Dual oxidase maturation factor 2 (DUOXA2) is necessary for the enzymatic activity of dual oxidase 2 (DUOX2) to generate hydrogen peroxide production during thyroid hormone synthesis. We describe two Korean children, who were initially suspected to have transient congenital hypothyroidism (CH), but later confirmed to have permanent CH caused by DUOXA2 mutation. Treatment with levothyroxine was discontinued after confirming thyroid-stimulating hormone (TSH) level to be below 10 μU/mL and normal thyroid scan at the first or second trial-off therapy. However, after therapy cessation, TSH elevated to more than 10 μU/mL, and goiter developed in case 2. As a result, levothyroxine was resumed. Next-generation sequencing showed compound heterozygous mutations of DUOXA2 at Y138X and Y246X in case 1 and homozygous mutations of DUOXA2 at Y246X in case 2. In this report, a longer follow-up is recommended even after treatment termination in transient CH, and genetic studies might help assess the permanence of hypothyroidism in cases of mildly elevated TSH after trial-off therapy.

Background: Few studies evaluate the epidemiology and risk factors of Clostridioides difficile infection (CDI) in Asian patients with inflammatory bowel disease (IBD). We investigated the year-end prevalence, cumulative incidence and risk factors of CDI in Asian patients with IBD using a large-scale population-based cohort in Korea. Methods: Using the National Health Insurance Service database, we identified patients with IBD and sex- and age-matched controls without IBD between 2008 and 2018. The year-end prevalence and cumulative incidence of CDI were compared among patients with Crohn’s disease (CD) and ulcerative colitis (UC) with controls. The risk factors for CDI were evaluated. Results: Among the 54,836 patients with IBD and 109,178 controls, CDI occurred in 293 patients with IBD and 87 controls. The annual year-end prevalence of CDI in patients with IBD increased from 8.6/10,000 persons in 2008 to 22.3/10,000 persons in 2018. The risk of CDI was higher in both patients with CD and UC than that in the matched controls (hazard ratio [HR], 7.285; 95% confidence interval [CI], 5.388–9.851; P < 0.001 and HR, 7.487; 95% CI, 5.796–9.670; P < 0.001, respectively). Among patients with IBD, the risk factors for CDI included older age, female sex, high Charlson comorbidity index score, and IBD-related medications including oral 5-aminosalicylic acid, immunomodulatory agents, biologics, and steroids used for > 90 days. Conclusion The risk of CDI in Korean patients with IBD was approximately seven times higher than that in controls without IBD, and the annual year-end prevalence of CDI continuously increased from 2008 to 2018.

BACKGROUND: Although the World Health Organization (WHO) classification of lung squamous cell carcinoma (SCC) was revised in 2015, its clinical implications for lung SCC subsets remain unclear. We investigated whether the morphologic characteristics of lung SCC, including keratinization, were associated with clinical parameters and clinical outcome of patients. METHODS: A total of 81 patients who underwent curative surgical resection of diagnosed lung SCC, were enrolled in this study. Attributes such as keratinization, tumor budding, single cell invasion, and nuclear size within the tumor, as well as immunohistochemistry of Bcl-xL and pS6 expressions, were evaluated. RESULTS: The keratinizing and nonkeratinizing subtypes did not differ with respect to age, sex, TNM stage, and morphologic parameters such as nuclear diameter, tumor budding, and single cell invasion at the tumor edge. Most patients with the keratinizing subtype (98.0%) had a history of smoking, whereas the nonkeratinizing group had a relatively higher proportion of never-smokers relative to the keratinizing group (24.0% vs. 2.0%; p=0.008, chi-square test). Expression of pS6 (a surrogate marker of mammalian target of rapamycin complex 1 [mTORC1] signaling that regulates keratinocyte differentiation), and Bcl-xL (a key anti-apoptotic molecule that may inhibit keratinization), did not correlate significantly with the presence of keratinization. Patients with the keratinizing subtype had a significantly shorter overall survival (85.2 months vs. 135.7 months, p=0.010, log-rank test), and a multivariate analysis showed that keratinization was an independent, poor prognostic factor (hazard ratio, 2.389; 95% confidence interval, 1.090–5.233; p=0.030). CONCLUSION: In lung SCC, keratinization is associated with a poor prognosis, and might be associated with smoking.
bcl-X Protein ; Biomarkers ; Carcinoma, Squamous Cell* ; Classification ; Epithelial Cells* ; Humans ; Immunohistochemistry ; Keratinocytes ; Lung* ; Multivariate Analysis ; Prognosis ; Sirolimus ; Smoke ; Smoking ; World Health Organization

Purpose: Tumor radioresistance and dose-limiting toxicity restrict the curative potential of radiotherapy, requiring novel approaches to overcome the limitations and augment the efficacy. Here, we investigated the effects of signal transducer and activator of transcription 3 (STAT3) activation and autophagy induction by irradiation on antiapoptotic proteins and the effectiveness of the BH3 mimetic ABT-737 as a radiosensitizer using K-ras mutant non-small cell lung cancer (NSCLC) cells and a Kras G12D :p53 fl/fl mouse (KP mouse) model. Materials and Methods: A549 and H460 cells were irradiated, and the expression of Bcl-2 family proteins, JAK/STAT transcriptional pathway, and autophagic pathway were evaluated by immunoblotting. The radiosensitizing effects of ABT-737 were evaluated using A549 and H460 cell lines with clonogenic assays and also by a KP mouse model with microcomputed tomography and immunohistochemistry. Results: In A549 and H460 cells and mouse lung tissue, irradiation-induced overexpression of the antiapoptotic molecules BclxL, Bcl-2, Bcl-w, and Mcl-1 through JAK/STAT transcriptional signaling induced dysfunction of the autophagic pathway. After treatment with ABT-737 and exposure to irradiation, the number of surviving clones in the cotreatment group was significantly lower than that in the group treated with radiation or ABT-737 alone. In the KP mouse lung cancer model, cotreatment with ABT-737 and radiation-induced significant tumor regression; however, body weight changes in the combination group were not significantly different, suggesting that combination treatment did not cause systemic toxicity. Conclusion These findings supported the radiosensitizing activity of ABT-737 in preclinical models, and suggested that clinical trials using this strategy may be beneficial in K-ras mutant NSCLC.

PURPOSE: Patients with ovotesticular disorder of sex development (DSD) and mixed gonadal dysgenesis (MGD) usually present with asymmetric gonads and have wide phenotypic variations in internal and external genitalia. The differential diagnosis of these conditions is based on karyotype and pathological findings of the gonads. This study investigated the clinical features at presentation, karyotype, sex of rearing, and pubertal outcomes of patients with ovotesticular DSD and MGD.METHODS: The study comprised 23 patients with DSD who presented with asymmetric gonads. The presenting features, karyotype, sex of rearing, and pubertal outcomes were reviewed retrospectively.RESULTS: All 23 patients presented with ambiguous genitalia at a median age of 1 month (range, 1 day–1.6 years). Müllerian duct remnants were identified in 15 of 23 patients (65.2%). Fourteen patients were diagnosed with ovotesticular DSD, whereas the other 9 were diagnosed with MGD. Eight of 14 patients (57.1%) with ovotesticular DSD were raised as males, while 7 of 9 patients with MGD (77.8%) were assigned as males. One male-assigned patient with ovotesticular DSD changed to female sex at age 20 years.CONCLUSION: Patients with ovotesticular DSD and MGD manifest overlapping clinical presentations and hormonal profiles. It is difficult to determine the sex of rearing and predict long-term pubertal outcomes. Therefore, long-term follow-up is required to monitor spontaneous puberty, sex outcome, and urological and gynecological complications.
Adolescent ; Diagnosis, Differential ; Disorders of Sex Development ; Female ; Follow-Up Studies ; Genitalia ; Gonadal Dysgenesis ; Gonadal Dysgenesis, Mixed ; Gonads ; Humans ; Karyotype ; Male ; Ovotesticular Disorders of Sex Development ; Puberty ; Retrospective Studies

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype lacking targeted therapies and is characterized by highrecurrence rates and poor prognosis. Recent advances in targeting DNA damage response (DDR) pathways using poly (ADP‒ri-bose) polymerase (PARP) inhibitors offer promising therapeutic strategies, especially for TNBC patients with BRCA1/2 mutations.This study reports the development and characterization of ART-446, a novel and selective CHK2 inhibitor. ART-446 showed potent activity against TNBC, regardless of BRCA deficiency, and it also reversed PARP inhibitor resistance. ART-446 potentlyinhibited CHK2 (IC50 : 9.06 nM) with high selectivity over other kinases; it synergized with the PARP inhibitor olaparib, enhancingDNA damage, inducing G2/M cell cycle arrest, and promoting apoptosis in both BRCA-mutant and wild-type TNBC cells. Mechanistic analyses revealed that ART-446 sensitized BRCA mutant and WT cells to PARP inhibitors by impairing DNA repair and increasing the accumulation of DNA damage. Importantly, ART-446 disrupted both homologous recombination and nonhomologous end-joining repair pathways, addressing a key limitation of PARP inhibitor monotherapy—resistance in BRCA-proficient cancers.In vivo, the combination of ART-446 and olaparib significantly reduced tumor growth in TNBC xenograft models without noticeable toxicity. The combined treatment increased DNA damage signaling, as evidenced by elevated γH2AX levels, and enhanced the sensitivity of BRCA2-deficient cells to ART-446. These findings underscore the potential of ART-446 to exploit DNA repair deficiencies and overcome resistance mechanisms associated with PARP inhibitors. By addressing the limitations of current treatments and expanding the utility of PARP inhibitors, ART-446 represents a promising candidate for DDR-targeted therapies, offering a novel approach to improve the outcomes of patients with TNBC.

While advances in cancer treatment have led to improved survival rates, cancer survivors are at a significant risk of developing atherosclerotic cardiovascular disease (ASCVD).This review examines the risk, diagnosis, and prevention of ASCVD in this population.Cancer survivors, especially those diagnosed with certain types, face a significantly higher risk of developing ASCVD than the general population. We introduce the “triad model” to explain this increased risk of ASCVD among cancer patients. This model includes three interconnected components: common catalysts, cancer influence, and treatment impact.The factors contributing to this model are the shared risk factors between cancer and ASCVD, such as smoking, obesity, and systemic inflammation; the direct effects of cancer on cardiovascular health through chronic systemic inflammation and endothelial damage;and the significant effects of anticancer treatments, including chemotherapy and radiation, which can worsen cardiovascular complications and hasten the progression of ASCVD.Furthermore, cancer survivors are at a higher risk of developing and dying from ASCVD, highlighting the necessity for tailored guidelines and strategies for ASCVD prevention and management in this population. The review explores the utility of diagnostic tools, such as coronary artery calcium scoring, in predicting and managing ASCVD risk. It also emphasizes the importance of prevention strategies that include regular cardiovascular monitoring and lifestyle modifications. Finally, the relationship between cancer survival and cardiovascular health highlights the importance of integrated and comprehensive care approaches.Continued research, the development of prediction models, and specific preventative strategies are essential to improve cancer survivors’ overall health outcomes.

While advances in cancer treatment have led to improved survival rates, cancer survivors are at a significant risk of developing atherosclerotic cardiovascular disease (ASCVD).This review examines the risk, diagnosis, and prevention of ASCVD in this population.Cancer survivors, especially those diagnosed with certain types, face a significantly higher risk of developing ASCVD than the general population. We introduce the “triad model” to explain this increased risk of ASCVD among cancer patients. This model includes three interconnected components: common catalysts, cancer influence, and treatment impact.The factors contributing to this model are the shared risk factors between cancer and ASCVD, such as smoking, obesity, and systemic inflammation; the direct effects of cancer on cardiovascular health through chronic systemic inflammation and endothelial damage;and the significant effects of anticancer treatments, including chemotherapy and radiation, which can worsen cardiovascular complications and hasten the progression of ASCVD.Furthermore, cancer survivors are at a higher risk of developing and dying from ASCVD, highlighting the necessity for tailored guidelines and strategies for ASCVD prevention and management in this population. The review explores the utility of diagnostic tools, such as coronary artery calcium scoring, in predicting and managing ASCVD risk. It also emphasizes the importance of prevention strategies that include regular cardiovascular monitoring and lifestyle modifications. Finally, the relationship between cancer survival and cardiovascular health highlights the importance of integrated and comprehensive care approaches.Continued research, the development of prediction models, and specific preventative strategies are essential to improve cancer survivors’ overall health outcomes.

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype lacking targeted therapies and is characterized by highrecurrence rates and poor prognosis. Recent advances in targeting DNA damage response (DDR) pathways using poly (ADP‒ri-bose) polymerase (PARP) inhibitors offer promising therapeutic strategies, especially for TNBC patients with BRCA1/2 mutations.This study reports the development and characterization of ART-446, a novel and selective CHK2 inhibitor. ART-446 showed potent activity against TNBC, regardless of BRCA deficiency, and it also reversed PARP inhibitor resistance. ART-446 potentlyinhibited CHK2 (IC50 : 9.06 nM) with high selectivity over other kinases; it synergized with the PARP inhibitor olaparib, enhancingDNA damage, inducing G2/M cell cycle arrest, and promoting apoptosis in both BRCA-mutant and wild-type TNBC cells. Mechanistic analyses revealed that ART-446 sensitized BRCA mutant and WT cells to PARP inhibitors by impairing DNA repair and increasing the accumulation of DNA damage. Importantly, ART-446 disrupted both homologous recombination and nonhomologous end-joining repair pathways, addressing a key limitation of PARP inhibitor monotherapy—resistance in BRCA-proficient cancers.In vivo, the combination of ART-446 and olaparib significantly reduced tumor growth in TNBC xenograft models without noticeable toxicity. The combined treatment increased DNA damage signaling, as evidenced by elevated γH2AX levels, and enhanced the sensitivity of BRCA2-deficient cells to ART-446. These findings underscore the potential of ART-446 to exploit DNA repair deficiencies and overcome resistance mechanisms associated with PARP inhibitors. By addressing the limitations of current treatments and expanding the utility of PARP inhibitors, ART-446 represents a promising candidate for DDR-targeted therapies, offering a novel approach to improve the outcomes of patients with TNBC.

While advances in cancer treatment have led to improved survival rates, cancer survivors are at a significant risk of developing atherosclerotic cardiovascular disease (ASCVD).This review examines the risk, diagnosis, and prevention of ASCVD in this population.Cancer survivors, especially those diagnosed with certain types, face a significantly higher risk of developing ASCVD than the general population. We introduce the “triad model” to explain this increased risk of ASCVD among cancer patients. This model includes three interconnected components: common catalysts, cancer influence, and treatment impact.The factors contributing to this model are the shared risk factors between cancer and ASCVD, such as smoking, obesity, and systemic inflammation; the direct effects of cancer on cardiovascular health through chronic systemic inflammation and endothelial damage;and the significant effects of anticancer treatments, including chemotherapy and radiation, which can worsen cardiovascular complications and hasten the progression of ASCVD.Furthermore, cancer survivors are at a higher risk of developing and dying from ASCVD, highlighting the necessity for tailored guidelines and strategies for ASCVD prevention and management in this population. The review explores the utility of diagnostic tools, such as coronary artery calcium scoring, in predicting and managing ASCVD risk. It also emphasizes the importance of prevention strategies that include regular cardiovascular monitoring and lifestyle modifications. Finally, the relationship between cancer survival and cardiovascular health highlights the importance of integrated and comprehensive care approaches.Continued research, the development of prediction models, and specific preventative strategies are essential to improve cancer survivors’ overall health outcomes.