LC3B drives transcription-associated homologous recombination via direct interaction with R-loops.

Exploring the connection between ubiquitin-like modifiers (ULMs) and the DNA damage response (DDR), we employed several advanced DNA damage and repair assay techniques and identified a crucial role for LC3B. Notably, its RNA recognition motif (RRM) plays a pivotal role in the context of transcription-associated homologous recombination (HR) repair (TA-HRR), a particular subset of HRR pathways. Surprisingly, independent of autophagy flux, LC3B interacts directly with R-loops at DNA lesions within transcriptionally active sites via its RRM, promoting TA-HRR. Using native RNA immunoprecipitation (nRIP) coupled with high-throughput sequencing (nRIP-seq), we discovered that LC3B also directly interacts with the 3'UTR AU-rich elements (AREs) of BRCA1 via its RRM, influencing its stability. This suggests that LC3B regulates TA-HRR both proximal to and distal from DNA lesions. Data from our LC3B depletion experiments showed that LC3B knockdown disrupts end-resection for TA-HRR, redirecting it towards the non-homologous end joining (NHEJ) pathway and leading to chromosomal instability, as evidenced by alterations in sister chromatid exchange (SCE) and interchromosomal fusion (ICF). Thus, our findings unveil autophagy-independent functions of LC3B in DNA damage and repair pathways, highlighting its importance. This could reshape our understanding of TA-HRR and the interaction between autophagy and DDR.

Causes of death and associated factors with death after liver transplantation: a nationwide database study.

BACKGROUND/AIMS: This study investigated overall, 1-year, and 5-year mortality rate, the causes of death, and associated factors with death in liver transplantation recipients. METHODS: A total of 11,590 liver transplant recipients identified from National Health Insurance Service database between 2006 and 2017 were included. Factors associated with all-cause of death were analyzed by Cox proportional regression models. Cumulative mortality rate according to the underlying indication was estimated by Kaplan-Meier method. RESULTS: The 12-year survival rate for all liver transplant recipients was 68%. In the overall, 1-year, and 5-year mortality of liver transplant recipients, hepatic death was the highest contributing risk, accounting for >65% of the causes of death. Deaths from cirrhosis and liver failure accounted for a high proportion of deaths within 1 year after transplantation, and deaths from malignant tumors such as hepatocellular carcinoma were high among late-stage deaths. DISCUSSION: Although the most common cause of death from liver transplantation is due to primary disease, there was a difference in the pattern of major causes of death according to the period from transplantation to death. If appropriate medical intervention is performed at each period after transplantation, the survival rate can be improved.

Secondary Malignancies in Multiple Myeloma in Korean Patients: A Nationwide Population-Based Study.

Purpose: This study investigated the incidence of secondary malignancy in multiple myeloma (MM) patients compared with that in the general population using a population-based database covering all residents in Korea. Materials and Methods: Based on the national health insurance system in Korea, all people primarily diagnosed with MM between January 1, 2010 to December 31, 2018 were identified. A total of 9,985 MM patients aged ≥20 years in Korea were included. Results: Among them, 237 (2.4%) developed secondary malignancies by 2018. The standardized incidence rates (SIRs) of all secondary malignancies in MM patients were 0.87 (95% confidence interval [CI]=0.76-0.98), with a higher incidence of hematologic malignancies than in the general population with an SIR of 3.80 (95% CI=2.61-5.00). The incidence rates of both lymphoid malignancy (SIR=3.56; 95% CI=2.31-4.82) and myeloid malignancy (SIR=3.78; 95% CI=1.16-6.39) were higher in MM patients than in the general population. In contrast, a lower incidence of solid cancer was observed in MM patients than in the general population (SIR=0.76, 95% CI=0.65-0.86). There was no significant difference in survival in MM patients without secondary malignancies, with hematologic malignancy, and with solid cancer (p-value=0.413). Conclusion: MM patients had a greater risk of secondary malignancies, especially hematologic malignancies, than the general population. Future studies with a focus on analyzing patients' history, treatment details, and genetic information in various stages of MM patients are needed to better understand the mechanism behind this increased risk.

Sex Differences in Attitudes Toward Marriage and Childbearing Based on the Assumption of Being BRCA1/2 Mutation Carriers Among Young People.

PURPOSE: This study investigated changes in attitudes toward marriage and childbearing assuming a BRCA1/2 mutation carrier status among healthy, unmarried individuals in Korea. METHODS: A nationally representative sample of healthy, unmarried individuals aged 20-39 years was surveyed. A questionnaire on marriage and childbearing intentions was administered to the participants before and after providing them with information on BRCA1/2 mutation carriers' breast and ovarian cancer risks and their autosomal dominant inheritance pattern. The participants were asked about their attitudes toward childbearing through preimplantation genetic diagnosis (PGD). RESULTS: Of the participants who initially wanted to marry, the assumption that they or their partners had BRCA1/2 mutation caused 25.3% to no longer want to get married and 36.2% to change their attitude from wanting to bear children to no longer wanting them. Females were more likely than males to change their attitudes toward marriage and childbearing. The participants who had negative attitudes toward genetic testing were more likely to change their attitudes regarding marriage and childbearing than those who were favorable toward both disclosure and testing. More than 50% of the participants who did not want children were willing to bear children through PGD when it was assumed that they were BRCA mutation carriers. CONCLUSION: On the assumption of being carriers, general, young, and healthy females were more likely than males to negatively change their attitudes toward marriage and childbearing. Public education on the implications of living with mutation carriers and reproductive options may be required.

Attitudes toward Risk-Reducing Mastectomy and Risk-Reducing Salpingo-oophorectomy among Young, Unmarried, Healthy Women in Korea.

PURPOSE: This study investigated the attitudes toward risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) as cancer prevention options for BRCA1/2 carriers in healthy, young, unmarried Korean women. MATERIALS AND METHODS: A nationally representative sample of 600 women, aged 20-39 years, completed a questionnaire on sociodemographic variables, preference for genetic testing, and intention to undergo risk-reducing surgeries after receiving information on the cancer risk of BRCA1/2 mutations and benefits of risk-reducing surgeries. RESULTS: A total of 54.7% and 57.7% had the intention to undergo RRM and RRSO, respectively, on the assumption that they were BRCA1/2 carriers. Older age and no intention to undergo genetic testing were associated with a reduced likelihood of undergoing RRM (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.14 to 0.61 for age 35-39 years and OR, 0.35; 95% CI, 0.20 to 0.62 for no intention for genetic testing) and RRSO (OR, 0.39; 95% CI, 0.19 to 0.79 for age 35-39 years and OR, 0.30; 95% CI, 0.17 to 0.53 for no intention for genetic testing). Women who chose to be single were likely to undergo risk-reducing surgeries (OR, 1.67; 95% CI, 1.07 to 2.60 for RRM and OR, 1.56; 95% CI, 1.00 to 2.44 for RRSO). CONCLUSION: More than 50% of healthy, unmarried, young Korean women were inclined to undergo prophylactic surgeries if they were BRCA1/2 mutation carriers. Further studies on decision-making process for cancer prevention in individuals at high risk for cancer need to be conducted.

USP39 promotes non-homologous end-joining repair by poly(ADP-ribose)-induced liquid demixing.

Mutual crosstalk among poly(ADP-ribose) (PAR), activated PAR polymerase 1 (PARP1) metabolites, and DNA repair machinery has emerged as a key regulatory mechanism of the DNA damage response (DDR). However, there is no conclusive evidence of how PAR precisely controls DDR. Herein, six deubiquitinating enzymes (DUBs) associated with PAR-coupled DDR were identified, and the role of USP39, an inactive DUB involved in spliceosome assembly, was characterized. USP39 rapidly localizes to DNA lesions in a PAR-dependent manner, where it regulates non-homologous end-joining (NHEJ) via a tripartite RG motif located in the N-terminus comprising 46 amino acids (N46). Furthermore, USP39 acts as a molecular trigger for liquid demixing in a PAR-coupled N46-dependent manner, thereby directly interacting with the XRCC4/LIG4 complex during NHEJ. In parallel, the USP39-associated spliceosome complex controls homologous recombination repair in a PAR-independent manner. These findings provide mechanistic insights into how PAR chains precisely control DNA repair processes in the DDR.

De Novo Cancer Incidence after Cholecystectomy in Korean Population.

Background: Cancer development after cholecystectomy remains debatable. We estimated the major cancer incidence rates after cholecystectomy stratified by age and sex. Methods: The records of 408,769 subjects aged >20 years were extracted from the National Health Insurance database from 2008 to 2016. The risks of major cancers were compared between the cholecystectomy and general populations using standardised incidence ratios (SIR). Results: The overall cancer incidence was comparable between cholecystectomy patients and the general population. However, patients aged <65 years who underwent cholecystectomy had a higher cancer risk than those aged ≥65 years and the general population (SIR 2.62; 95% confidence interval [CI] 2.15-3.08; SIR 1.36, 95% CI 1.32-1.40; and SIR 0.90, 95% CI 0.87-0.92 in men and SIR 1.91; 95% CI 1.71-2.10; SIR 1.07; 95% CI 1.03-1.10; and SIR 0.90; 95% CI 0.87-0.94 in women aged 20-34, 35-64, and ≥65 years at cholecystectomy). Colorectal and liver cancer incidences after cholecystectomy were higher than those in the general population regardless of age group and sex (SIR, 1.55 for colorectal cancer in men and women; SIR, 1.25 and 1.51 for liver cancer in men and women, respectively). However, for other major cancers, the risk was higher in patients who underwent cholecystectomy at a younger age than in those who underwent cholecystectomy at an age ≥65 years. Conclusion: Patients with cholecystectomy, especially those undergoing cholecystectomy at a younger age, need preventive strategies based on the cancer type.

Stress-induced NEDDylation promotes cytosolic protein aggregation through HDAC6 in a p62-dependent manner.

Stress-coupled NEDDylation potentially regulates the aggregation of nuclear proteins, which could protect the nuclear ubiquitin-proteasome system from proteotoxic stress. However, it remains unclear how NEDDylation controls protein-aggregation responses to diverse stress conditions. Here, we identified HDAC6 as a direct NEDD8-binding partner that regulates the formation of aggresome-like bodies (ALBs) containing NEDDylated cytosolic protein aggregates during ubiquitin stress. HDAC6 colocalizes with stress-induced ALBs, and HDAC6 inhibition suppresses ALBs formation, but not stress-induced NEDDylation, suggesting that HDAC6 carries NEDDylated-proteins to generate ALBs. Then, we monitored the ALBs-associated proteostasis network and found that p62 directly controls ALBs formation as an acceptor of NEDDylated cytosolic aggregates. Interestingly, we also observed that ALBs are highly condensed in chloroquine-treated cells with impaired autophagic flux, indicating that ALBs rely on autophagy. Collectively, our data suggest that NEDD8, HDAC6, and p62 are involved in the management of proteotoxic stress by forming cytosolic ALBs coupled to the aggresome-autophagy flux.

Transfusion Status in Liver and Kidney Transplantation Recipients-Results from Nationwide Claims Database.

BACKGROUND: This study analyzed the status and trends of transfusion and its associated factors among liver and kidney transplantation recipients. METHODS: A total of 10,858 and 16,191 naïve liver or kidney transplantation recipients from 2008 to 2017 were identified through the National Health Insurance Service database. The prescription code for transfusion and the presence, number, and amount of each type of transfusion were noted. The odds ratios and 95% confidence intervals were determined to identify significant differences in transfusion and blood components by liver and kidney transplantation recipient characteristics. RESULTS: In this study, 96.4% of liver recipients and 59.7% of kidney recipients received transfusions related to the transplantation operation, mostly platelet and fresh frozen plasma. Higher perioperative transfusion in women and declining transfusion rates from 2008 to 2017 were observed in both liver and kidney recipients. In liver recipients, the transfusion rate in those who received organs from deceased donors was much higher than that in those who received organs from living donors; however, the mortality rate according to transfusion was higher only in recipients of deceased donor organs. In kidney recipients, a higher mortality rate was observed in those receiving transfusion than that in patients without transfusion. CONCLUSIONS: In Korea, the transfusion rates in liver and kidney recipients were relatively higher than those in other countries. Sociodemographic factors, especially sex and year of transplantation, were associated with transfusion in solid organ recipients, possibly as surrogates for other causal clinical factors.

Factors Associated with Health Behaviors in Thyroid Cancer Survivors.

In this study, we compared health behaviors, including current smoking, drinking, and physical inactivity, in thyroid cancer survivors and non-cancer controls and investigated the factors associated with unhealthy behaviors among survivors. Baseline data from the Health Examinees study, collected from 2004 to 2013, were used. Thyroid cancer survivors (n = 942), defined as those who had received a clinical diagnosis of thyroid cancer, and 9,420 matched non-cancer controls without past history of any cancer were included in the analysis. The prevalence of smoking, alcohol consumption, and physical inactivity in thyroid cancer survivors were 2.3%, 26.6%, and 52.0%, respectively, with adjusted OR (aOR) and 95% CI between survivors and non-cancer controls of 0.35 (95% CI = 0.08-1.56), 0.46 (95% CI = 0.29-0.74), and 0.65 (95% CI = 0.44-0.96). The prevalence of unhealthy behaviors was higher among male thyroid cancer survivors than female thyroid cancer survivors. In thyroid cancer survivors, those who smoked were more likely to drink (aOR = 4.55 [95% CI = 1.61-12.85]) and those who were physically inactive were less likely to drink (aOR = 0.58 [95% CI = 0.42-0.82]). Current drinking and physical inactivity contributed to a higher likelihood of smoking (aOR = 4.31 [95% CI = 1.35-13.73] and 6.34 [95% CI = 1.65-24.34]). Thyroid cancer survivors had better health behaviors than the non-cancer controls. However, some survivors still had unhealthy lifestyles, especially displaying a clustering of unhealthy behaviors. Thus, health behavior promotion through medical intervention is important for thyroid cancer survivors.

Heterogenous Effect of Risk Factors on Breast Cancer across the Breast Density Categories in a Korean Screening Population.

We evaluated the heterogeneity of the effect of known risk factors on breast cancer development based on breast density by using the Breast Imaging-Reporting and Data System (BI-RADS). In total, 4,898,880 women, aged 40-74 years, who participated in the national breast cancer screening program in 2009-2010 were followed up to December 2018. Increased age showed a heterogeneous association with breast cancer (1-year hazard ratio (HR) = 0.92, 1.00 (reference), 1.03, and 1.03 in women with BI-RADS density category 1, 2, 3, and 4, respectively; P-heterogeneity < 0.001). More advanced age at menopause increased breast cancer risk in all BI-RADS categories. This was more prominent in women with BI-RADS density category 1 but less prominent in women in other BI-RADS categories (P-heterogeneity = 0.009). In postmenopausal women, a family history of breast cancer, body mass index ≥ 25 kg/m2, and smoking showed a heterogeneous association with breast cancer across all BI-RADS categories. Other risk factors including age at menarche, menopause, hormone replacement therapy after menopause, oral contraceptive use, and alcohol consumption did not show a heterogeneous association with breast cancer across the BI-RADS categories. Several known risk factors of breast cancer had a heterogeneous effect on breast cancer development across breast density categories, especially in postmenopausal women.

De novo cancer incidence after kidney and liver transplantation: Results from a nationwide population based data.

The cancer risk among solid organ transplantation recipients in East-Asia has been insufficiently studied. This study estimated de novo cancer incidence in kidney and liver recipients 2008-2015, compared with the general population in Korea using nationwide data. This is a retrospective cohort study using nationwide health insurance claims data. The study population was comprised of cancer-free 10,085 kidney recipients and 3,822 liver recipients. Standardized incidence ratio (SIR) of cancer using indirect standardization was calculated. Compared with the general population, the cancer risk increased by 3.19-fold in male and 2.56-fold in female kidney recipients. By cancer type, a notably increased SIR was observed for Kaposi sarcoma, renal cancer, skin cancer, and non-Hodgkin's lymphoma in male and for bladder cancer, renal cancer, and non-Hodgkin's lymphoma in female kidney recipients. In liver recipients, the SIR of all cancers was 3.43 in males and 2.30 in females. In male liver recipients, the SIRs for Kaposi sarcoma, non-Hodgkin's lymphoma, myeloid leukemia, and skin cancer and in female recipients those for non-Hodgkin's lymphoma and liver cancer were prominent. A greatly higher SIRs for overall cancer and non-Hodgkin's lymphoma in kidney and liver recipients aged 0-19 were observed, compared with recipients in other age group. The incidence of de novo cancer in kidney and liver recipients was higher than the general population and common types were different. Strategies of cancer prevention and screening after kidney and liver transplantation should be developed in response to the incidence of common types of de novo cancers.

Affinity improvement by fine tuning of single-chain variable fragment against aflatoxin B1.

Aflatoxin B1 (AFB1) produced in Aspergillus flavus is a major hepatocarcinogen found in foods and feed. For effective immunological detection of AFB1 at low concentrations, the development of high affinity antibody for AFB1 is required. Previously, an affinity-maturated single-chain variable fragment containing 6 mutations (scFv-M37) was isolated from an artificial mutagenic library, which showed a 9-fold higher affinity than its wild type scFv. In this study, the effect of the 6 mutated residues on the affinity improvement was characterized using surface plasmon resonance analysis, which identified a deleterious mutation (VH-A110T) located on a framework region of the scFv-M37. The back mutation of VH-A110T resulted in a 3.2-fold affinity improvement, which was attributed to decrease of dissociation rate constant (kd) in interaction between AFB1 and the back mutant scFv. The biophysical analyses using circular dichroism and gel filtration revealed that the back mutation of VH-A110T caused a subtle conformational change of the scFv toward tighter binding to AFB1.

Towards high-performance DPP-based sensitizers for DSC applications.

A novel, asymmetric DPP bridge/core was synthesized and tested in DSC devices. By desymmetrising the DPP core/bridge, a remarkable IPCE of >80% and a maximum power conversion efficiency of 7.7% were achieved. With the use of a wide-bandgap co-sensitizer, 8.6% PCE was realized under standard AM1.5G sunlight.

A structural study of DPP-based sensitizers for DSC applications.

Four D-π-A sensitizers comprising a thienyl-diketopyrrolopyrrole (ThDPP) bridge were synthesized and tested in iodide/triiodide liquid electrolyte DSC devices. The dye series was strategically designed to develop a structure-property relationship. The best performing sensitizer utilized a phenyl-based anchor and triphenylamine donor (η = 5.03%).

Allogeneic blood transfusion given before radiotherapy is associated with the poor clinical outcome in patients with cervical cancer.

PURPOSE: To analyze the effect of allogeneic blood transfusion on clinical outcome in 119 patients with stage IIB cervical cancer who were treated with radiotherapy +/- chemotherapy. PATIENTS AND METHODS: Medical records were examined for hemoglobin levels before and during radiotherapy, history of allogeneic blood transfusions and the time point when transfusions were given. These factors were retrospectively analyzed along with other clinical risk factors for influences on the patients' clinical outcomes. RESULTS: Thirty-two patients (26.9%) received packed red blood cell transfusion (mean, 3.4 units; range, 1-12 units) before or during radiotherapy. Median follow-up period was 39.3 months (range, 7.6-58.4 months). Patients with history of transfusion showed poorer metastasis-free survival and a trend toward poorer overall survival than non-transfused patients. When patients who received transfusions were sub-divided by the time of transfusion, those who received transfusions before radiotherapy had significantly poorer clinical outcome than those who received transfusions during radiotherapy. In a multivariable analysis, patients with pretreatment transfusion showed a higher risk of distant metastasis (HR = 3.75, 95% CI: 1.28-12.15, p = 0.017) and decreased overall survival rates (HR = 4.62, 95% CI: 1.15-18.54, p = 0.031) compared with those of other patients. CONCLUSION: Our results suggest that allogeneic blood transfusions given before radiotherapy may be associated with higher incidence of distant metastases and decreased survival in patients with stage IIB cervical cancer.