• Molecules and Cells
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• v.45 no.7
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• pp.454-464
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• 2022

DJ-1 is one of the causative genes of early-onset familial Parkinson's disease (PD). As a result, DJ-1 influences the pathogenesis of sporadic PD. DJ-1 has various physiological functions that converge to control the levels of intracellular reactive oxygen species (ROS). Based on genetic analyses that sought to investigate novel antioxidant DJ-1 downstream genes, pyruvate dehydrogenase (PDH) kinase (PDK) was demonstrated to increase survival rates and decrease dopaminergic (DA) neuron loss in DJ-1 mutant flies under oxidative stress. PDK phosphorylates and inhibits the PDH complex (PDC), subsequently downregulating glucose metabolism in the mitochondria, which is a major source of intracellular ROS. A loss-of-function mutation in PDK was not found to have a significant effect on fly development and reproduction, but severely ameliorated oxidative stress resistance. Thus, PDK plays a critical role in the protection against oxidative stress. Loss of PDH phosphatase (PDP), which dephosphorylates and activates PDH, was also shown to protect DJ-1 mutants from oxidative stress, ultimately supporting our findings. Further genetic analyses suggested that DJ-1 controls PDK expression through hypoxia-inducible factor 1 (HIF-1), a transcriptional regulator of the adaptive response to hypoxia and oxidative stress. Furthermore, CPI-613, an inhibitor of PDH, protected DJ-1 null flies from oxidative stress, suggesting that the genetic and pharmacological inhibition of PDH may be a novel treatment strategy for PD associated with DJ-1 dysfunction.

• Research in Plant Disease
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• v.30 no.3
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• pp.268-277
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• 2024

Erwinia pyrifoliae is a gram-negative bacterial pathogen that commonly causes black shoot blight in pear and apple tree. Although the pathogenicity of this bacterial species is very similar to E. amylovora, there is no specific explanation of its pathogenic genes and mechanisms. In this study, our investigation into E. pyrifoliae pathogenicity involved generating seven YKB12327 mutant strains using Tn5 transposon mutagenesis. Observations revealed weakened growth rate and loss of pathogenicity in these mutants. Whole-genome sequencing and alignment analysis identified transposon insertions within the coding sequences of five strains and in the intergenic region of two strains. Annotation analysis elucidated genes directly or indirectly associated with pathogenicity. Notably, mutant strain MT16 displayed a transposon insertion mutation in the cyclic-di-GMP phosphodiesterase (pdeF) gene, a key player in bacterial signaling, governing microbial behavior and adaptation to environmental changes. Our findings provide insights into the genetic regulation of E. pyrifoliae pathogenicity, suggesting potential avenues for further research aimed at understanding and controlling this bacterial pathogen by targeting pdeF to mitigate apple black shoot blight disease.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5671-5674
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• 2013

Incidence of breast cancer shows geographical variation, even within areas of ethnic homogeneity. Saudi Arabia has witnessed an increase in occurrence of breast cancer in its unexplored ethnic populations over the past few years. We aimed at determining whether any association exists between single nucleotide polymorphisms in breast cancer associated gene 1 (BRCA1) and breast cancer associated gene 2 (BRCA2) and the risk of breast cancer. TaqMan based Real Time Polymerase chain reaction genotyping assays were used to determine the frequency of single nucleotide polymorphisms in BRCA1 (rs799917) and BRCA2 (rs144848) in a group of 100 breast cancer patients and unaffected age matched controls of Saudi Arabian origin. The present data revealed that neither BRCA1 nor the BRCA2 studied variant show any significant association with the disease. This study failed to find any role of the concerned variants in breast cancer either as risk or as prognostic factors. The small number of patients registered was one of the limitations of this study. In summary, comparison of mutation profile with other ethnic populations and regions reflected both differences and similarities indicating co-exposure to a unique set of risk factors. The differences could be due to exposure to particular environmental carcinogens; different lifestyle, reproductive pattern; dietary or cultural practices of Saudi Arabian women that need further investigations.

• The Plant Pathology Journal
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• v.36 no.3
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• pp.218-230
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• 2020

Net blotch of barley caused by Pyrenophora teres (Died.) Drechsler, is one of the most destructive diseases on barley in Algeria. It occurs in two forms: P. teres f. teres and P. teres f. maculata. A total of 212 isolates, obtained from 58 fields sampled in several barley growing areas, were assessed for fungicide sensitivity by target gene analysis. F129L and G137R mitochondrial cytochrome b substitution associated with quinone outside inhibitors (QoIs) resistance, and succinate dehydrogenase inhibitors (SDHIs) related mutations (B-H277, C-N75S, C-G79R, C-H134R, and C-S135R), were analyzed by pyrosequencing. In vitro sensitivity of 45 isolates, towards six fungicides belonging to three chemical groups (QoI, demethylase inhibitor, and SDHI) was tested by microtiter technique. Additionally, sensitivity towards three fungicides (azoxystrobin, fluxapyroxad, and epoxiconazole) was assessed in planta under glasshouse conditions. All tested isolates were QoI-sensitive and SDHI-sensitive, no mutation that confers resistance was identified. EC₅₀ values showed that pyraclostrobin and azoxystrobin are the most efficient fungicides in vitro, whereas fluxapyroxad displayed the best disease inhibition in planta (81% inhibition at 1/9 of the full dose). The EC₅₀ values recorded for each form of net blotch showed no significant difference in efficiency of QoI treatments and propiconazole on each form. However, in the case of fluxapyroxad, epoxiconazole and tebuconazole treatments, analysis showed significant differences in their efficiency. To our knowledge, this study is the first investigation related to mutations associated to QoI and SDHI fungicide resistance in Algerian P. teres population, as well as it is the first evaluation of the sensitivity of P. teres population towards these six fungicides.

• Radiation Oncology Journal
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• v.26 no.1
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• pp.65-73
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• 2008

Purpose: Women with breast cancer diagnosed at an age of 40 years or younger have a greater prevalence of germline BRCA1 and BRCA2 mutations than the prevalence of women with breast cancer diagnosed at older ages. Several immunohistochemical characteristics have been identified in breast cancers from studies of Caucasian women with BRCA1/2 mutations having familial or early-onset breast cancers. The aim of this study is to determine whether early-onset breast cancer in BRCA1 or BRCA2 mutation carriers, who were not selected from a family history, could be distinguished by the use of immunohistochemical methods and could be distinguished from breast cancer in women of a similar age without a germline BRCA1 or BRCA2 mutation. We also analyzed the prognostic difference between BRCA1/2 related and BRCA1/2 non-related patients by the use of univariate and multivariate analysis. Materials and Methods: Breast cancer tissue specimens from Korean women with early-onset breast cancers were studied using a tumor tissue microarray. Immunohistochemical staining of estrogen receptor(ER), progesterone receptor(PR) and HER-2, as well as the histology and grade of these specimens, were compared. The prognostic impact of immunohistochemical and histological factors as well as the BRCA1/2 mutation status was investigated separately. Results: There were 14 cases and 16 deleterious BRCA1/2 mutations among 101 patients tested. A family history(4/14) and bilateral breast cancers(3/9) were high risk factors for BRCA1/2 mutations. BRCA1/2-associated cancers demonstrated more expression of ER-negative(19.4% versus 5.1%, p=0.038) and HER-2 negative than BRCA1/2 negative tumors, especially for tumors with BRCA1 tumors The BRCA1/2 mutation rate for patients with triple negative tumors(negative expression of ER, PR and HER-2) was 24.2%. Tumor size, nodal status, and HER-2 expression status were significantly associated with disease free survival, as determined by univariate and multivariate analysis, but the BRCA1/2 status was not a prognostic factor. Conclusion: Breast cancer that occurs in women with a germline BRCA1 or BRCA2 mutations have recognizable immunohistochemical features, which may be useful in identifying individuals that are more likely to carry germline mutations. Although the BRCA1/2 mutation status was not a prognostic factor in Korean women with early-onset breast cancer, more cases with a longer follow-up period are needed for further study.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.23 no.1
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• pp.25-30
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• 2023

Leigh syndrome is a rare progressive neurodegenerative mitochondrial disorder with clinical and genetic heterogeneity. Recently, balletic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes from Leigh and West syndrome to a rare syndrome CAGSSS characterized by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia syndrome (OMIM#616007). We describe a child with Korean Leigh syndrome with urologic manifestations resulting from a compound heterozygote mutation in IARS2. A 5-year-old girl visited the emergency room with a complaint of abdominal pain accompanied by abdominal distension. Abdominal-pelvic CT showed a markedly distended urinary bladder without definite obstructive lesions. She was diagnosed with neurogenic bladder dysfunction based on a urodynamic study. She had global delayed development due to neurologic regression after 6 months of age and a history of bilateral cataract surgery at the age of 2 years. Her brain magnetic resonance imaging showed symmetrically increased signal intensities in the bilateral putamen and caudate nuclei with diffuse cerebral atrophy. No gene variants were identified through whole-mitochondrial genome analysis. Whole exome sequencing was performed for diagnosis, and compound heterozygous pathogenic variants were identified in IARS2: c.2446C>T (p. Arg816Ter) and c.2450G>A (p. Arg817His). To the best of our knowledge, this is the first case report of bladder dysfunction manifestation in a patient with IARS2-related Leigh syndrome. Thus, it broadens the clinical and genetic spectrum of IARS2-associated diseases.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.15 no.2
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• pp.87-92
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• 2015

Mucopolysaccharidosis (MPS) is an inherited disease entity associated with lysosomal enzyme deficiencies. MPS type 2, also known as Hunter syndrome, has a characteristic morphology primarily involving x-l inked recessive defects and iduronate-2-sulfatase gene mutation. The purpose of this case report is to provide important clues to help pediatricians identify Hunter syndrome patients earlier (i.e., before the disease progresses). A 30-month-old boy showed developmental delay and decreased speech ability. Physical examinations revealed a flat nose and extensive Mongolian spots. Brain magnetic resonance images (MRIs) showed bilateral multiple patchy T2 hyperintense lesions in the periventricular and deep white matter, several cyst-like lesions in the body of the corpus callosum, and diffuse brain atrophy, which were in keeping with the diagnosis. Based on these findings, the patient was suspected of having MPS. In the laboratory findings, although the genetic analysis of IDS (Iduronate-2-sulfatase) did not show any pathogenic variant, the enzymatic activity of IDS was not detected. We could confirm the diagnosis of MPS, because other sulfatases, such as ${\alpha}$-L-iduronidase, were detected in the normal range. Early enzymatic replacement therapy is essential and has a relatively good prognosis. Therefore, early diagnosis should be made before organ damage becomes irreversible, and brain MRIs can provide additional diagnostic clues to help distinguish the disorder.

• Journal of Physiology & Pathology in Korean Medicine
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• v.17 no.3
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• pp.719-727
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• 2003

Background and purpose: Hypertension and obesity has been implicated in the most important risk factors for stroke. The original finding that the G-protein beta3 subunit (GNB3) C825T allele associates with essential hypertension and obesity has been confirmed in several different populations. Hence, our objective was to determine whether the GNB3 C825T polymorphism predicts interindividual variation in stroke. Method: We recruited 361 stroke patients (cerebral infarction, n=278; intracerebral hemorrhage (ICH), n=83) and 199 healthy control subjects. Subjects were genotyped for GNB3 C825T mutation and findings were investigated for association with stroke. Result: The GNB3 T/T type was significantly associated with cerebral infarction prevalence (OR, 1.98; 95% Cl, 1.14-3.46; p=0.015). While, ICH was not found to be significantly associated with GNB3 T/T type (OR, 1.63; 95% ICH, 0.74-3.56; p=0.219). Similarly, no significant association was determined between GNB T/C type, and cerebral infarction (OR, 1.09; 95% Cl, 0.68-1.74; p=0.716), and ICH (OR, 1.14; 95% Cl, 0.59-2.21; p=0.697). Conclusion: In clinical characteristics, this study shows no differences among GNB3 genotypes, that are BMI, WH ratio. hypertension rate, and ischemic heart disease rate, total lipid level, triglycerides level, total cholesterol level, HDL cholesterol level, prothrombine time, with the exception of LDL cholesterol concentrations. However, our subjects showed an inverse relationship between LDL cholesterol level and the risk of cerebral infarction. We have shown that the GNB3 T/T genotype is strongly associated with cerebral infarction. (OR, 1.98; 95% Cl, 1.14-3.46; p=0.015).

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.2707-2712
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• 2015

Background: The human homologue of the mouse double minute 2 (MDM2) gene is a negative regulator of Tp53. MDM2-309T>G a functional promoter polymorphism was found to be associated with overexpression thereby attenuation of Tp53 stress response and increased cancer susceptibility. We have planned to evaluate the possible role of MDM2-309T>G polymorphism with risk and response to chemotherapy in AML. Materials and Methods: A total of 223 de novo AML cases and 304 age and sex matched healthy controls were genotyped for the MDM2-309T>G polymorphism through the tetra-primer amplification refractory mutation system (ARMS)-PCR method. In order to assess the functional relationship of -309T>G SNP with MDM2 expression level, we quantified MDM2 mRNA in 30 primary AML blood samples through quantitative RT-PCR. Both the (-309T>G) genotypes and the MDM2 expression were correlated with disease free survival (DFS) rates among patients who have achieved complete remission (CR) after first induction chemotherapy. Results: MDM2-309T>G polymorphism was significantly associated with AML development (p<0.0001). The presence of either GG genotype or G allele at MDM2-309 confered 1.79 (95% CI: 1.12-2.86; p<0.001) and 1.46 fold (95%CI: 1.14-1.86; p= 0.003) increased AML risk. Survival analysis revealed that CR+ve cases with GG genotype had significantly increased DFS rates (16months, p=0.05) compared to CR+ve TT (11 months) and TG (9 months) genotype groups. Further, MDM2 expression was also found to be significantly elevated in GG genotype patients (p=0.0039) and among CR+ve cases (p=0.0036). Conclusions: The MDM2-309T>G polymorphism might be involved in AML development and also serve as a good prognostic indicator.

• Radiation Oncology Journal
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• v.26 no.4
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• pp.204-212
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• 2008

Purpose: This study was performed to evaluate the disease-free survival and risk factors of recurrence in early breast cancer patients who have undergone breast conserving surgery and radiation therapy. Materials and Methods: From March 1997 to December 2002, 77 breast cancer patients who underwent breast conserving surgery and radiation therapy were reviewed retrospectively. The median follow-up time was 58.4 months (range $43.8{\sim}129.4$ months) and the mean subject age was 41 years. The frequency distribution of the different T stages, based on the tumor characteristics was 38 (49.3%) for T1, 28 (36.3%) for T2, 3 for T3, 7 for T is and 1 for an unidentified sized tumor. In addition, 52 patients (67.5%) did not have axillary lymph metastasis, whereas 14 patients (18.1%) had $1{\sim}3$ lymph node metastases and 3 (0.03%) had more than 4 lymph node metastases. The resection margin was negative in 59 patients, close (${\leq}2\;mm$) in 15, and positive in 4. All patients received radiation therapy at the intact breast using tangential fields with a subsequent electron beam boost to the tumor bed at a total dose ranging from 59.4 Gy to 66.4 Gy. Patients with more than four positive axillary lymph nodes received radiation therapy ($41.4{\sim}60.4\;Gy$) at the axillary and supraclavicular area. Chemotherapy was administered in 59 patients and tamoxifen or fareston was administered in 29 patients. Results: The 5 year overall survival and disease-free survival rates were 98.08% and 93.49%, respectively. Of the 77 patients, a total of 4 relapses (5.2%), including 1 isolated supraclavicular relapse, 1 supraclavicular relapse with synchronous multiple distant relapses, and 2 distant relapses were observed. No cases of local breast relapses were observed. Lymph node metastasis or number of metastatic lymph nodes was not found to be statistically related with a relapse (p=0.3289) nor disease-free survival (p=0.1430). Patients with positive margins had a significantly shorter disease-free survival period (p<0.0001) and higher relapse rates (p=0.0507). However, patients with close margins were at equal risk of relapse and disease-free survival as with negative margins (p=1.000). Patients younger than 40 years of age had higher relapse rates (9.3% vs. 0%) and lower disease-free survival periods, but the difference was not statistically significant (p=0.1255). The relapse rates for patients with tumors was 14% for tumor stage T2, compared to 0% for tumor stage T1 tumors (p=0.0284). A univariate analysis found that disease-free survival and relapse rates, T stage, positive resection margin and mutation of p53 were significant factors for clinical outcome. Conclusion: The results of this study have shown that breast conservation surgery and radiation therapy in early breast cancer patients has proven to be a safe treatment modality with a low relapse rate and high disease-free survival rate. The patients with a positive margin, T2 stage, and mutation of p53 are associated with statistically higher relapse rates and lower disease-free survival.