WSB1 promotes tumor metastasis by inducing pVHL degradation.

The von Hippel-Lindau tumor suppressor pVHL is an E3 ligase that targets hypoxia-inducible factors (HIFs). Mutation of VHL results in HIF up-regulation and contributes to processes related to tumor progression such as invasion, metastasis, and angiogenesis. However, very little is known with regard to post-transcriptional regulation of pVHL. Here we show that WD repeat and SOCS box-containing protein 1 (WSB1) is a negative regulator of pVHL through WSB1's E3 ligase activity. Mechanistically, WSB1 promotes pVHL ubiquitination and proteasomal degradation, thereby stabilizing HIF under both normoxic and hypoxic conditions. As a consequence, WSB1 up-regulates the expression of HIF-1α's target genes and promotes cancer invasion and metastasis through its effect on pVHL. Consistent with this, WSB1 protein level negatively correlates with pVHL level and metastasis-free survival in clinical samples. This work reveals a new mechanism of pVHL's regulation by which cancer acquires invasiveness and metastatic tendency.

BRCA and Breast Cancer-Related High-Penetrance Genes.

Genetic susceptibility explains 5-10% of all breast cancer cases. High-penetrance breast cancer susceptibility genes deliberate a greater than tenfold relative risk of breast cancer. BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer, and TP53, PTEN, and SKT11 (LKB1) are rarely present. The prevalence of BRCA1 and BRCA2 genetic alterations differ in various ethnic groups. The Korean Hereditary Breast Cancer (KOHBRA) Study, nationwide-scale study, was established to acquire evidence for the accurate risk assessment and management of hereditary breast and ovarian cancer (HBOC) in Korea prospectively since 2007. In this chapter, we review previous research related to hereditary breast cancer and summarize the present concepts and research results centered on the Korean Hereditary Breast Cancer Research at this time.

Saccharobisindole, Neoasterric Methyl Ester, and 7-Chloro-4(1H)-quinolone: Three New Compounds Isolated from the Marine Bacterium Saccharomonospora sp.

Analysis of the chemical components from the culture broth of the marine bacterium Saccharomonospora sp. CNQ-490 has yielded three novel compounds: saccharobisindole (1), neoasterric methyl ester (2), and 7-chloro-4(1H)-quinolone (3), in addition to acremonidine E (4), pinselin (5), penicitrinon A (6), and penicitrinon E (7). The chemical structures of the three novel compounds were elucidated by the interpretation of 1D, 2D nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HRMS) data. Compound 2 generated weak inhibition activity against Bacillus subtilis KCTC2441 and Staphylococcus aureus KCTC1927 at concentrations of 32 µg/mL and 64 µg/mL, respectively, whereas compounds 1 and 3 did not have any observable effects. In addition, compound 2 displayed weak anti-quorum sensing (QS) effects against S. aureus KCTC1927 and Micrococcus luteus SCO560.

Risk Factors for Abdominal Aortic Aneurysm in the Korean Population.

BACKGROUND: Ultrasound screening shows a clinical benefit in reducing abdominal aortic aneurysm (AAA)-related mortality. However, its cost-effectiveness remains unclear. Understanding the relationship between risk factors and AAA is important to maximize the benefit of AAA screening. However, risk factors for AAA have not been reported in Korea. The purpose of this study is to determine the prevalence of, and risk factors for, AAA among the Korean population. METHODS: The study population consisted of patients >50 years of age who consented for AAA screening. Screening was performed as follows for all participants: collection of demographic information, including risk factors, physical examination, and ultrasound screening. We measured the maximal diameter of the aorta from the outer to outer layer at 5 levels: suprarenal, renal, and infrarenal aorta, and bilateral common iliac arteries. AAA was defined as maximal aortic diameter >3 cm. The risk factors and risk ratio for AAA were determined. Chi-square test and a logistic regression model were used for statistical analysis. All P-values <0.05 were considered significant. RESULTS: A total of 2,035 participants were enrolled. Among them, 908 (44.6%) were men and 1,127 (55.4%) were women. Mean age was 66.9 ± 10.3 years (range 23-95). AAA was detected in 18 of 908 (2.0%) men and 4 of 1,127 (0.4%) women. The presence of an AAA was significantly correlated with male sex (P < 0.001), advanced age (P = 0.01), smoking (P < 0.001), alcohol consumption (P < 0.01), and the presence of pulmonary disease (P = 0.01). Multivariate analysis revealed that smoking was the only significant risk factor for AAA. CONCLUSIONS: The prevalence of AAA was 2.0% in men and 0.4% in women. Male sex, old age, smoking, alcohol use, and pulmonary disease are possible risk factors for AAA in the general Korean population. Smoking is the strongest risk factor for the development of AAA.

Surgical outcomes of robotic thyroidectomy vs. conventional open thyroidectomy for papillary thyroid carcinoma.

BACKGROUND: The purpose of this study was to compare the surgical outcomes of robotic thyroidectomy (RT) using bilateral axillo-breast approach (BABA) with conventional open thyroidectomy (OT) in papillary thyroid carcinoma patients. METHODS: Between January 2009 and December 2013, 815 patients who had received thyroidectomy for papillary thyroid carcinoma were enrolled. Of these, 126 patients received RT and 689 patients underwent OT. Age, gender, body mass index, extent of surgery, tumor size, multiplicity, bilaterality, extrathyroidal extension, and tumor stage were used for the propensity score matching analysis. One hundred and nine patients were selected in each group, and surgical outcomes were compared between the two groups. RESULTS: The RT group showed a significantly longer operating time (290.6 ± 74.4 vs. 107.9 ± 30.8 min, P < 0.001). However, the mean hospital stay after surgery (3.6 ± 0.8 vs. 3.4 ± 1.2 days, P = 0.293), postoperative complication rates (major and minor, P = 0.754 and P = 0.852), and pain score (postoperative day, P = 0.669; postoperative day 1, P = 0.952) were comparable between the two groups. There was no difference in the number of metastatic lymph nodes, but the mean number of retrieved lymph nodes in the RT group was lesser than that in the OT group (3.5 ± 3.5 vs. 5.3 ± 5.2, P = 0.002). CONCLUSIONS: Robotic thyroidectomy via the BABA may be a safe and acceptable surgical technique. But, further development that resolves the limitation of central node dissection is needed.

Chronic Intussusception Caused by Diffuse Large B-Cell Lymphoma in a 6-Year-Old Girl Presenting with Abdominal Pain and Constipation for 2 Months.

The classical triad of abdominal pain, vomiting, and bloody stool is absent in chronic intussusception for more than 2 weeks. Here, we report a 6-year-old female with recurrent abdominal pain for 2 months. Ultrasonography of the abdomen revealed an ileocolic-type intussusception. The lesion accompanying the tight fibrous adhesion was treated by resection and ileocolic anastomosis. It was diagnosed as intussusception with diffuse large B-cell lymphoma. A high index of suspicion for abdominal pain in children should result in the correct diagnosis and appropriate management.

The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study.

The Korean Hereditary Breast Cancer (KOHBRA) study was established to evaluate the prevalence and spectrum of BRCA1/2 mutations in Korean breast cancer patients at risk for hereditary breast and ovarian cancer. A total of 2953 subjects (2403 index patients and 550 family members of affected carriers) from 36 centers participated in this study between May 2007 and December 2013. All participants received genetic counseling and BRCA genetic testing. In total, 378 mutation carriers among 2403 index patients were identified. The prevalence of BRCA mutations in specific subgroups was as follows: 22.3 % (274/1228) for breast cancer patients with a family history of breast/ovarian cancers, 8.8 % (39/441) for patients with early-onset (<35 years) breast cancer without a family history, 16.3 % (34/209) for patients with bilateral breast cancer, 4.8 % (1/21) for male patients with breast cancer, and 37.5 % (3/8) for patients with both breast and ovarian cancer. From an analysis of the mutation spectrum, 63 BRCA1 and 90 BRCA2 different mutations, including 44 novel mutations, were identified. The c.7480 (p.Arg2494Ter) mutation in BRCA2 (10.1 %) was the most commonly identified in this cohort. The KOHBRA study is the largest cohort to identify BRCA mutation carriers in Asia. The results suggest that the prevalence of BRCA mutations in familial breast cancer patients is similar to that among Western cohorts. However, some single risk factors without family histories (early-onset breast cancer, male breast cancer, or multiple organ cancers) may limit the utility of BRCA gene testing in the Korean population.

The protective effect of parity in hormone receptor-positive, Ki-67 expressing breast cancer.

BACKGROUND: Epidemiologic studies showed that the experience of pregnancy is associated with a reduced risk of breast cancer. We hypothesized that parity may differentially be associated with the development of invasive breast cancer by each subtype. METHODS: We reviewed the clinical, radiological, and pathological records of women diagnosed with invasive ductal carcinoma of the breast at Samsung Medical Center between 2005 and 2009. Clinicopathologic results were assessed by χ(2) and Fisher's exact tests with a Bonferroni correction for categorical variables, and by the Kruskal-Wallis test for nonparametric continuous variables. A multinomial logistic regression model was used for multivariate analysis. RESULTS: Among a total of 3,095 patients, 283 (9.14 %) patients were nulliparous. Older age, higher pN, and expression of HER2 were associated with parity. In the analysis between parity and molecular subtypes, parity also had a variable influence on breast cancer subtypes (p = 0.032). Intergroup analysis with multiple comparison showed that luminal B subtype was related to nulliparity compared with HER2-positive subtypes (p = 0.03). CONCLUSIONS: The effect of parity on the development of breast cancer differed by hormone receptor and HER2 expression. It seems that parity might have a protective effect against hormone receptor-positive breast cancer, especially cancers expressing HR+ and Ki-67. Further basic research to define and understand this result is ongoing.

Breast Cancer and Therapy-Related Cardiovascular Toxicity.

The global incidence of breast cancer is on the rise, a trend also observed in South Korea. However, thanks to the rapid advancements in anticancer therapies, survival rates are improving. Consequently, post-treatment health and quality of life for breast cancer survivors are emerging as significant concerns, particularly regarding treatment-related cardiotoxicity. In this review, we delve into the cardiovascular complications associated with breast cancer treatment, explore surveillance protocols for early detection and diagnosis of late complications, and discuss protective strategies against cardiotoxicity in breast cancer patients undergoing anticancer therapy, drawing from multiple guidelines.

Differential Cardiovascular Outcomes of Each Antihypertensive Drug Class in Patients With Hypertension and Breast Cancer Undergoing Doxorubicin-Containing Chemotherapy.

PURPOSE: The preemptive use of renin-angiotensin system (RAS) inhibitors may reduce doxorubicin (DOX)-related cardiotoxicity. Using the national insurance claims data of Korea, this study compared cardiovascular (CV) outcomes following the use of four major antihypertensive drug classes in patients with hypertension and breast cancer who underwent DOX-containing chemotherapy. METHODS: A total of 4,722 patients with hypertension and breast cancer who underwent DOX-containing chemotherapy were included. The outcomes were compared between patients who used RAS inhibitors, calcium channel blockers (CCBs), beta-blockers (BBs), and thiazide and thiazide-like diuretics (TDs). The primary outcome was a composite of incident heart failure and serious ventricular arrhythmias, including ventricular tachycardia and fibrillation, ischemic heart disease, and stroke. RESULTS: In the propensity score-matched population, there were no significant differences in the primary outcome between RAS inhibitor and CCB users; however, patients with diabetes who used CCBs had a worse primary outcome than those who used RAS inhibitors (adjusted hazard ratio [aHR], 1.93; 95% confidence interval [CI], 1.06-3.51). BB and TD users had a worse primary outcome compared with RAS inhibitor (aHR, 1.88; 95% CI, 1.30-2.71 in BB users and aHR, 2.55; 95% CI, 1.37-4.75 in TD users) or CCB (aHR, 1.54; 95% CI, 1.09-2.16 in BB users and aHR, 2.08; 95% CI, 1.13-3.82 in TD users) users. CONCLUSION: RAS inhibitors are preferred for the treating hypertension and improving CV outcomes in patients with hypertension and breast cancer undergoing DOX-containing chemotherapy, particularly in patients with comorbid diabetes. However, CCBs are equivalent to RAS inhibitors and are more favorable than BBs and TDs in terms of improving CV outcomes.

Myxoid Liposarcoma of the Breast Mimicking Phyllodes Tumor: A Case Report.

Myxoid liposarcoma is an extremely rare malignant breast tumor. We report the case of a 44-year-old woman who had myxoid liposarcoma of the breast with a history of phyllodes tumor and describe the imaging findings on US, mammography, and MRI. Before surgery, the mass was considered to be a recurrent phyllodes tumor. However, using US, we retrospectively identified some differences between myxoid liposarcomas and phyllodes tumors.

Complementary and alternative medicine use and assessment of quality of life in Korean breast cancer patients: a descriptive study.

PURPOSE: The worldwide use of complementary and alternative medicine (CAM) among cancer patients has increased, with breast cancer patients being more likely to use CAM compared with any other cancer patients. However, few surveys have systematically described CAM use among Korean breast cancer patients. This study investigated the use of CAM among patients who were diagnosed with breast cancer, along with the relevant demographic and clinical factors related to CAM use. We also compared the difference in quality of life between CAM users and nonusers. METHODS: A total of 661 patients were invited to participate in this study during routine clinic visits, with 425 patients ultimately participating. Three hundred ninety-nine questionnaires were completed and used in the final analysis. Quality of life was evaluated based on the Korean versions of the EORTC QLQ-C30 and EORTC QLQ-BR23. RESULTS: Previous or current CAM usage was reported by 229 patients (57.4%). Independent factors related to CAM use were marital status, cancer stage, and coexisting illness. The common types of CAM use included exercise therapy (43.2%) and ingestion of vitamins and minerals (41.9%). The reasons for CAM use were to boost the immune system (53.2%), promote health (46.8%) and prevent recurrence (37.7%). Large proportions (70.4%) of CAM users did not discuss their CAM use with their physicians. Only a small number of CAM users (2.5%) answered that they were unsatisfied with their CAM use, with most CAM users reporting that they would continue their CAM use. Quality of life was not significantly different between CAM users and nonusers. CONCLUSIONS: A significant number of patients with breast cancer have used CAM, and health care providers should be aware of the variety of CAM methods and their patients' CAM uses for the proper management of breast cancer.

Bilateral superficial cervical plexus block for parathyroidectomy during pregnancy: A case report.

BACKGROUND: Primary hyperparathyroidism (PHPT) is the most common cause of pregnancy-related hypercalcemia. PHPT can cause maternal and fetal complications in pregnant women. General anesthesia for non-obstetric surgery in pregnant women is associated with maternal hazards and concerns regarding long-term neonatal neurocognitive effects. Surgical removal of the lesion in mid-pregnancy is currently the primary treatment option for pregnant patients with PHPT. However, the blood calcium concentration at which surgery should be considered remains under discussion due to the risk of miscarriage. CASE SUMMARY: A 31-year-old nulliparous woman at 11 wk of gestation was admitted to our hospital for parathyroidectomy. The patient had a history of intrauterine fetal death with unknown etiology at 16 wk of gestation 1 year prior. Her blood test results showed that the serum calcium level was elevated to 12.9 mg/dL, and the parathyroid hormone level was elevated to 157 pg/mL. In a neck ultrasound, it revealed a 0.8 cm × 1.5 cm sized oval, hypoechoic mass in the upper posterior of the left thyroid gland, which was compatible with parathyroid adenoma. Superficial cervical plexus block (SCPB) for parathyroidectomy was performed. After surgery, the obstetrician checked the status of the fetus, and there were no abnormal signs. Since then her calcium level returned to normal values after one week of surgery and a healthy male neonate of 2910 g was delivered vaginally at 38 wk of gestation. CONCLUSION: Our case suggests that SCPB can be an anesthetic option for parathyroidectomy during the first trimester of pregnancy.

The antioncogenic effect of Beclin-1 and FOXP3 is associated with SKP2 expression in gastric adenocarcinoma.

ABSTRACT: An overexpression of S-phase kinase-associated protein 2 (SKP2) is frequently observed in human cancer progression and metastasis, and evidence suggests that SKP2 plays a proto-oncogenic role both in vitro and in vivo. However, the function of SKP2 in gastric adenocarcinoma remains largely obscure. We investigated SKP2 expression in human gastric carcinomas.Tissue samples were acquired from 182 cases of gastric adenocarcinoma that were surgically resected from 2006 to 2012. Immunohistochemical staining for SKP2, Beclin-1, and forkhead box protein P3 (FOXP3) was performed. Pearson chi-square test was used to evaluate the associations among clinicopathological variables. The Kaplan-Meier method, the log-rank test, and the Cox proportional-hazards model were used in the analysis of the overall survival (OS) and disease-free survival (DFS).As a result, SKP2 overexpression in gastric adenocarcinomas showed a significant correlation with several favorable clinical factors, including the tumor size, T category, N category, lymphatic invasion, vascular invasion, OS, and DFS. SKP2 expression was positively correlated with the tumoral FOXP3, Beclin-1 expression, and regulatory T cell (Treg) infiltration. The difference in DFS between the SKP2 positive and negative group was attenuated by FOXP3 high expression, Beclin-1 high expression, and Tregs infiltration. Attenuation of the difference in OS by FOXP3 high expression, Beclin-1 high expression, and Tregs infiltration was not significant. In multivariable analysis, SKP2 expression was not correlated with OS and DFS.Our study showed a complex interrelationship between SKP2 and Beclin-1 and FOXP3 expression in gastric adenocarcinoma. The antioncogenic effect of Beclin-1 and FOXP3 expression in gastric adenocarcinoma is related to SKP2 expression.

Clinical Significance of Receptor-Interacting Protein 3 and Parkin, Essential Molecules for Necroptosis, in Breast Cancer.

PURPOSE: Receptor-interacting protein 3 (RIP3) is the main initiator of necroptosis. Parkin prevents the formation of the RIP1-RIP3 complex by promoting polyubiquitination of RIP3. However, the mechanism by which necroptosis affects the clinical features of breast cancer and prognosis is not known. Here, we aimed to study the effect of necroptosis on the clinical features and prognosis of breast cancer by assessing the expression of RIP3 and Parkin. METHODS: Tissue microarrays (TMAs) were constructed from 257 cases of breast cancer. Immunohistochemistry was performed on 4-µm tissue sections from each TMA block. The χ² test, Kaplan-Meier survival analysis with log-rank test, and Cox regression proportional hazard model were used for statistical analysis. RESULTS: Low RIP3 expression resulted in a large tumor size and high nuclear grade. Low RIP3 expression was correlated with human epidermal growth factor receptor 2 positivity, short overall survival (OS), and short disease-free survival (DFS). The triple negative breast cancer group with low RIP3 expression and lymph node (LN) positive group with low RIP3 expression had the shortest OS. High Parkin expression was associated with high histological grade, estrogen and/or progesterone receptor negativity, and lymphatic emboli, but was not correlated with OS and DFS. OS was correlated with LN metastasis and RIP3 loss and DFS with large tumor size, LN metastasis, and RIP3 loss. CONCLUSION: Low RIP3 and high Parkin expression are associated with aggressive clinical features in breast cancer. RIP3, a molecular marker of necroptosis, is an independent factor associated with survival in breast cancer. Further in-depth studies are needed to investigate the role of necroptosis in breast cancer development, metastasis, and treatment in the future.

Selective Inhibition of Human Monoamine Oxidase B by 5-hydroxy-2-methyl-chroman-4-one Isolated from an Endogenous Lichen Fungus Daldinia fissa.

Inhibitory activities against monoamine oxidases (MAOs) and cholinesterases (ChEs) and antioxidant activity were evaluated for 195 extracts from Ukraine-derived endogenous lichen fungi (ELF). Among them, an ELF13 (identified as Daldinia fissa) extract showed the highest inhibitory activity against MAO-B, and 5-hydroxy-2-methyl-chroman-4-one (HMC) was isolated as a ~ 4-fold selective inhibitor of MAO-B (IC50 = 3.23 µM) compared to MAO-A (IC50 = 13.97 µM). HMC is a reversible competitive inhibitor with a Ki value of 0.896 µM. No cytotoxicity was observed in normal and cancer cells at 50 µM of HMC. HMC showed blood-brain barrier permeability and high gastrointestinal absorption in silico pharmacokinetics. The docking simulation results showed that the binding affinity of HMC for MAO-B (-7.3 kcal/mol) was higher than that of MAO-A (-6.1 kcal/mol) and that HMC formed a hydrogen bond interaction with Cys172 of MAO-B (distance: 3.656 Å), whereas no hydrogen bonding was predicted with MAO-A. These results suggest that HMC can be considered a candidate for the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

Comparison of immunologic outcomes of laparoscopic vs open approaches in clinical stage III colorectal cancer.

PURPOSE: Improved survival in patients with stage III colon cancer after a laparoscopic colectomy (LC) has been reported by Lacy et al. (Lancet 359:2224-2229, 6), and preserved immunity was suggested as the reason for the survival advantage. The aim of our study was to clarify the existence of an immunological benefit after laparoscopic colon cancer surgery (LC) compared to open colon surgery (OC). METHODS: From January 2006 to November 2007, 74 patients with clinical stage III colon cancer were prospectively assigned to undergo a LC (n = 35) or an OC (n = 39). The immune factors were examined preoperatively, and on the first and fifth days postoperatively (POD1 and POD5). RESULTS: The cellular immune factors were significantly decreased; however, there was no significant difference between the LC and OC groups except for the mHLA-DR. The LC group had a better preserved mHLA-DR on POD5 than did the OC group (p = 0.015), in addition to a faster recovery (p < 0.005). CONCLUSION: The mHLA-DR on POD5 was affected less by the LC compared to the OC. The LC demonstrated minimal immunological advantage when compared to the OC. However, further study is required to clarify the immunological benefits of the LC on colorectal cancer prognosis.

Early Prediction of Tumor Response to Neoadjuvant Chemotherapy and Clinical Outcome in Breast Cancer Using a Novel FDG-PET Parameter for Cancer Stem Cell Metabolism.

Cancer stem cells (CSCs) contribute to chemoresistance and tumor relapse. By using the distinct metabolic phenotype of CSC, we designed novel PET parameters for CSC metabolism and investigated their clinical values. Patients with breast cancer who underwent 18F-FDG PET/CT before neoadjuvant chemotherapy (NAC) were retrospectively included. We developed a method to measure CSC metabolism using standardized uptake value histogram data. The predictive value of novel CSC metabolic parameters for pathologic complete response (pCR) was assessed with multivariable logistic regression. The association between the CSC parameter and disease-free survival (DFS) was also determined. We identified 82 patients with HER2-positive/triple-negative subtypes and 38 patients with luminal tumors. After multivariable analysis, only metabolic tumor volume for CSC (MTVcsc) among metabolic parameters remained the independent predictor of pCR (OR, 0.12; p = 0.022). MTVcsc successfully predicted pathologic tumor response to NAC in HER2-positive/triple-negative subtypes (accuracy, 74%) but not in the luminal subtype (accuracy, 29%). MTVcsc was also predictive of DFS, with a 3-year DFS of 90% in the lower MTVcsc group (<1.75 cm3) versus 72% in the higher group (>1.75 cm3). A novel data-driven PET parameter for CSC metabolism provides early prediction of pCR after NAC and DFS in HER2-positive and triple-negative subtypes.

Trends in Risk-Reducing Mastectomy and Risk-Reducing Salpingo-Oophorectomy in Korean Carriers of the BRCA1/2 Mutation.

PURPOSE: BRCA1/2 mutations are associated with risks of breast and ovarian cancer. In Korea, incidences of BRCA1/2 genetic testing and risk-reducing surgery (RRS) have increased with insurance coverage and the Angelina Jolie effect. The aim of this study was to identify trends in RRS performed in Korean women with the BRCA1/2 mutation. METHODS: We retrospectively reviewed the medical records of BRCA1/2 mutation carriers with (affected carriers) and without (unaffected carriers) breast cancer until August 2018 from 25 Korean Hereditary Breast Cancer (KOHBRA)-affiliated hospitals. RESULTS: The numbers of contralateral risk-reducing mastectomy (RRM) and risk-reducing bilateral salpingo-oophorectomy (RRBSO) in affected carriers have increased 5.8- and 3.6-fold, respectively, since 2013. The numbers of RRBSO in unaffected carriers has increased 8-fold since 2013. The number of institutions that perform RRS has increased gradually. The number of hospitals that perform contralateral RRM on affected carriers increased from 3 in 2012 to 11 in 2018, and that of those that perform RRBSO increased from 7 to 17. The number of hospitals that perform bilateral RRM on unaffected carriers increased from 1 in 2012 to 2 in 2018, and that of those that perform RRBSO increased from 1 to 8. However, the hospitals showed differences in the rates of RRM or RRBSO performed. CONCLUSION: The incidence of RRS increased each year throughout the study period. However, in Korea, the rate of RRS procedures depended on the hospital.

The AMPK-Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome.

The receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 play important roles in necroptosis that are closely linked to the inflammatory response. Although the activation of necroptosis is well characterized, the mechanism that tunes down necroptosis is largely unknown. Here we find that Parkin (also known as PARK2), an E3 ubiquitin ligase implicated in Parkinson's disease and as a tumour suppressor, regulates necroptosis and inflammation by regulating necrosome formation. Parkin prevents the formation of the RIPK1-RIPK3 complex by promoting polyubiquitination of RIPK3. Parkin is phosphorylated and activated by the cellular energy sensor AMP-activated protein kinase (AMPK). Parkin deficiency potentiates the RIPK1-RIPK3 interaction, RIPK3 phosphorylation and necroptosis. Parkin deficiency enhances inflammation and inflammation-associated tumorigenesis. These findings demonstrate that the AMPK-Parkin axis negatively regulates necroptosis by inhibiting RIPK1-RIPK3 complex formation; this regulation may serve as an important mechanism to fine-tune necroptosis and inflammation.