Comparative Biological Half-Life of Penthiopyrad and Tebufenpyrad in Angelica Leaves and Establishment of Pre-Harvest Residue Limits (PHRLs).

To prevent pesticides from exceeding maximum residue limits (MRLs) in crops during export and shipment, it is necessary to manage residue levels during the pre-harvest stages. Therefore, the Republic of Korea establishes pre-harvest residue limits (PHRLs) per crop and pesticide. This study was conducted to set PHRLs for penthiopyrad and tebufenpyrad in angelica leaves, where the exceedance rates of MRLs are expected to be high. The LOQ of the analytical method used was 0.01 mg/kg and it demonstrated good linearity, with a correlation coefficient of 0.999 or higher within the quantitation range of 0.005 to 0.5 mg/kg. The recovery and storage stability accuracy values were in the range of 94.5-111.1%, within the acceptable range (70-120%, RSD ≤ 20%). The matrix effect for both pesticides was in the medium-to-strong range, and it did not significantly impact the quantitative results as a matrix-matched calibration method was employed. Using the validated method, residue concentrations of penthiopyrad 20 (%) EC and tebufenpyrad 10 (%) EC were analyzed. Both pesticides exhibited a decreasing residue trend over time. In Fields 1-3 and their integrated results, the biological half-life was within 2.6-4.0 days for penthiopyrad and 3.0-4.2 days for tebufenpyrad. The minimum value of the regression coefficient in the dissipation curve regression equation was selected as the dissipation constant. The selected dissipation constants for penthiopyrad in Fields 1-3 and their integration were 0.1221, 0.2081, 0.2162, and 0.1960. For tebufenpyrad, the dissipation constants were 0.1451, 0.0960, 0.1725, and 0.1600, respectively. The dissipation constant was used to calculate PHRL per field. Following the principles of the PHRL proposal process, residue levels (%) on PHI dates relative to MRLs were calculated, and fields for proposing PHRLs were selected. For penthiopyrad, since the residue level (%) was less than 20%, the PHRL for Field 3 with the largest dissipation constant was proposed. For tebufenpyrad, as the residue level (%) exceeded 80%, the PHRL proposal could not established. It is deemed necessary to reassess the MRL and 'guidelines for safe use' for tebufenpyrad in angelica leaves.

Survival dynamics of stick insect and the impact of environmental factors on natural fungal infection during the rainy season.

Phasmatodea, commonly known as stick insects, are recognized as noteworthy pests globally, impacting agriculture and forest ecosystems. Among them, the outbreak of Ramulus mikado has emerged as a notable concern in East Asian forests. Recently, Metarhizium phasmatodeae has been identified as utilizing stick insects as hosts. We have observed evidence of this entomopathogenic fungus infecting stick insects. Given the increase in these occurrences during the rainy period, this study investigated the relationship between the survival of R. mikado and the M. phasmatodeae infection during the rainy seasons of 2022 and 2023. We collected stick insects in two representative forests of the Republic of Korea and examined insect survival, fungal infection, and various environmental factors. No infections were detected in specimens collected in June before the rainy season, but from July onwards, both the mortality of R. mikado and the fungal infection substantially increased. By the last sampling date of each year, 75% (2022), 71.4% (2023) of the specimens were infected, and over 90% of the total individuals succumbed as a result. Fungi isolated from deceased R. mikado were successfully identified as M. phasmatodeae using morphological and taxonomic approaches. Various statistical analyses, including principal component analysis and modeling, revealed a robust association between fungal infection and the survival of stick insects. The results highlight the correlation between mass deaths of stick insects and fungal infection, particularly during the summer rainy season. These findings offer valuable insights for forecasting R. mikado population in the upcoming year and developing effective pest control strategies.

Association between glycemic status and the risk of gastric cancer in pre/peri-and postmenopausal women: A nationwide cohort study.

PURPOSE: This study aimed to assess the correlation between glycemic status (prediabetes and type 2 diabetes mellitus) and the risk of gastric cancer according to menopausal status. METHODS: A total of 982,559 pre/peri-menopausal and 1445,419 postmenopausal women aged ≥ 40, who underwent the Korean national health screening in 2009, were included and followed up until 2018. Hazard ratio (HR) and 95% confidence interval (CI) were calculated for development of gastric cancers according to hyperglycemic status in both groups using Cox proportional hazards models. RESULTS: Over a mean follow-up period of 8.3 years, 3259 (0.33%) pre/peri-menopausal women and 13,245 (0.92%) postmenopausal women were diagnosed with gastric cancer. In postmenopausal women, only diabetes mellitus conferred a higher risk of gastric cancer compared to normal glycemic status (HR, 1.15; 95% CI, 1.09-1.20), with an increasing trend of gastric cancers from prediabetes to diabetes (P for trend < 0.001) observed regardless of menopausal status. Obesity, smoking, and heavy alcohol consumption was associated with increased gastric cancer risk mainly in the postmenopausal period. CONCLUSIONS: The risk of gastric cancer escalates with deteriorating glycemic status in a dose-response manner. Diabetes mellitus is linked with an elevated risk of gastric cancer in postmenopausal women.

Impact of Bevacizumab on Clinical Outcomes in Patients With Platinum-resistant Relapsed Ovarian Cancer.

BACKGROUND/AIM: Over the past several decades, new anti-cancer drugs have been developed for the treatment of epithelial ovarian cancer. The development of drugs has led to changes in improving the prognosis of ovarian cancer patients. One of these drugs, bevacizumab, is used for advanced or recurrent ovarian cancer. In this study, we aimed to evaluate survival improvement in patients with platinum-resistant relapsed epithelial ovarian cancer (PR-ROC) after introduction of bevacizumab in real world experience. PATIENTS AND METHODS: We retrospectively divided patients with PR-ROC into two groups: bevacizumab plus chemotherapy (BEV-CT group) and chemotherapy alone (CT group). Progression-free survival (PFS), the primary endpoint, between two groups was compared to evaluate whether survival outcomes were improved. In addition, overall survival (OS) was also compared. RESULTS: A total of 154 patients were included in the study: 57 and 97 patients in the BEV-CT and CT groups, respectively. OS was significantly longer in the BEV-CT group than in the CT group. The use of bevacizumab was identified as a favorable prognostic factor for OS. In a subgroup analysis confined to second-line chemotherapy, PFS and OS were statistically different between groups. More patients in the CT group suffered hematologic adverse events of grade 3 or above than patients in the BEV-CT group. CONCLUSION: In a real-world clinical setting, introduction of bevacizumab led to improvement of OS in patients with PR-ROC with a tolerable toxicity.

Association between menopausal hormone therapy and the risk of gastric cancer: A Korean nationwide population-based cohort study.

OBJECTIVE: Gastric cancer (GC) is more common in men than women, but also more common among postmenopausal than premenopausal women. The protective effect of reproductive hormones against GC remains unclear. Therefore, we evaluated the association between menopausal hormone therapy (MHT) and the risk of GC in women. METHODS: We investigated the national cohort data of women aged over 40 years who underwent health checkups by the Korean National Health Insurance Service in 2009. After excluding individuals with missing data and those previously diagnosed with cancer, 1,354,621 postmenopausal women were included and divided into groups according to their MHT history. We followed the study population until 2018 and analyzed the hazard ratios (HR) with 95 % confidence intervals (CIs) for the incidence rate of GC in a multivariate adjusted model. RESULTS: The number of women with and without a history of MHT was 214,723 (15.9 %) and 1,139,898 (84.1 %), respectively. During the mean 8.32 ± 0.8 years of follow-up, a total of 12,496 GC cases developed in the study population (10,962 MHT non-users; 1534 MHT users). In the adjusted model, MHT was associated with a 12 % decrease in the development of GC relative to non-use of MHT (HR 0.88; 95 % CI 0.83-0.93). Exposure to MHT for >2 years was linked to a reduction in GC risk, particularly when initiated before the age of 50, giving a 45 % risk reduction. CONCLUSIONS: According to our large-scale prospective national cohort study, exogenous MHT is associated with a decreased risk of GC in postmenopausal women.

Enhancing Post-Surgical Rehabilitation Outcomes in Patients with Chronic Ankle Instability: Impact of Subtalar Joint Axis Balance Exercises Following Arthroscopic Modified Broström Operation.

Background and Objectives: This study aimed to evaluate the effects of subtalar joint axis-based balance exercises on the anterior talofibular ligament (ATFL) thickness, ankle strength, and ankle stability after an arthroscopic modified Broström operation (AMBO) for chronic ankle instability (CAI). Materials and Methods: The study included 47 patients diagnosed with CAI who underwent AMBO and were randomly divided into three groups: control (n = 11), general balance exercise (n = 17), and subtalar joint axis balance exercise (n = 19), regardless of the affected area. Participants in the exercise rehabilitation group performed exercises for 60 min twice a week for six weeks, starting six weeks after AMBO. ATFL thickness, ankle strength, and ankle dynamic stability were measured using musculoskeletal ultrasonography, Biodex, and Y-balance test, respectively, before and after treatment. Results: Compared with the remaining groups, the subtalar joint axis balance exercise group had reduced ATFL thickness (p = 0.000), improved ankle strength for eversion (p = 0.000) and inversion (p = 0.000), and enhanced ankle stability (p = 0.000). Conclusions: The study results suggest that subtalar joint axis-based balance exercises may contribute to the early recovery of the ankle joint after AMBO.

The iterative implementation of a comprehensive enhanced recovery after surgery protocol in all spinal surgery in Korea: a comparative analysis of clinical outcomes and medical costs between primary spinal tumors and degenerative spinal diseases.

OBJECTIVE: Most studies on the enhanced recovery after surgery (ERAS) protocol in spine surgery have focused on patients with degenerative spinal diseases (DSDs), resulting in a lack of evidence for a comprehensive ERAS protocol applicable to patients with primary spine tumors (PSTs) and other spinal diseases. The authors had developed and gradually adopted components of the comprehensive ERAS protocol for all spine surgical procedures from 2003 to 2011, and then the current ERAS protocol was fully implemented in 2012. This study aimed to evaluate the impact and the applicability of the comprehensive ERAS protocol across all spine surgical procedures and to compare outcomes between the PST and DSD groups. METHODS: Adult spine surgical procedures were conducted from 2003 to 2021 at the Seoul National University Hospital Spine Center and data were retrospectively reviewed. The author divided the study periods into the developing ERAS (2003-2011) and post-current ERAS (2012-2021) periods, and outcomes were compared between the two periods. Surgical procedures for metastatic cancer, infection, and trauma were excluded. Interrupted time series analysis (ITSA) was used to assess the impact of the ERAS protocol on medical costs and clinical outcomes, including length of stay (LOS) and rates of 30-day readmission, reoperation, and surgical site infection (SSI). Subgroup analyses were conducted on the PST and DSD groups in terms of LOS and medical costs. RESULTS: The study included 7143 surgical procedures, comprising 1494 for PSTs, 5340 for DSDs, and 309 for other spinal diseases. After ERAS protocol implementation, spine surgical procedures showed significant reductions in LOS and medical costs by 22% (p = 0.008) and 22% (p < 0.001), respectively. The DSD group demonstrated a 16% (p < 0.001) reduction in LOS, whereas the PST group achieved a 28% (p < 0.001) reduction, noting a more pronounced LOS reduction in PST surgical procedures (p = 0.003). Medical costs decreased by 23% (p < 0.001) in the DSD group and 12% (p = 0.054) in the PST group, with a larger cost reduction for DSD surgical procedures (p = 0.021). No statistically significant differences were found in the rates of 30-day readmission, reoperation, and SSI between the developing and post-current ERAS implementation periods (p = 0.65, p = 0.59, and p = 0.52, respectively). CONCLUSIONS: Comprehensive ERAS protocol implementation significantly reduced LOS and medical costs in all spine surgical procedures, while maintaining comparable 30-day readmission, reoperation, and SSI rates. These findings suggest that the ERAS protocol is equally applicable to all spine surgical procedures, with a more pronounced effect on reducing LOS in the PST group and on reducing medical costs in the DSD group.

An LC-MS/MS Method for the Simultaneous Analysis of 380 Pesticides in Soybeans, Kidney Beans, Black Soybeans, and Mung Beans: The Effect of Bean Grinding on Incurred Residues and Partitioning.

The significance of sample grinding is frequently disregarded during the development of analytical methods, which are often validated with spiked samples that may not accurately reflect incurred residues. This study investigated the particle size of ground beans as a key factor in optimizing extraction efficiency in order to develop a simple quick, easy, cheap, effective, rugged, and safe (QuEChERS)-based modified method for identifying 380 pesticides in beans using liquid chromatography-tandem mass spectrometry. The efficacy of pesticide extraction was found to be significantly affected by particle size. With small particle sizes (>40 mesh), no supernatant was recovered after QuEChERS partitioning. Therefore, a simple modification was performed before partitioning. The modified method was validated for selective extraction of pesticides, limits of quantification, linearity, accuracy, and precision. This method is simple to implement and, therefore, useful for the analysis of pesticide residues in beans.

Clinical implications of histologic subtypes on survival outcomes in primary mucinous ovarian carcinoma.

OBJECTIVE: In 2014, the World Health Organization introduced a new histologic classification by dividing primary mucinous ovarian carcinoma (PMOC) into two: expansile (ES) or infiltrative subtypes (IS). This study investigated the clinical implications of these histological subtypes on survival outcomes. METHODS: Data from 131 patients with PMOC who underwent primary surgery between 2003 and 2021 were analyzed. The patients baseline characteristics, surgical and pathological information were collected. Survival outcomes were calculated, while factors affecting them were also investigated. RESULTS: During 55.9 months of median follow-up, 27 (20.6%) patients experienced recurrence and 20 (15.3%) died. Among 131 patients, 113 patients were classified into 87 (77%) ES and 26 (23%) IS after a slide review. Advanced stage, lymph node involvement, and residual tumors after surgery were more common in the IS, showing poorer prognosis. In multivariate analyses, advanced stage and residual tumors after surgery were associated with worse survival, while the IS showed no statistical significance. In subgroup analysis for stage I disease, survival did not vary between subtypes. Nevertheless, patients in the IS group who underwent fertility-sparing surgeries demonstrated a 5-year progression-free survival (PFS) rate of 83.3%, significantly lower than patients without fertility preservation, irrespective of histologic subtypes (5-year PFS rate: 97.9%; P = 0.002 for the ES, 5-year PFS rate: 100%; P = 0.001 for the IS). CONCLUSIONS: The IS of PMOC had poorer survival outcomes and a higher proportion of advanced-stage tumors. Although its independent prognostic significance remains uncertain, adjuvant chemotherapy should be considered for patients with fertility preservation in the IS group.

Impact of supradiaphragmatic lymphadenectomy on the survival of patients in stage IVB ovarian cancer with thoracic lymph node metastasis.

Introduction: To evaluate the survival impact of supradiaphragmatic lymphadenectomy as part of debulking surgery in stage IVB ovarian cancer with thoracic lymph node metastasis (LNM). Methods: We retrospectively enrolled patients diagnosed with stage IVB ovarian, fallopian or primary peritoneal cancer between 2010 and 2020, carrying cardiophrenic, parasternal, anterior mediastinal or supraclavicular lymph nodes ≥5 mm on axial chest computed tomography. All tumors were classified into the abdominal (abdominal tumors and cardiophrenic lymph nodes) and supradiaphragmatic (parasternal, anterior mediastinal or supraclavicular lymph nodes) categories depending on the area involved. Residual tumors were classified into <5 vs ≥5 mm in the abdominal and supradiaphragmatic areas. Based on the site of recurrence, they were divided into abdominal, supradiaphragmatic and other areas. Results: A total of 120 patients underwent primary debulking surgery (PDS, n=68) and interval debulking surgery after neoadjuvant chemotherapy (IDS/NAC, n=53). Residual tumors in the supradiaphragmatic area ≥5 mm adversely affected progression-free survival (PFS) and overall survival (OS) with marginal significance after PDS despite the lack of effect on survival after IDS/NAC (adjusted hazard ratios [HRs], 6.478 and 6.370; 95% confidence intervals [CIs], 2.224-18.864 and 0.953-42.598). Further, the size of residual tumors in the abdominal area measuring ≥5 mm diminished OS after IDS/NAC (adjusted HR, 9.330; 95% CIs, 1.386-62.800). Conclusion: Supradiaphragmatic lymphadenectomy during PDS may improve survival in patients diagnosed with stage IVB ovarian cancer manifesting thoracic LNM. Further, suboptimal debulking surgery in the abdominal area may be associated with poor OS after IDS/NAC. Trial registration: ClinicalTrials.gov (NCT05005650; https://clinicaltrials.gov/ct2/show/NCT05005650; first registration, 13/08/2021).Research Registry (Research Registry UIN, researchregistry7366; https://www.researchregistry.com/browse-the-registry#home/?view_2_search=researchregistry7366&view_2_page=1).

Factors Affecting Incurred Pesticide Extraction in Cereals.

This study investigated the effect of milling on the yields of incurred residues extracted from cereals. Rice, wheat, barley, and oat were soaked in nine pesticides (acetamiprid, azoxystrobin, imidacloprid, ferimzone, etofenprox, tebufenozide, clothianidin, hexaconazole, and indoxacarb), dried, milled, and passed through sieves of various sizes. The quick, easy, cheap, effective, rugged, and safe method and liquid chromatography-tandem mass spectrometry extracted and quantified the incurred pesticides, respectively. For rice and oat, the yields were higher for vortexed samples than for soaked samples. For rice, the yields improved as the extraction time increased from 1 to 5 min. The optimized method was validated based on the selectivity, limit of quantitation, linearity, accuracy, precision, and the matrix effect. For rice and barley, the average yields improved as the particle size decreased from <10 mesh to >60 mesh. For 40-60-mesh wheat and oat, all pesticides (except tebufenozide in oat) had the highest yields. For cereals, 0.5 min vortexing, 5 min extraction, and >40-mesh particle size should be used to optimize incurred pesticide extraction.

Defining Sentinel Injuries of Suspected Child Abuse by Age Using International Classification of Diseases-10: A Delphi Study.

OBJECTIVE: To address child abuse effectively requires accurate assessment of the magnitude of the problem. Although it is difficult to assess the scale of child abuse cases nationwide, it can be estimated through the incidence of sentinel injuries, which are defined as minor but unusual injuries such as bruises or wounds in children of precruising age. Therefore, this study aimed to define disease codes for sentinel injuries by age as a preliminary study to elucidate the incidence of sentinel injuries among patients who visited hospitals nationwide. METHOD: This study was designed using the Delphi method with a structured questionnaire. An extensive literature review was conducted to develop the questionnaire. The 9 participants selected as experts in child abuse were all experienced pediatric emergency medicine specialists working at pediatric emergency medicine training hospitals in South Korea, and 8 participants responded to the first survey. The Delphi method comprised 3 rounds of online surveys using Google Forms and Excel sheet questionnaire via e-mail. Only questions that achieved consensus were selected and assigned a sentinel injury disease code. RESULTS: In total, 105 questions regarding the definition of sentinel injury disease codes were surveyed as to whether they should be included as sentinel injuries, categorized by type (bruises, burns, open wounds/lacerations, and others) and anatomical location. Among them, 5 (62.5%) or more participants agreed on 92 items. CONCLUSIONS: Using the Delphi method, we defined disease codes for sentinel injuries in children aged younger than 12 months, possibly enabling assessment of the incidence of child abuse based on national data. Future research is needed to validate this result and investigate the incidence of sentinel injuries using the defined disease codes and to determine their association with actual cases of child abuse.

Monitoring and risk analysis of residual pesticides drifted by unmanned aerial spraying.

This study aimed to investigate the residual characteristics of pesticides drifted by unmanned aerial spray according to buffer strip, windbreak, and morphological characteristics of non-target crops, suggest prevention for drift reduction, and finally conduct a risk analysis on pesticides exceeding the maximum residue limit (MRL) or uniform level (0.01 mg/kg) of the positive list system (PLS). Non-target crops were collected around the aerial sprayed area (paddy rice) in Boryeong, Seocheon, and Pyeongtaek after UAV spray. When pesticides were detected in more than three samples, Duncan's multiple range test was performed. In cases where pesticides were detected in only two samples, an independent sample t-test was conducted (p < 0.05). The drift rate of pesticides tends to decrease by up to 100% as the buffer distance from aerial sprayed area increases or when a windbreak, such as maize, is present between two locations. Thus, the reduction of drifted pesticides could be effective if both factors were applied near the UAV spray area. Moreover, the residue of drifted pesticides was found to be the highest in leafy vegetables such as perilla leaves or leaf and stem vegetables such as Welsh onion, followed by fruit vegetables and cucurbits, owing to the morphological characteristics of crops. Therefore, selecting pulse or cereal such as soybean or maize as a farm product near the UAV spray area can be considered to minimize the drift. For pesticides that exceed the MRL or PLS uniform level, %acceptable dietary intake is 0-0.81% with no risk. Additionally, employing pesticides approved for both paddy rice and farm products in UAV spraying can effectively minimize instances where MRL or PLS are exceeded. Therefore, this study aims to provide farmers with effective guidelines for mitigating drift. Furthermore, we strive to promote stable and uninterrupted food production while facilitating the utilization of agricultural technologies such as UAV spraying to address labor shortages and ensure sustainable food security.

Receptor-specific contributions of caveolae, PKC, and Src tyrosine kinase to serotonergic and adrenergic regulation of Kv channels and vasoconstriction.

AIMS: Caveolae are invaginated, Ω-shaped membrane structures. They are now recognized as portals for signal transduction of multiple chemical and mechanical stimuli. Notably, the contribution of caveolae has been reported to be receptor-specific. However, details of how they differentially contribute to receptor signaling remain unclear. MAIN METHODS: Using isometric tension measurements, patch-clamping, and western blotting, we examined the contribution of caveolae and their related signaling pathways to serotonergic (5-HT2A receptor-mediated) and adrenergic (α1-adrenoceptor-mediated) signaling in rat mesenteric arteries. KEY FINDINGS: Disruption of caveolae by methyl-ß-cyclodextrin effectively blocked vasoconstriction mediated by the 5-HT2A receptor (5-HT2AR), but not by the α1-adrenoceptor. Caveolar disruption selectively impaired 5-HT2AR-mediated voltage-dependent K+ channel (Kv) inhibition, but not α1-adrenoceptor-mediated Kv inhibition. In contrast, both serotonergic and α1-adrenergic effects on vasoconstriction, as well as Kv currents, were similarly blocked by the Src tyrosine kinase inhibitor PP2. However, inhibition of protein kinase C (PKC) by either GO6976 or chelerythrine selectively attenuated the effects mediated by the α1-adrenoceptor, but not by 5-HT2AR. Disruption of caveolae decreased 5-HT2AR-mediated Src phosphorylation, but not α1-adrenoceptor-mediated Src phosphorylation. Finally, the PKC inhibitor GO6976 blocked Src phosphorylation by the α1-adrenoceptor, but not by 5-HT2AR. SIGNIFICANCE: 5-HT2AR-mediated Kv inhibition and vasoconstriction are dependent on caveolar integrity and Src tyrosine kinase, but not on PKC. In contrast, α1-adrenoceptor-mediated Kv inhibition and vasoconstriction are not dependent on caveolar integrity, but rather on PKC and Src tyrosine kinase. Caveolae-independent PKC is upstream of Src activation for α1-adrenoceptor-mediated Kv inhibition and vasoconstriction.

Survival outcomes of laparoscopic versus open radical hysterectomy in early cervical cancer with incidentally identified high-risk factors.

OBJECTIVE: Previously, we suggested that patients with cervical cancer (CC) with tumors ≤2 cm on preoperative magnetic resonance imaging (MRI) are safe candidates for laparoscopic radical hysterectomy (LRH). Here, we aim to investigate whether LRH deteriorates the prognosis of patients with incidentally identified high-risk factors; lymph node metastasis (LNM) or parametrial invasion (PMI). METHODS: We identified patients with 2009 FIGO stage IB1 CC who underwent Type C LRH or open radical hysterectomy (ORH) at three tertiary hospitals between 2000 and 2019. Those with a tumor ≤2 cm on preoperative MRI who were not suspicious of LNM or PMI preoperatively were included, while those who were indicated to receive adjuvant treatment but did not actually receive it were excluded. Survival outcomes were compared between the LRH and ORH groups in the overall population, then narrowed down to those with LNM, and then to those with PMI. RESULTS: In total, 498 patients were included: 299 in the LRH group and 199 in the ORH group. The LRH and ORH groups showed similar 3-year progression-free survival (PFS) (94.0% vs. 93.6%; P = 0.615) and 5-year overall survival (OS) rates (97.2% vs. 96.8%; P = 0.439). On pathologic examination, 49 (9.8%) and 16 (3.2%) patients had LNM and PMI, respectively, and 10 (2.0%) had both. In the LNM subgroup, 5-year PFS rate was not significantly different between the LRH and ORH groups (73.2% vs. 91.7%; P = 0.169). In the PMI subgroup, no difference in PFS was observed between the two groups (P = 0.893). CONCLUSIONS: LRH might not deteriorate recurrence and mortality rates in CC patients with tumors ≤2 cm when adjuvant treatment is appropriately administered, even if pathologic LNM and PMI are incidentally identified.

Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism.

Changes in the DNA damage response (DDR) and cellular metabolism are two important factors that allow cancer cells to proliferate. DDR is a set of events in which DNA damage is recognized, DNA repair factors are recruited to the site of damage, the lesion is repaired, and cellular responses associated with the damage are processed. In cancer, DDR is commonly dysregulated, and the enzymes associated with DDR are prone to changes in ubiquitination. Additionally, cellular metabolism, especially glycolysis, is upregulated in cancer cells, and enzymes in this metabolic pathway are modulated by ubiquitination. The ubiquitin-proteasome system (UPS), particularly E3 ligases, act as a bridge between cellular metabolism and DDR since they regulate the enzymes associated with the two processes. Hence, the E3 ligases with high substrate specificity are considered potential therapeutic targets for treating cancer. A number of small molecule inhibitors designed to target different components of the UPS have been developed, and several have been tested in clinical trials for human use. In this review, we discuss the role of ubiquitination on overall cellular metabolism and DDR and confirm the link between them through the E3 ligases NEDD4, APC/CCDH1, FBXW7, and Pellino1. In addition, we present an overview of the clinically important small molecule inhibitors and implications for their practical use.

Murine Coronavirus Disease 2019 Lethality Is Characterized by Lymphoid Depletion Associated with Suppressed Antigen-Presenting Cell Functionality.

The disease severity of coronavirus disease 2019 (COVID-19) varies considerably from asymptomatic to serious, with fatal complications associated with dysregulation of innate and adaptive immunity. Lymphoid depletion in lymphoid tissues and lymphocytopenia have both been associated with poor disease outcomes in patients with COVID-19, but the mechanisms involved remain elusive. In this study, human angiotensin-converting enzyme 2 (hACE2) transgenic mouse models susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were used to investigate the characteristics and determinants of lethality associated with the lymphoid depletion observed in SARS-CoV-2 infection. The lethality of Wuhan SARS-CoV-2 infection in K18-hACE2 mice was characterized by severe lymphoid depletion and apoptosis in lymphoid tissues related to fatal neuroinvasion. The lymphoid depletion was associated with a decreased number of antigen-presenting cells (APCs) and their suppressed functionality below basal levels. Lymphoid depletion with reduced APC function was a specific feature observed in SARS-CoV-2 infection but not in influenza A infection and had the greatest prognostic value for disease severity in murine COVID-19. Comparison of transgenic mouse models resistant and susceptible to SARS-CoV-2 infection revealed that suppressed APC function could be determined by the hACE2 expression pattern and interferon-related signaling. Thus, we demonstrated that lymphoid depletion associated with suppressed APC function characterizes the lethality of COVID-19 mouse models. Our data also suggest a potential therapeutic approach to prevent the severe progression of COVID-19 by enhancing APC functionality.