in lead-associated neurobehavioral dysfunctions that occur at increased blood lead levels. This study evaluates the changes in neurobehavioral performance of lead workers as blood levels are reduced. We tested 27 lead workers in a lead glaze factory using the computer-based and automated Chinese edition of Neurobehavioral Evaluation System 2 (C-NES II) in 1994, 1996, and 1997. The association of blood lead levels and C-NES II results were analyzed by longitudinal data analysis methods, repeated ANOVA and mixed model analyses after adjustment for potential confounders. Over these 4 years, the mean lead blood levels of workers were reduced from 26.3(SD=12.0) to 8.3(SD=6.9) microg/dL. Based on a mixed model analysis, we found that the negative effects of exposure to lead on neurobehavioral performance can be reversed to some extent with lowering levels of blood lead. During this period, we found significant improvements in 3 subtests: finger tapping, pattern comparison reaction time, and memory. This study tentatively concluded that reversibility of the neurobehavioral performance after reduction of the lead exposure, which encourages industrial hygiene and personal health promotion to reduce their body lead burden. However, though use of NES is more sensitive to detect the changes, the chronic symptoms (using standardized questionnaire) were found to decline slowly when blood lead level is reduced, with no statistically significant difference. The result means that to avoid the lead exposure primarily is essential to prevent chronic symptoms. We conclude that the most important way to prevent and possibly reverse chronic symptoms of lead poisoning remains to be the avoidance of exposure to lead.

Adult↗
PubMed2004

Differentiated thyroid carcinoma: the new UICC 6th edition TNM classification system in a retrospective analysis of 169 patients.

AIM: To compare the new, 6th edition, UICC TNM staging system with the former edition, we updated TNM staging in patients with differentiated thyroid carcinoma. METHODS: The new and old TNM classification systems for differentiated thyroid carcinoma were applied in a retrospective analysis of 169 patients who underwent therapy with radioiodine (131I) from 1975 through 2002 at the Department of Nuclear Medicine, Frankfurt. RESULTS: According to the new staging system, 83 patients (49%) were classified as T1 compared to 54 patients (32%) based on the former edition; 32 patients (19%) as T2 compared to 61 (36%) patients formerly. In 44 patients with minimal extrathyroid extension, formerly classified T4, the new TNM staging changed to T3, and no patient was classified T4. The one year relapse-free survival fraction under the former edition staging was 100% for T1 and 92.2% for T2, compared to 96.8% for new edition T1 and 93.3% for T2. CONCLUSION: The new TNM classification causes a significant change in staging. New T1 classified tumors had a slightly worse relapse-free survival fraction compared with the old T1 carcinomas. For patients treated at our department, the altered criteria for classifying extrathyroid extensions have had only a minor impact on disease management.

Disease-Free Survival↗
PubMed2006

Breast imaging and reporting data system (BIRADS): magnetic resonance imaging.

This article reviews the technical aspects and interpretation criteria in breast MR imaging based on the first edition of breast imaging and reporting data system (BIRADS) published by the American College of Radiology (ACR) in 2003. In a second article, practical cases will be proposed for training the readers. The major aims of using this lexicon are: first to use a logical and standardized description of MR lesions, secondly to obtain a structured MR report with a clear final impression (BIRADS assessment categories), and thirdly to help comparison between different clinical studies based on similar breast MRI terminology.

Breast Neoplasms↗
PubMed2026

Optimized TadA-derived base editors efficiently manipulate mRNA splicing by A-to-G and C-to-K editing in potato.

Pre-messenger RNA (pre-mRNA) splicing is a critical mechanism for post-transcriptional regulation in plants. Through alternative splicing, plants produce diverse transcriptomes and proteomes that finely regulate development as well as responses to biotic and abiotic stresses. However, modulating the generation of specific splicing isoforms for functional characterization remains challenging, particularly in the non-model crop potato. Here, we show that two optimized TadA-derived base editors efficiently induce diverse mRNA splice variants by targeting specific splice sites. By evaluating multiple adenosine deaminases and performing multi-dimensional optimization, we developed an efficient adenine base editor RTF-ABE8e for potato. RTF-ABE8e achieved 100% editing efficiency at two StDL1 target sites in stable transgenic potato, with homozygous editing frequencies as high as 93.3% and 91.1%, respectively. We also developed RTF-TadDE, a dual-base editor based on a TadA-derived dual deaminase, for A-to-G and C-to-K (K&#x2009;=&#x2009;T/G) mutations in potato with an overall editing efficiency comparable to that of RTF-ABE8e. By targeting different splice sites with these base editors, we obtained diverse splicing isoforms carrying premature termination codons (PTCs) at StDL1 and StPDS and robust mutant phenotypes. These base editors enable efficient and precise editing of splice sites to trigger missplicing, making them powerful tools for manipulating splicing in plants.

Solanum tuberosum↗
PubMed2003

Tertiary structure base pairs between D- and TpsiC-loops of Escherichia coli tRNA(Leu) play important roles in both aminoacylation and editing.

To ensure the fidelity of protein biosynthesis, aminoacyl-tRNA synthetases (aaRSs) must recognize the tRNA identity elements of their cognate tRNAs and discriminate their cognate amino acids from structurally similar ones through a proofreading (editing) reaction. For a better understanding of these processes, we investigated the role of tRNA(Leu) tertiary structure in the aminoacylation and editing reactions catalyzed by leucyl-tRNA synthetase (LeuRS). We constructed a series of Escherichia coli tRNA(Leu) mutated transcripts with alterations of the nucleotides involved in tertiary interactions. Our results revealed that any disturbance of the tertiary interaction between the tRNA(Leu) D- and TpsiC-loops affected both its aminoacylation ability and its ability to stimulate the editing reaction. Moreover, we found that the various tertiary interactions between the D- and TpsiC-loops (G18:U55, G19:C56 and U54:A58) functioned differently within the aminoacylation and editing reactions. In these two reactions, the role of base pair 19:56 was closely correlated and dependent on the hydrogen bond number. In contrast, U54:A58 was more important in aminoacylation than in editing. Taken together, our results suggest that the elbow region of tRNA formed by the tertiary interactions between the D- and TpsiC-loops affects the interactions between tRNA and aaRS effectively both in aminoacylation and in editing.

Acylation↗
PubMed1999

Nuclear genes from Tx CMS maintainer lines are unable to maintain atp6 RNA editing in any anther cell-type in the sorghum bicolor A3 cytoplasm.

RNA editing and cytoplasmic male sterility are two important phenomena associated with higher plant mitochondria. We recently have shown a potential function of RNA editing in CMS development. The frequency of atp6 RNA editing was specifically reduced in anthers of male-sterile Sorghum bicolor, which increased in frequency in partially restored progeny. Here we present data that show that the loss of RNA editing capability also occurs in a second nuclear background that allows the expression of male sterility. Loss of RNA editing thus appears to be associated with unique combinations of male-sterile cytoplasm and non-restoring nuclear backgrounds. In addition, the reduction of RNA editing affects both gametophytic and sporophytic anther cell-types but not other floral tissues. An analysis of F(2) plants exhibiting different levels of fertility indicates a co-segregation of fertility restoration and atp6 RNA editing. The atp6 transcript abundance is similar in seedlings and anthers of male-sterile, partially restored, and male-fertile lines and thus is not associated with loss of atp6 RNA editing in anthers. A model for RNA editing and male sterility based on the data available is presented. Functional correlations with other CMS systems are also discussed.

Cell Nucleus↗
PubMed2004

[Comment on guidelines for treatment of Parkinson's disease].

The guidelines for the therapy of Parkinson's disease (PD) based on the concept of evidence-based medicine (EBM) were edited by the Japanese Society of Neurology in 2002. The author described his impression of these guidelines from a user's viewpoint after using these guidelines. In the chapter on the therapeutic efficacy and safety of drugs, compared with other antiparkinsonian drugs, levodopa seems to be only briefly described. Because the therapy of PD highly depends on the effect of levodopa, a more detailed description of levodopa will be helpful for neurologists. In the chapter on general and detailed discussions, the use of a dopamine agonist (DA) for young PD patients is recommended because DA prevents motor complications; this is the most emphasized part based on the concept of EBM in the guidelines. Measures of managing various complications based on various lines of evidence and experiences of members of Ad hoc committee for the treatment of PD are well documented in this chapter. In general, since the guidelines are technical ones, they clearly describe how to treat PD patients. For the effective use of these guidelines, neurologists should have the ability to correctly determine PD symptoms, some knowledge about the pharmacology of antiparkinsonian drugs particularly levodopa and DA, and balanced thinking regarding the management of PD patients.

Evidence-Based Medicine↗