PKA inhibition is a central step in D,L-methadone-induced ER Ca2+ release and subsequent apoptosis in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a hematologic cancer that mostly affects children. It accounts for over a quarter of ALL pediatric cancers, causing most of the cancer death among children. Previously, we demonstrated that D,L-methadone causes ALL cell apoptosis via µ-opioid receptor 1 (OPRM1)-triggered ER Ca2+ release and decrease in Ca2+ efflux, elevating [Ca2+]i. However, the precise mechanism by which D,L-methadone induces ER Ca2+ release remains to be defined. Here, we show that in ALL cells, D,L-methadone-induced ER Ca2+ release is blocked by inhibition of Gαi, but not Gßϒ, indicating that the process is dependent on Gαi. Activation of adenylyl cyclase (AC) with forskolin or treatment with 8-CPT-cAMP blocks D,L-methadone-induced ER Ca2+ release, indicating that the latter results from Gαi-dependent downregulation of AC and cAMP. The 14-22 amide (myr) PKA inhibitor alone elicits ER Ca2+ release, and subsequent treatment with D,L-methadone does not cause additional ER Ca2+ release, indicating that PKA inhibition is a key step in D,L-methadone-induced ER Ca2+ release and can bypass the D,L-methadone-OPRM1-AC-cAMP step. This is consistent with the decrease in PKA-dependent (i) inhibitory PLCß3 Ser1105 phosphorylation that leads to PLCß3 activation and ER Ca2+ release, and (ii) BAD Ser118 phosphorylation, which together ultimately result in caspase activation and apoptosis. Thus, our findings indicate that D,L-methadone-induced ER Ca2+ release and subsequent apoptosis in ALL cells is mediated by Gαi-dependent downregulation of the AC-cAMP-PKA-PLCß3/BAD pathway. The fact that 14-22 amide (myr) alone effectively kills ALL cells suggests that PKA may be targeted for ALL therapy.

Evaluation of histological variants of upper tract urothelial carcinoma as prognostic factor after radical nephroureterectomy.

PURPOSE: To evaluate the impact of variant histology on patients with upper tract urothelial carcinoma (UTUC) survival outcomes. MATERIALS AND METHODS: A total of 519 patients underwent radical nephroureterectomy without neoadjuvant therapy for UTUC at a single institution between May 2003 and December 2019. Multivariate Cox regression analysis evaluated the impact of variant histology on progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: Among 84 patients (16.2%) with variant histology, the most frequent variant type was squamous cell differentiation (64.3%), followed by glandular differentiation (25.0%) and sarcomatoid variant (2.4%). They showed pathologically advanced T stage (for ≥ T3, 59.5% vs 33.3%, p < 0.001), higher tumor grade (96.4% vs 85.7%, p = 0.025), and higher rates of lymph node metastasis (17.9% vs 7.8%, p = 0.015), angiolymphatic invasion (41.7% vs 25.7%, p = 0.003), tumor necrosis (57.1% vs 29.0%, p < 0.001) and positive surgical margin (13.1% vs 5.7%, p = 0.015). On multivariate Cox regression analyses, variant histology was significantly associated with worse PFS (hazard ratio [HR] 2.23; 95% confidence interval [CI] 1.55-3.21; p < 0.001), CSS (HR 2.67; 95% CI 1.35-5.30; p = 0.005) and OS (HR 2.22; 95% CI 1.27-3.88; p = 0.005). In subgroup analysis, no significant survival gains of adjuvant chemotherapy occurred in patients with variant histology. CONCLUSIONS: Variant histology was associated with adverse pathologic features and poor survival outcomes. Our results suggest that patients with variant histology may require a close follow-up schedule and novel adjuvant therapy other than chemotherapy postoperatively.

The role of preoperative immune cell metrics in renal cell carcinoma with a tumor thrombus.

INTRODUCTION: The objective of this study was to stratify preoperative immune cell counts by cancer specific outcomes in patients with renal cell carcinoma (RCC) and a tumor thrombus after radical nephrectomy with tumor thrombectomy. METHODS: Patients with a diagnosis of RCC with tumor thrombus that underwent radical nephrectomy with thrombectomy across an international consortium of seven institutions were included. Patients who were metastatic at diagnosis and those who received preoperative medical treatment were also included. Retrospective chart review was performed to collect demographic information, past medical history, preoperative lab work, surgical pathology, and follow up data. Neutrophil counts, lymphocyte counts, monocyte counts, neutrophil to lymphocyte ratios (NLR), lymphocyte to monocyte ratios (LMR), and neutrophil to monocyte ratios (NMR) were compared against cancer-specific outcomes using independent samples t-test, Pearson's bivariate correlation, and analysis of variance. RESULTS: One hundred forty-four patients were included in the study, including nine patients who were metastatic at the time of surgery. Absolute lymphocyte count preoperatively was greater in patients who died from RCC compared to those who did not (2 vs 1.4; p < 0.001). Patients with tumor pathology showing perirenal fat invasion had a greater neutrophil count compared to those who did not (7.5 vs 5.5; p = 0.010). Patients with metastatic RCC had a lower LMR compared to those without metastases after surgery (2.5 vs 3.2; p = 0.041). Tumor size, both preoperatively and on gross specimen, had an interaction with multiple immune cell metrics (p < 0.05). CONCLUSIONS: Preoperative immune metrics have clinical utility in predicting cancer-specific outcomes for patients with RCC and a tumor thrombus. Additional study is needed to determine the added value of preoperative serum immune cell data to established prognostic risk calculators for this patient population.

Machine learning models for predicting the onset of chronic kidney disease after surgery in patients with renal cell carcinoma.

BACKGROUND: Patients with renal cell carcinoma (RCC) have an elevated risk of chronic kidney disease (CKD) following nephrectomy. Therefore, continuous monitoring and subsequent interventions are necessary. It is recommended to evaluate renal function postoperatively. Therefore, a tool to predict CKD onset is essential for postoperative follow-up and management. METHODS: We constructed a cohort using data from eight tertiary hospitals from the Korean Renal Cell Carcinoma (KORCC) database. A dataset of 4389 patients with RCC was constructed for analysis from the collected data. Nine machine learning (ML) models were used to classify the occurrence and nonoccurrence of CKD after surgery. The final model was selected based on the area under the receiver operating characteristic (AUROC), and the importance of the variables constituting the model was confirmed using the shapley additive explanation (SHAP) value and Kaplan-Meier survival analyses. RESULTS: The gradient boost algorithm was the most effective among the various ML models tested. The gradient boost model demonstrated superior performance with an AUROC of 0.826. The SHAP value confirmed that preoperative eGFR, albumin level, and tumor size had a significant impact on the occurrence of CKD after surgery. CONCLUSIONS: We developed a model to predict CKD onset after surgery in patients with RCC. This predictive model is a quantitative approach to evaluate post-surgical CKD risk in patients with RCC, facilitating improved prognosis through personalized postoperative care.

Design, Synthesis, and Acid-Responsive Disassembly of Shell-Sheddable Block Copolymer Labeled with Benzaldehyde Acetal Junction.

Smart nanoassemblies degradable through the cleavage of acid-labile linkages have attracted significant attention because of their biological relevance found in tumor tissues. Despite their high potential to achieve controlled/enhanced drug release, a systematic understanding of structural factors that affect their pH sensitivity remains challenging, particulary in the consruction of effective acid-degradable shell-sheddable nanoassemblies. Herein, the authors report the synthesis and acid-responsive degradation through acid-catalyzed hydrolysis of three acetal and ketal diols and identify benzaldehyde acetal (BzAA) exhibiting optimal hydrolysis profiles in targeted pH ranges to be a suitable candidate for junction acid-labile linkage. The authors explore the synthesis and aqueous micellization of well-defined poly(ethylene glycol)-based block copolymer bearing BzAA linkage covalently attached to a polymethacrylate block for the formation of colloidally-stable nanoassemblies with BzAA groups at core/corona interfaces. Promisingly, the investigation on acid-catalyzed hydrolysis and disassembly shows that the formed nanoassemblies meet the criteria for acid-degradable shell-sheddable nanoassemblies: slow degradation at tumoral pH = 6.5 and rapid disassembly at endo/lysosomal pH = 5.0, while colloidal stability at physiological pH = 7.4. This work guides the design principle of acid-degradable shell-sheddable nanoassemblies bearing BzAA at interfaces, thus offering the promise to address the PEG dilemma and improve endocytosis in tumor-targeting drug delivery.

Survival pattern of metastatic renal cell carcinoma patients according to WHO/ISUP grade: a long-term multi-institutional study.

The World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading of renal cell carcinoma (RCC) is classified from grade 1-4, regardless of subtype. The National Comprehensive Cancer Network (NCCN) guidelines (2022) state that if there is an adverse pathological feature, such as grade 3 or higher RCC in stage 1 patients, more rigorous follow-up imaging is recommended. However, the RCC guidelines do not provide specific treatment or follow-up policies by tumor grade. Therefore, this study attempted to find out whether tumor grade affects survival rates in patients with metastatic RCC. The Korean Renal Cancer Study Group (KRoCS) database includes 3108 patients diagnosed with metastatic RCC between September 1992 and February 2017, with treatment methods, progression, and survival data collected from 11 tertiary hospitals. To obtain information on survival rates or causes of death, we utilized the Korea National Statistical Office database and institutional medical records. Data were accessed for research purpose on June, 2023. We then reviewed these sources to gather comprehensive and reliable data on the outcomes of our study cohort. This database was retrospectively analyzed, and out of 3108 metastatic RCC patients, 911 had been identified as WHO/ISUP grade. Grades were classified into either a low-grade (WHO/ISUP grade 1-2) or a high-grade group (WHO/ISUP grade 3-4). The patients were then analyzed related to progression and overall survival (OS). In metastatic clear cell RCC patients, the 1-year OS rate was 69.4% and the median OS was 17.0 months (15.5-18.5) followed up to 203.6 months. When comparing the patient groups, 119 low-grade and 873 high-grade cases were identified. No baseline difference was observed between the two groups, except that the high-grade group had a higher ECOG 1 ratio of 50.4% compared with 34.5% for the low-grade group (p = 0.009). There was a significant difference in OS between high-grade and low-grade groups. OS was 16.0 months (14.6-17.4) in the high-grade group and 28.0 months (21.1-34.9) in the low-grade group (p < 0.001). However, there was no difference in progression-free survival (PFS) rates with 9.0 months (8.0-10.0) for the high-grade group and 10.0 months (6.8-13.2) for the low-grade group (p = 0.377) in first-line treatment. In multivariable analysis, WHO/ISUP grade was a risk factor (HR = 1.511[1.135-2.013], p = 0.005) that influenced the OS. In conclusion, WHO/ISUP grade is a major data source that can be used as a ubiquitous marker of metastatic RCC in pre-IO era. Depending on whether the RCC is high or low grade, the follow-up schedule will need to be tailored according to grade, with higher-grade patients needing more active treatment as it can not only affect the OS in the previously known localized/locoregional recurrence but also the metastatic RCC patient.

Retrospective Multicenter Analysis of Prognostic Risk Factors for One Year Recurrence in Patient With Renal Cell Carcinoma After Partial or Radical Nephrectomy: Results of Korean Renal Cancer Study Group (KRoCS) Database.

BACKGROUND: We sought to identify prognostic risk factors for one year recurrence in patient with renal cell carcinoma (RCC) after partial or radical nephrectomy. METHODS: We performed a retrospective study of 1,269 patients with RCC after partial or radical nephrectomy and diagnosed recurrence using Korean Renal Cancer Study Group (KRoCS) database between January 1991 and March 2017. Recurrence-free survival (RFS), and overall survival (OS) were calculated using the Kaplan-Meier method and multivariate Cox regression analysis were performed to evaluate independent prognostic factors for recurrence. RESULTS: The median patient age was 56 years and median follow-up period was 67 months. Multivariable analysis demonstrated BMI greater than or equal to 23 and less than 30 (vs. BMI less than 23, hazard ratio [HR]: 0.707, P = 0.020) reduced recurrence one year postoperatively. Eastern Cooperative Oncology Group performance status (ECOG PS) greater than or equal to 1 (vs. ECOG PS 0, HR: 1.548, P = 0.007), high pathological T stage (pT2 vs. pT1, HR: 2.622, P < 0.001; pT3 vs. pT1, HR: 4.256, P < 0.001; pT4 vs. pT1, HR: 4.558, P < 0.001), and tumor necrosis (vs. no tumor necrosis, HR: 2.822, P < 0.001) were independent predictive factors for early recurrence within one year in patients with RCC. Statistically significant differences on RFS and OS were found among pathological T stages (pT2 vs. pT1; pT3 vs. pT1; pT4 vs. pT1, all P < 0.001). CONCLUSION: This large multicenter study demonstrated ECOG PS greater than or equal to 1, high pathological T stage, tumor necrosis and BMI less than 23 were significant prognostic risk factors of early recurrence within one year in patients with RCC who underwent nephrectomy.

Partial gland ablation using high-intensity focused ultrasound versus robot-assisted radical prostatectomy: a propensity score-matched study.

Background: We compared the clinical outcomes of robot-assisted radical prostatectomy (RARP) and partial gland ablation (PGA) using high-intensity focused ultrasound (HIFU) in localized prostate cancer. Methods: We analyzed 3,859 patients who had undergone RARP and PGA using HIFU. According to the propensity score for each treatment, 137 patients after PGA were matched to 3,722 patients after RARP at a 1:4 ratio using the nearest neighbor method. Results: The matched cohort comprised 685 subjects (RARP, 548; PGA, 137), with a median follow-up period of 22 months. Treatment failures were identified in 13.9% and 9.1% of patients in the PGA and RARP groups, respectively, after a median follow-up of 36 months postoperatively. Kaplan-Meier analyses revealed significantly longer failure-free (P < 0.001) and salvage-free survival (P = 0.003) in the RARP group than in the PGA group. There was no significant difference in the postoperative urinary symptom score (P = 0.748), but the postoperative erectile function score was significantly higher in the PGA group (P < 0.001). The rate of urinary incontinence (any pad) was significantly lower in the PGA group than that in the RARP group (P < 0.001). Postoperative complications were more frequent in the PGA group (P = 0.003); however, there was no significant difference in high-grade complications (≥3) (P = 0.467). Conclusion: PGA using HIFU showed statistically inferior oncological outcomes compared with RARP for failure-free survival and salvage-free survival. However, functional outcomes regarding postoperative incontinence and erectile dysfunction were more favorable in the PGA group.

Computer tomography-based shape of tumor contour and texture of tumor heterogeneity are independent prognostic indicators for clinical T1b-T2 renal cell carcinoma.

PURPOSE: To evaluate association between computer tomography (CT)-based features of renal cell carcinoma (RCC) and survival outcomes. METHODS: Data of 958 patients with clinical T1b-T2 RCC who underwent partial/radical nephrectomy from June 2003 to March 2022 were retrospectively evaluated. CT images of patients were reviewed by two radiologists for texture analysis of tumor heterogeneity and shape analysis of tumor contour. Patients were divided into three groups according to patterns of CT-based features: (1) favorable feature group (n = 117); (2) intermediate feature group (n = 606); and (3) unfavorable feature group (n = 235). Kaplan-Meier survival analysis and multivariate Cox regression analysis were performed to evaluate overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS). RESULTS: RCCs with unfavorable CT-based feature showed larger size on CT, higher nuclear grade, higher rate of histologic necrosis, and higher rate of capsular invasion than those in the other two groups (all p < 0.001). Unfavorable feature was associated with poorer OS (p = 0.001), CSS (p < 0.001), and RFS (p < 0.001) on Kaplan-Meier analysis. In multivariate analysis, intermediate and unfavorable features were independent predictors for recurrence (hazard ratio [HR] 2.51, 95% confidence interval [CI] 1.09-5.79, p = 0.031 and HR 3.71, 95% CI 1.58-8.73, p = 0.003, respectively), but not for overall death or RCC-specific death. CONCLUSIONS: A combination of irregular tumor contour feature with heterogeneous tumor texture feature on CT is associated with poor RFS in clinical T1b-T2 RCC preoperatively.

Does COVID-19 Infection within 1 Week after Total Knee Arthroplasty Affect Patients' Early Clinical Outcomes? A Matched Case-Control Study.

Recent studies have reported the impact of previous COVID-19 infection on the early clinical outcome after total knee arthroplasty (TKA). However, the timing of infection before the surgery was not constant and a study on patients with COVID-19 infection within 1 week after TKA is lacking. This study aimed to determine the effect of COVID-19 infection within one week after TKA on the postoperative outcomes and to compare the early clinical outcomes to those who were not infected with COVID-19 before and after surgery. No significant differences were observed between the two groups in terms of clinical outcomes or complications. The length of the hospital stay (LOS) was significantly longer for the COVID-19 group than for the non-COVID-19 group (p < 0.05). The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were higher for the study group on postoperative days 9 and 12 than for those in the control group (p < 0.05). However, D-dimer levels were not significantly different between the two groups. We should cautiously consider that COVID-19 infection within 1 week after TKA may be associated with increased ESR, CRP levels, and length of hospital stay, but they are not associated with the worsening of early clinical outcomes or the occurrence of complications.

Reconstruction of a temporal scalp defect without ipsilateral donor vessel possibilities using a local transposition flap and a latissimus dorsi free flap anastomosed to the contralateral side: a case report.

Scalp defects necessitate diverse approaches for successful reconstruction, taking into account factors such as defect size, surrounding tissue, and recipient vessel quality. This case report presents a challenging scenario involving a temporal scalp defect where ipsilateral recipient vessels were unavailable. The defect was effectively reconstructed utilizing a transposition flap and a latissimus dorsi free flap, which was anastomosed to the contralateral recipient vessels. Our report underscores the successful reconstruction of a scalp defect in the absence of ipsilateral recipient vessels, emphasizing the importance of employing appropriate surgical interventions without necessitating vessel grafts.

Interpretation of the effects of anthropogenic chlorine on nitrate formation over northeast Asia during KORUS-AQ 2016.

The Weather Research and Forecasting-Community Multiscale Air Quality (WRF-CMAQ) model, implemented with anthropogenic chlorine (Cl) emissions, was evaluated against ground and NASA DC-8 aircraft measurements during the Korea-United States Air Quality (KORUS-AQ) 2016 campaign. The latest anthropogenic Cl emissions, including gaseous HCl and particulate chloride (pCl-) emissions from the Anthropogenic Chlorine Emissions Inventory of China (ACEIC-2014) (over China) and a global emissions inventory (Zhang et al., 2022) (over outer China), were used to examine the impacts of Cl emissions and the role of nitryl chloride (ClNO2) chemistry in N2O5 heterogeneous reactions on secondary nitrate (NO3-) formation across the Korean Peninsula. The model results against aircraft measurements clearly showed significant Cl- underestimations due mainly to the high gas-particle (G/P) partitioning ratios at aircraft measurement altitudes such as 700-850 hPa, but the ClNO2 simulations were reasonable. Several simulations of CMAQ-based sensitivity experiments against ground measurements indicated that although addition of Cl emission did not significantly alter NO3- formation, the activated ClNO2 chemistry with Cl emissions showed the best model performance with the reduced normalized mean bias (NMB) of 18.7 % compared to a value of 21.1 % for the Cl emissions-free case. In our model evaluation, ClNO2 accumulated during the night but quickly produced Cl radical due to ClNO2 photolysis at sunrise, which modulated other oxidation radicals (e.g., ozone [O3] and hydrogen oxide radicals [HOx]) in the early morning. In the morning hours (0800-1000 LST), the HOx were the dominant oxidants, contributing 86.6 % of the total oxidation capacity (sum of major oxidants such as O3 and HOx species), while oxidability was enhanced by up to ∼6.4 % (increase in 1 h HOx average of 2.89 × 106 molecules·cm-3) in the early morning mainly due to the changes in OH (+7.2 %), hydroperoxyl radical (HO2)(+10.0 %), and O3 (+4.2 %) over the Seoul Metropolitan Area, during the KORUS-AQ campaign. Our results improve understanding of the atmospheric changes in the PM2.5 formation pathway caused by ClNO2 chemistry and Cl emissions over northeast Asia.

Machine learning based prediction for oncologic outcomes of renal cell carcinoma after surgery using Korean Renal Cell Carcinoma (KORCC) database.

We developed a novel prediction model for recurrence and survival in patients with localized renal cell carcinoma (RCC) after surgery and a novel statistical method of machine learning (ML) to improve accuracy in predicting outcomes using a large Asian nationwide dataset, updated KOrean Renal Cell Carcinoma (KORCC) database that covered data for a total of 10,068 patients who had received surgery for RCC. After data pre-processing, feature selection was performed with an elastic net. Nine variables for recurrence and 13 variables for survival were extracted from 206 variables. Synthetic minority oversampling technique (SMOTE) was used for the training data set to solve the imbalance problem. We applied the most of existing ML algorithms introduced so far to evaluate the performance. We also performed subgroup analysis according to the histologic type. Diagnostic performances of all prediction models achieved high accuracy (range, 0.77-0.94) and F1-score (range, 0.77-0.97) in all tested metrics. In an external validation set, high accuracy and F1-score were well maintained in both recurrence and survival. In subgroup analysis of both clear and non-clear cell type RCC group, we also found a good prediction performance.

Strategy for resurfacing complex extremity defect with chimeric, linked flaps: A review with a 10-year experience at major trauma center.

For the reconstruction of the extensive and/or three-dimensional soft-tissue defect in upper and lower extremities, chimeric flaps composed of multiple flaps or tissues with separate vascular supplies can supply economical use of tissue and superior esthetic results. Herein, we investigated the effectiveness of the thoracodorsal axis chimeric flap through the review the largest collection of long-term data. A retrospective review of all patients who received the thoracodorsal axis chimeric flap in complex three-dimensional defects of extremities between January of 2012 and December of 2021. A total of 55 type I/IP classical chimeric flaps, 19 type II/IIP anastomotic chimeric flaps, five type III perforator chimeric flaps, and seven type IV mixed chimeric flaps were analyzed. As the reconstructed area became proximal, flap dimensions increased significantly. And the optimal flap type depended on the location. The TDAp flap can provide large dimensions of skin paddle with latissimus dorsi and serratus anterior muscles with acceptable donor-site morbidities. The TDAp chimeric flaps constructed by microvascular anastomosis of two free flaps can provide large skin dimensions but also tissues with different properties. These characteristics make it possible to resurface the large and extensive defects, reconstruct the complex distal extremity defects, needing tissues with different properties, and cover the three-dimensional defect, obliterating the dead space. The thoracodorsal axis chimeric flap could be a favorable option for extensive, complex, or three-dimensional defects of the upper and lower extremities based on its reliability of the vascular system.

Requirement for ER-mitochondria Ca2+ transfer, ROS production and mPTP formation in L-asparaginase-induced apoptosis of acute lymphoblastic leukemia cells.

Acute lymphoblastic leukemia (aLL) is a malignant cancer in the blood and bone marrow characterized by rapid expansion of lymphoblasts. It is a common pediatric cancer and the principal basis of cancer death in children. Previously, we reported that L-asparaginase, a key component of acute lymphoblastic leukemia chemotherapy, causes IP3R-mediated ER Ca2+ release, which contributes to a fatal rise in [Ca2+]cyt, eliciting aLL cell apoptosis via upregulation of the Ca2+-regulated caspase pathway (Blood, 133, 2222-2232). However, the cellular events leading to the rise in [Ca2+]cyt following L-asparaginase-induced ER Ca2+ release remain obscure. Here, we show that in acute lymphoblastic leukemia cells, L-asparaginase causes mitochondrial permeability transition pore (mPTP) formation that is dependent on IP3R-mediated ER Ca2+ release. This is substantiated by the lack of L-asparaginase-induced ER Ca2+ release and loss of mitochondrial permeability transition pore formation in cells depleted of HAP1, a key component of the functional IP3R/HAP1/Htt ER Ca2+ channel. L-asparaginase induces ER Ca2+ transfer into mitochondria, which evokes an increase in reactive oxygen species (ROS) level. L-asparaginase-induced rise in mitochondrial Ca2+ and reactive oxygen species production cause mitochondrial permeability transition pore formation that then leads to an increase in [Ca2+]cyt. Such rise in [Ca2+]cyt is inhibited by Ruthenium red (RuR), an inhibitor of the mitochondrial calcium uniporter (MCU) that is required for mitochondrial Ca2+ uptake, and cyclosporine A (CsA), an mitochondrial permeability transition pore inhibitor. Blocking ER-mitochondria Ca2+ transfer, mitochondrial ROS production, and/or mitochondrial permeability transition pore formation inhibit L-asparaginase-induced apoptosis. Taken together, these findings fill in the gaps in our understanding of the Ca2+-mediated mechanisms behind L-asparaginase-induced apoptosis in acute lymphoblastic leukemia cells.

Optimal management of renal cell carcinoma in octogenarians: Retrospective analysis using updated Korean Renal Cell Carcinoma (KORCC) database.

BACKGROUND: There is few of optimal management guideline in elderly patients with renal cell carcinoma (RCC). To compare the survival outcomes of octogenarian RCC group and younger RCC group after surgery using nationwide multi-institutional database. METHODS: A total of 10,068 patients who underwent surgery for RCC were included in the current retrospective, multi-institutional study. A propensity score matching (PSM) analysis was conducted to control other confounding factors in analyzing survival outcomes of octogenarian and younger group RCCs. Kaplan-Meier curve analysis to calculate the survival estimates for cancer-specific survival (CSS) and overall survival (OS), and multivariate Cox-proportional hazard regression analyses to evaluate the significant variables associated with the survival outcomes were also performed. RESULTS: Both groups were well-balanced in all baseline characteristics. In a total cohort, Kaplan-Meier survival analysis showed a significantly decreased 5-year and 8-year CSS and OS in the octogenarian group compared with the younger group. However, in a PSM cohort, no significant differences were evident between the two groups in terms of CSS (5-year, 87.3% vs. 87.0%; 8-year, 82.2% vs. 78.9%, respectively, log-rank test, p = 0.964). In addition, age ≥ 80 years (HR, 1.199; 95% CI, 0.497-2.896, p = 0.686) was not a significant prognostic factor of CSS in a PSM cohort. CONCLUSIONS: The octogenarian RCC group after surgery had comparable survival outcomes compared with younger group after PSM analysis. For the life expectancy of octogenarian is getting longer, active treatment is considerable in patients with good performance status.

Preparation of a Convertible Spacer Containing a Disulfide Group for Versatile Functionalization of Oligonucleotides.

The protocols described in this article provide details regarding the synthesis and characterization of a disulfide containing linker phosphoramidite for terminal functionalization of synthetic oligonucleotides. The linker is first synthesized from 6-mercaptohexanol in two steps and is incorporated at the 5' end of short DNA oligonucleotides using automated solid-phase synthesis. The linker contains a terminal tosylate group which is post-synthetically displaced by altering the deprotection conditions to yield a variety of functional handles (N3 , NH2 , OMe, SH) or alternatively, the tosylate can be displaced directly with primary amines such as tert-butylamine. The linker system is also compatible with RNA oligonucleotides enabling the introduction of various functional handles (N3 , NH2 ). The protocol outlined in this procedure provides access to a versatile linker for the terminal functionalization of oligonucleotides containing a disulfide bond which may serve useful in the synthesis of reduction-responsive oligonucleotide conjugates. As a proof of concept, in this protocol the linker is used to modify a dT10 oligonucleotide and then conjugated by copper(I)-mediated azide-alkyne cycloaddition (CuAAC) to an alkyne-modified poly(ethylene glycol) which shows concentration dependent release of the oligonucleotide upon treatment with 1,4-dithiothreitol, a reducing agent. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Preparation of disulfide linker phosphoramidite 3 Basic Protocol 2: Synthesis, functionalization, and characterization of DNA oligonucleotides containing disulfide linker phosphoramidite 3 Basic Protocol 3: Displacement of terminal tosylate functionalized DNA with primary aliphatic amines Basic Protocol 4: Synthesis of oligonucleotide-PEG conjugate Support Protocol: Preparation of PEG-alkyne.

Polygenic risk score for tumor aggressiveness and early-onset prostate cancer in Asians.

We attempted to assess the performance of an ethnic-specific polygenic risk score (PRS) designed from a Korean population to predict aggressive prostate cancer (PCa) and early-onset (age < 60). A PRS score comprised of 22 SNPs was computed in 3695 patients gathered from one of 4 tertiary centers in Korea. Males with biopsy or radical prostatectomy-proven PCa were included for analysis, collecting additional clinical parameters such as age, BMI, PSA, Gleason Group (GG), and staging. Patients were divided into 4 groups of PRS quartiles. Intergroup differences were assessed, as well as risk ratio and predictive performance based on GG using logistic regression analysis and AUC. No significant intergroup differences were observed for BMI, PSA, and rate of ≥ T3a tumors on pathology. Rate of GG ≥ 2, GG ≥ 3, and GG ≥ 4 showed a significant pattern of increase by PRS quartile (p < 0.001, < 0.001, and 0.039, respectively). With the lowest PRS quartile as reference, higher PRS groups showed sequentially escalating risk for GG ≥ 2 and GG ≥ 3 pathology, with a 4.6-fold rise in GG ≥ 2 (p < 0.001) and 2.0-fold rise in GG ≥ 3 (p < 0.001) for the highest PRS quartiles. Combining PRS with PSA improved prediction of early onset csPCa (AUC 0.759) compared to PRS (AUC 0.627) and PSA alone (AUC 0.736). To conclude, an ethnic-specific PRS was found to predict susceptibility of aggressive PCa in addition to improving detection of csPCa when combined with PSA in early onset populations. PRS may have a role as a risk-stratification model in actual practice. Large scale, multi-ethnic trials are required to validate our results.

Biodegradable and hydrophobic nanofibrous membranes produced by solution blow spinning for efficient oil/water separation.

The development of nanofibrous oil-water separation materials is explosively progressing, but the remarkably low productivity is the main factor hindering their practical application. In this study, biodegradable polybutylene succinate (PBS) nanofibers with excellent productivity (27.0 g/h per nozzle) were successfully fabricated using the solution blow spinning (SBS) process, breaking away from the conventional electrospinning method. The prepared PBS nanofibers exhibited extremely thin fiber diameters (130 nm) with high porosity (97.4%). Without any chemical modification or inorganic/organic hybrid materialization, the PBS nanofibrous membrane showed excellent oil adsorption capacity (minimum: 18.7 g/g and maximum: 38.5 g/g) and separation efficiency; water and oil mixtures (99.4-99.98%) and emulsions (98.1-99.5%) compared to conventional organic polymer-based nanofibers. In terms of disposal after use, this biodegradable nanofibrous membrane was able to return to nature through hydrolysis and biodegradation processes.

Establishment of Prospective Registry of Active Surveillance for Prostate Cancer: The Korean Urological Oncology Society Database.

PURPOSE: To establish a prospective registry for the active surveillance (AS) of prostate cancer (PC) using the Korean Urological Oncology Society (KUOS) database and to present interim analysis. MATERIALS AND METHODS: The KUOS registry of AS for PC (KUOS-AS-PC) was organized in May 2019 and comprises multiple institutions nationwide. The eligibility criteria were as follows: patients with (1) pathologically proven PC; (2) pre-biopsy prostate-specific antigen (PSA) ≤20 ng/mL; (3) International Society of Urological Pathology (ISUP) grade 1 or 2 (no cribriform pattern 4); (4) clinical T stage ≤T2c; (5) positive core ratio ≤50%; and (6) maximal cancer involvement in the core ≤50%. Detailed longitudinal clinical information, including multi-parametric magnetic resonance imaging and disease-specific outcomes, was recorded. RESULTS: From May 2019 to June 2021, 296 patients were enrolled, and 284 were analyzed. The mean±standard deviation (SD) age at enrollment was 68.7±8.2 years. The median follow-up period was 11.2 months (5.9-16.8 mo). Majority of patients had pre-biopsy PSA ≤10 ng/mL (91.2%), PSA density <0.2 ng/mL² (79.7%), ISUP grade group 1 (94.4%), single positive core (65.7%), maximal cancer involvement in the core ≤20% (78.1%), and clinical T stage of T1c or lower (72.9%). Fifty-two (18.3%) discontinued AS for various reasons. Interventions included radical prostatectomy (80.8%), transurethral prostatectomy (5.8%), primary androgen deprivation therapy (5.8%), radiation (5.8%), and focal therapy (1.9%). The mean±SD time to intervention was 8.9±5.2 months. The reasons for discontinuation included pathologic reclassification (59.6%), patient preference (25.0%), and radiologic reclassification (9.6%). Two (4.8%) patients with pathologic Gleason score upgraded to ISUP grade group 4, no biochemical recurrence. CONCLUSIONS: The KUOS established a successful prospective database of PC patients undergoing AS in Korea, named the KUOS-AS-PC registry.