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Binh Thang Tran,1,2 Nhu Hiep Pham,3 Thanh Xuan Nguyen,3 Kui Son Choi,1,4 Dae Kyung Sohn,1,5 Sun-Young Kim,1 Jae Kyung Suh,6 Thuy Duyen Nguyen,1,7 Van Sang Phan,2 Dinh Trung Tran,8 The Thanh Nguyen,9 Thi Thanh Binh Nguyen,10 Minh Tu Nguyen,11 Jin-Kyoung Oh1,12 1Department of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea; 2Faculty of Public Health, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam; 3Department of Abdominal Emergency and Pediatric Surgery, Hue Central Hospital, Hue City, Vietnam; 4National Cancer Control Institute; National Cancer Center, Goyang, Republic of Korea; 5Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, South Korea; 6Division of Healthcare Technology Assessment Research, National Evidence-Based Healthcare Collaborating Agency, Seoul, Korea; 7Center for Population Health Sciences, Hanoi University of Public Health, Hanoi, Vietnam; 8Faculty of Public Health, Da Nang University of Medical Technology and Pharmacy, Da Nang City, Vietnam; 9Department of Endoscopy and Functional Exploration, Da Nang Oncology Hospital, Da Nang City, Vietnam; 10Department of Pediatrics, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam; 11Undergraduate Training Office, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam; 12Division of Cancer Prevention & Early Detection, National Cancer Center, Goyang, Republic of KoreaCorrespondence: Jin-Kyoung OhDepartment of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu, Goyang-si, Gyeonggi-do 410-769, Republic of KoreaTel +82-31-920-2921Fax +82-31-920-2929Email jkoh@ncc.re.krPurpose: Health-related quality of life (HRQoL) is an important construct in clinical settings, and it is crucial that it should be properly measured. As the EuroQol-5-dimensions-5 levels (EQ-5D-5L) is more effective for such measurement than the 3-level model, data on economic models, clinical studies, and public health evaluations previously collected through the EQ-5D-3L need to be revaluated using the EQ-5D-5L. This study evaluated colorectal cancer (CRC) patients’ HRQoL scores using the Vietnamese EQ-5D-5L value set.Patients and Methods: The cross-sectional study included CRC patients treated at a tertiary public hospital. HRQoL was assessed using the EQ-5D-5L, and HRQoL utility scores were calculated using the Vietnamese value set. Tobit regression examined factors associated with HRQoL.Results: The analysis included 197 CRC patients. Ages ranged from 20 to 87 years (M = 57.64, SD = 13.5); 42.2% and 57.8% were diagnosed with cancer of the colon or rectum/anus, respectively. Mean EQ-5D-5L was 0.561 (range, − 0.5115 to 1). Most participants experienced anxiety/depression (88%), followed by pain/discomfort (87%), mobility (71%), usual activity (69%), and self-care (67%). Advanced CRC stage (stage II: β − 0.303, se 0.08; stage III: β − 0.305, se 0.07; stage IV: β − 0.456, se 0.07) and surgery (β − 0.113, se 0.05) were negatively associated with EQ-5D-5L scores. Advanced education (high school: β 0.273, se 0.07); college/vocational: β 0.134se 0.05; university/higher: Coef 0.213, se 0.08;) and older age (age group 35− 44: β 0.253, se 0.10; 45− 54: β 0.327, se 0.09; 55− 64: β 0.355 se 0.09; 65+ β 0.204, se 0.09) were positively associated with EQ-5D-5L scores.Conclusion: Patients in advanced CRC stages or undergoing surgery experienced lower HRQoL and higher prevalence of anxiety/depression and pain/discomfort. Older age and high educational attainment predicted high HRQoL. This study provides information on CRC patients’ health utility based on various patient characteristics, which can be used in future economic evaluations.Keywords: HRQoL, EQ-5D-5L, utility, colorectal cancer, Vietnam

We examined the leukocyte relative telomere length (RTL) in Korean adolescent and young adult (AYA) survivors of childhood cancer and evaluated the association of leukocyte RTL with multiple factors, including malignancy type, cancer treatment, age, and chronic health conditions (CHCs). Eighty-eight AYA survivors of childhood cancer with a median follow-up period of 73 months were recruited. RTL in pediatric cancer survivors was not significantly shorter than the predicted value for age-matched references. Neither age at diagnosis nor duration of therapy influenced the RTL. Among the 43 patients with hematologic malignancies, those who underwent allogeneic hematopoietic stem cell transplantation (HSCT) showed a significant shortening of the RTL compared with those who did not ( p = 0.039). Among the 15 patients who underwent allogeneic HSCT, those who developed acute graft-versus-host disease (GVHD) of grade II or higher had significantly shorter RTL than those who did not ( p = 0.012). Patients with grade II CHCs had significantly shorter RTL than those without CHCs or with grade I CHCs ( p = 0.001). Survivors with ≥2 CHCs also exhibited shorter RTL ( p = 0.027). Overall, pediatric cancer survivors had similar telomere lengths compared to age-matched references. HSCT recipients and patients with severe or multiple CHCs had shorter telomeres. GVHD augmented telomere attrition in HSCT recipients.

Erectile dysfunction (ED) affects a significant proportion of men aged 40-70 and is caused by cavernous tissue dysfunction. Presently, the most common treatment for ED is phosphodiesterase 5 inhibitors; however, this is less effective in patients with severe vascular disease such as diabetic ED. Therefore, there is a need for development of new treatment, which requires a better understanding of the cavernous microenvironment and cell-cell communications under diabetic condition. Pericytes are vital in penile erection; however, their dysfunction due to diabetes remains unclear. In this study, we performed single-cell RNA sequencing to understand the cellular landscape of cavernous tissues and cell type-specific transcriptional changes in diabetic ED. We found a decreased expression of genes associated with collagen or extracellular matrix organization and angiogenesis in diabetic fibroblasts, chondrocytes, myofibroblasts, valve-related lymphatic endothelial cells, and pericytes. Moreover, the newly identified pericyte-specific marker, Limb Bud-Heart (Lbh) , in mouse and human cavernous tissues, clearly distinguishing pericytes from smooth muscle cells. Cell-cell interaction analysis revealed that pericytes are involved in angiogenesis, adhesion, and migration by communicating with other cell types in the corpus cavernosum; however, these interactions were highly reduced under diabetic conditions. Lbh expression is low in diabetic pericytes, and overexpression of LBH prevents erectile function by regulating neurovascular regeneration. Furthermore, the LBH-interacting proteins (Crystallin Alpha B and Vimentin) were identified in mouse cavernous pericytes through LC-MS/MS analysis, indicating that their interactions were critical for maintaining pericyte function. Thus, our study reveals novel targets and insights into the pathogenesis of ED in patients with diabetes., Competing Interests: SB, GY, JO, JS, JR No competing interests declared, JP Reviewing editor, eLife, (© 2023, Bae, Yin, Ock et al.)

Purpose: To identify the optimal photobiomodulation (PBM) parameters using molecular, histological, and erectile function analysis in cavernous nerve injury., Materials and Methods: A cavernous nerve injury was induced in 8-week-old C57BL/6J male mice that were subsequently divided randomly into age-matched control groups. Erectile function tests, penile histology, and Western blotting were performed 2 weeks after surgery and PBM treatment., Results: The PBM treatment was administered for five consecutive days with a light-emitted diode (LED) device that delivers 660 nm±3% RED light, and near infra-red 830 nm±2% promptly administered following nerve-crushing surgery and achieved a notable restoration of erectile function approximately 90% of the control values. Subsequent in-vitro and ex-vivo analyses revealed the regeneration of neurovascular connections in both the dorsal root ganglion and major pelvic ganglion, characterized by the sprouting of neurites. Furthermore, the expression levels of neurotrophic, survival, and angiogenic factors exhibited a substantial increase across all groups subjected to PBM treatment., Conclusions: The utilization of PBM employing LED with 660 nm, 830 nm, and combination of both these wavelengths, exhibited significant efficacy to restore erectile function in a murine model of cavernous nerve injury. Thus, the PBM emerges as a potent therapeutic modality with notable advantages such as efficacy, noninvasiveness, and non-pharmacological interventions for erectile dysfunction caused by nerve injury., Competing Interests: The authors have nothing to disclose., (Copyright © 2024 Korean Society for Sexual Medicine and Andrology.)

Background: The odds of erectile dysfunction are three times more prevalent in diabetes. Severe peripheral vascular and neural damage in diabetic patients responds poorly to phosphodiesterase-5 (PDE5) inhibitors. However, bone morphogenetic protein 2 is known to be involved in angiogenesis., Objectives: To assess the efficacy of bone morphogenetic protein 2 in stimulating angiogenesis and augmenting nerve regeneration in a mouse model of diabetic-induced erectile dysfunction., Materials and Methods: The induction of diabetes mellitus was performed by streptozotocin (50 mg/kg daily) administered intraperitoneally for 5 successive days to male C57BL/6 mice that were 8 weeks old. Eight weeks post-inductions, animals were allocated to one of five groups: a control group, a streptozotocin-induced diabetic mouse group receiving two intracavernous 20 μL phosphate-buffered saline injections, or one of three bone morphogenetic protein 2 groups administered two injections of bone morphogenetic protein 2 protein (1, 5, or 10 μg) diluted in 20 μL of phosphate-buffered saline within a 3-day interval between the first and second injections. The erectile functions were assessed 2 weeks after phosphate-buffered saline or bone morphogenetic protein 2 protein injections by recording the intracavernous pressure through cavernous nerve electrical stimulation. Angiogenic activities and nerve regenerating effects of bone morphogenetic protein 2 were determined in penile tissues, aorta, vena cava, the main pelvic ganglions, the dorsal roots, and from the primary cultured mouse cavernous endothelial cells. Moreover, fibrosis-related factor protein expressions were evaluated by western blotting., Results: Erectile function recovery to 81% of the control value in diabetic mice was found with intracavernous bone morphogenetic protein 2 injection (5 μg/20 μL). Pericytes and endothelial cells were extensively restored. It was confirmed that angiogenesis was promoted in the corpus cavernosum of diabetic mice treated with bone morphogenetic protein 2 through increased ex vivo sprouting of aortic rings, vena cava and penile tissues, and migration and tube formation of mouse cavernous endothelial cells. Bone morphogenetic protein 2 protein enhanced cell proliferation and reduced apoptosis in mouse cavernous endothelial cells and penile tissues, and promoted neurite outgrowth in major pelvic ganglia and dorsal root ganglia under high-glucose conditions. Furthermore, bone morphogenetic protein 2 suppressed fibrosis by reducing mouse cavernous endothelial cell fibronectin, collagen 1, and collagen 4 levels under high-glucose conditions., Conclusion: Bone morphogenetic protein 2 modulates neurovascular regeneration and inhibits fibrosis to revive the mouse erection function in diabetic conditions. Our findings propose that the bone morphogenetic protein 2 protein represents a novel and promising approach to treating diabetes-related erectile dysfunction., (© 2023 American Society of Andrology and European Academy of Andrology.)

To investigate the outcomes of children, adolescents, and young adults (AYAs) with malignant ovarian germ cell tumors (MOGCTs), we analyzed the data of 61 patients aged ≤39 years diagnosed with MOGCT between 2006 and 2022. Among 59 patients who received chemotherapy after initial diagnosis, 57 received BEP (standard dose of bleomycin with 30 units per week, n = 13) or bEP (reduced dose of bleomycin with 15 units/m 2 on day 1, n = 44). The 5-year overall survival (OS) and event-free survival (EFS) rates were 98.3% and 84.9%, respectively. Reduced bleomycin dose did not adversely affect survival. Normalization of tumor markers within 3 months after surgery was significantly associated with better EFS ( p < 0.01). Of the 59 surviving patients, 8 experienced surgery-related menopause, while 49 demonstrated menstrual recovery. After completion of chemotherapy, there was no significant difference in pulmonary function regarding bleomycin dose, and no overt nephrotoxicity. Approximately 60% and 25% of survivors experienced peripheral neuropathy at the end of chemotherapy and after 1 year, respectively ( p < 0.01). Children and AYAs with MOGCT have favorable survival rates with minimal long-term toxicity, which are not influenced by a reduced bleomycin dose. Rapid normalization of tumor markers is associated with improved outcomes.

As a peripheral nerve injury disease, cavernous nerve injury (CNI) caused by prostate cancer surgery and other pelvic surgery causes organic damage to cavernous blood vessels and nerves, thereby significantly attenuating the response to phosphodiesterase-5 inhibitors. Here, we investigated the role of heme-binding protein 1 (Hebp1) in erectile function using a mouse model of bilateral CNI, which is known to promote angiogenesis and improve erection in diabetic mice. We found a potent neurovascular regenerative effect of Hebp1 in CNI mice, demonstrating that exogenously delivered Hebp1 improved erectile function by promoting the survival of cavernous endothelial-mural cells and neurons. We further found that endogenous Hebp1 delivered by mouse cavernous pericyte (MCP)-derived extracellular vesicles promoted neurovascular regeneration in CNI mice. Moreover, Hebp1 achieved these effects by reducing vascular permeability through regulation of claudin family proteins. Our findings provide new insights into Hebp1 as a neurovascular regeneration factor and demonstrate its potential therapeutic application to various peripheral nerve injuries., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1), primarily produced by hepatocytes and neutrophils, is a multifunctional protein that modulates various signaling cascades, mainly TGFβ signaling. Serum LRG1 and neutrophil-derived LRG1 have different molecular weights due to differences in glycosylation, but the impact of the differential glycan composition in LRG1 on its cellular function is largely unknown. We previously reported that LRG1 can promote both angiogenic and neurotrophic processes under hyperglycemic conditions by interacting with LPHN2. Here, we determined the crystal structure of LRG1, identifying the horseshoe-like solenoid structure of LRG1 and its four N-glycosylation sites. In addition, our biochemical and cell-biological analyses found that the deglycosylation of LRG1, particularly the removal of glycans on N325, is critical for the high-affinity binding of LRG1 to LPHN2 and thus promotes LRG1/LPHN2-mediated angiogenic and neurotrophic processes in mouse tissue explants, even under normal glucose conditions. Moreover, the intracavernous administration of deglycosylated LRG1 in a diabetic mouse model ameliorated vascular and neurological abnormalities and restored erectile function. Collectively, these data indicate a novel role of LRG1 glycans as molecular switches that can tune the range of LRG1's cellular functions, particularly the LRG1/LPHN2 signaling axis., (© 2023. The Author(s).)

Background: Patients with relapsed osteosarcoma have poor treatment outcomes. High-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT) has been used in several high-risk malignant solid tumors; however, few studies have evaluated their role in treating osteosarcoma. We evaluated the effectiveness of HDCT/ASCT in relapsed pediatric osteosarcoma cases., Procedure: We retrospectively reviewed the medical records of 40 patients diagnosed with and treated for relapsed osteosarcoma at Asan Medical Center and Samsung Medical Center from January 1996 to July 2019., Results: The median age of this cohort was 13.4 years (range: 6.1-18.2). The cohort's 5-year overall survival (OS) was 51.0% ± 0.1% during a median follow-up period of 67.5 months. Twenty-five patients (62.5%) achieved complete remission (CR) with salvage treatment, and the 5-year OS was 82.4% ± 0.1%, whereas none of the remaining 15 patients who did not achieve CR survived (p < .0001). Of the 25 CR cases, 15 underwent subsequent HDCT/ASCT. We compared the effect of HDCT/ASCT among patients who achieved CR. There were no significant differences in the 5-year OS outcomes between patients who did and did not receive HDCT/ASCT (83.9% ± 0.1%, 13/15 vs. 80.0% ± 0.1%, 8/10, respectively; p = .923)., Conclusion: To our knowledge, we report the first comparative cohort study that proved HDCT/ASCT does not significantly improve survival outcomes in relapsed osteosarcoma. Achievement of CR remains the most crucial factor for good survival outcomes., (© 2023 Wiley Periodicals LLC.)

Severe vascular and nerve damage from diabetes is a leading cause of erectile dysfunction (ED) and poor response to oral phosphodiesterase 5 inhibitors. Argonaute 2 (Ago2), a catalytic engine in mammalian RNA interference, is involved in neurovascular regeneration under inflammatory conditions. In the present study, we report that Ago2 administration can effectively improve penile erection by enhancing cavernous endothelial cell angiogenesis and survival under diabetic conditions. We found that although Ago2 is highly expressed around blood vessels and nerves, it is significantly reduced in the penis tissue of diabetic mice. Exogenous administration of the Ago2 protein restored erectile function in diabetic mice by reducing reactive oxygen species production-signaling pathways (inducing eNOS Ser 1177 /NF-κB Ser 536 signaling) and improving cavernous endothelial angiogenesis, migration, and cell survival. Our study provides new evidence that Ago2 mediation may be a promising therapeutic strategy and a new approach for diabetic ED treatment.

Background: The incidence of diabetic erectile dysfunction (ED) is rapidly increasing, and due to the severe angiopathy caused by diabetes, current drugs are ineffective at treating ED. Insulin-like growth factor-binding protein 5 (IGFBP5) promotes cell death and induces apoptosis in various cell types., Objectives: To evaluate the effectiveness of IGFBP5 knockdown in improving erectile function in diabetic mice., Materials and Methods: Diabetes was induced by injecting streptozotocin (STZ) intraperitoneally into male 8-week-old C57BL/6 mice. Eight weeks after diabetes induction, mice were divided into four groups: a nondiabetic control group and three STZ-induced diabetic mice groups, which were administered intracavernous injections of phosphate buffered saline, scrambled control shRNA, or shRNA targeting mouse IGFBP5 (shIGFBP5) lentivirus particles. Two weeks later, we measured erectile function by electrically stimulating the bilateral cavernous nerve. To mimic diabetic angiopathy, primary cavernous endothelial cells (MCECs) from healthy mice were cultured and treated with glucose., Results: IGFBP5 expression in MCECs or cavernous tissues were significantly increased under diabetic conditions, and knockdown of IGFBP5 induced MCECs angiogenic activity under high-glucose conditions. STZ-induced diabetic mice had reduced erectile function, but shIGFBP5 treatment resulted in significant improvements (to 90% of the nondiabetic control group level). Furthermore, in diabetic mice, numbers of cavernous endothelial cells, pericytes, and neuronal cells were increased by shIGFBP5 treatment, which also increased eNOS Ser 1177 phosphorylation, decreased permeability and apoptosis of cavernous endothelial cells. In addition, IGFBP5 was found to mediate the AKT, ERK, p38 signaling pathways., Discussion and Conclusion: Knockdown of IGFBP5 improved erectile function in diabetic mice by promoting cell proliferation and reducing apoptosis and permeability. Local inhibition of IGFBP5 expression may provide a new treatment strategy for diabetic ED and other ischemic vascular or neurological diseases., (© 2022 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Purpose: Netarsudil is a Rho kinase inhibitor and the first new class of clinically useful ocular hypotensive agents. In this study, we conducted a systematic literature review and meta-analysis to summarize and synthesize the available evidence on the efficacy and safety of fixed-dose combination (FDC) therapy with netarsudil/latanoprost in patients with glaucoma., Methods: We identified relevant studies in PubMed, Ovid Medline, Embase, and Cochrane Central until April 2021. The quality of the studies and the level of evidence were assessed using the Risk of Bias tool. Efficacy was measured as the mean difference in reducing intraocular pressure (IOP), and safety was assessed by the risk of conjunctival hyperemia (CH) due to FDC therapy, netarsudil monotherapy, or latanoprost monotherapy., Results: Four studies met the predefined eligibility criteria and were included in the meta-analysis. The mean difference in the reduction in IOP after 2 weeks and 4 to 6 weeks of drug administration was -2.41 mmHg (95% confidence interval [CI], -2.95 to -1.87) and -1.77 mmHg (95% CI, -2.31 to -1.87), respectively, in patients receiving FDC therapy versus those receiving latanoprost monotherapy. On the other hand, latanoprost monotherapy had a greater effect in reducing IOP than netarsudil monotherapy after 4 to 6 weeks of administration (mean difference, 0.95 mmHg; 95% CI, 0.43 to 1.47). The risk of CH was significantly higher with both FDC therapy and netarsudil monotherapy compared to latanoprost monotherapy in week 12, where the relative ratio was 3.01 (95% CI, 1.95 to 4.66) and 2.33 (95% CI, 1.54 to 3.54), each., Conclusions: Netarsudil/latanoprost FDC therapy has a significantly greater effect on reducing IOP than latanoprost alone. The symptoms of CH were mostly mild, and only a few glaucoma patients discontinued the medication owing to CH in earlier clinical trials. Therefore, it would be beneficial to consider the administration of netarsudil/latanoprost FDC therapy in patients with glaucoma.

Purpose: Diabetes mellitus, one of the major causes of erectile dysfunction, leads to a poor response to phosphodiesterase-5 inhibitors. Heat shock protein 70 (Hsp70), a ubiquitous molecular chaperone, is known to play a role in cell survival and neuroprotection. Here, we aimed to assess whether and how Hsp70 improves erectile function in diabetic mice., Materials and Methods: Eight-week-old male C57BL/6 mice and Hsp70-Tg mice were used in this study. We injected Hsp70 protein into the penis of streptozotocin (STZ)-induced diabetic mice. Detailed mechanisms were evaluated in WT or Hsp70-Tg mice under normal and diabetic conditions. Primary MCECs, and MPG and DRG tissues were cultivated under normal-glucose and high-glucose conditions., Results: Using Hsp70-Tg mice or Hsp70 protein administration, we demonstrate that elevated levels of Hsp70 restores erectile function in diabetic mice. We found that cystathionine gamma-lyase (Cse) is a novel target of Hsp70 in this process, showing that Hsp70-Cse acts through the SDF1/HO-1/PI3K/Akt/eNOS/NF-κB p65 pathway to exert its neurovascular regeneration-promoting effects. Coimmunoprecipitation and pull-down assays using mouse cavernous endothelial cells treated with Hsp70 demonstrated physical interactions between Hsp70 and Cse with a dissociation constant of 1.8 nmol/L., Conclusions: Our findings provide novel and solid evidence that Hsp70 acts through a Cse-dependent mechanism to mediate neurovascular regeneration and restoration of erectile function under diabetic conditions., Competing Interests: The authors have nothing to disclose., (Copyright © 2022 Korean Society for Sexual Medicine and Andrology.)

Background: The incorporation of a reduced-intensity conditioning (RIC) regimen in hematopoietic cell transplantation (HCT) for patients with hemophagocytic lymphohistiocytosis (HLH) has decreased early mortality but is associated with a high rate of mixed chimerism and graft failure. Here, we present a successful single-center experience using busulfan and a fludarabine-based RIC regimen for the treatment of HLH., Methods: The medical records of pediatric patients with HLH who underwent HCT using a busulfan/ fludarabine-based RIC regimen between January 2008 and December 2017 were reviewed retrospectively., Results: Nine patients received HCT with a busulfan/fludarabine-based RIC regimen. Three patients had primary HLH, and the other six patients had secondary HLH with multiple reactivations. All three patients with primary HLH had UNC13D mutations. All patients achieved neutrophil and platelet engraftment at a median of 11 days (range, 10‒21) and 19 days (range, 13‒32), and all eight evaluable patients had sustained complete donor chimerism at the last follow-up. Two patients (22%) experienced grade 2 acute graft-versus- host disease (GVHD). Two patients (22%) developed chronic GVHD, and one died from chronic GVHD. One patient (11%) experienced reactivation 4 months after HCT from a syngeneic donor and died of the disease. The 8-year overall survival and event-free survival rates were 78%. No early treatment-related mortality within 100 days after HCT was observed., Conclusion: Our experience suggests that a busulfan/fludarabine-based RIC regimen is a viable option for pediatric patients with HLH who require HCT.

Diabetes mellitus is one of the main causes of erectile dysfunction (ED). Men with diabetic ED do not respond well to oral phosphodiesterase-5 inhibitors owing to neurovascular dysfunction. Pericyte-derived extracellular vesicle-mimetic nanovesicles (PC-NVs) are known to promote nerve regeneration in a mouse model of cavernous nerve injury. Here, we report that administration of PC-NVs effectively promoted penile angiogenesis and neural regeneration under diabetic conditions, thereby improving erectile function. Specifically, PC-NVs induced endothelial proliferation and migration and reduced cell apoptosis under diabetic conditions. In addition, PC-NVs induced neural regeneration in STZ-induced diabetic mice in dorsal root ganglion and major pelvic ganglion explants in vivo and ex vivo under high-glucose conditions. We found that lipocalin 2 (Lcn2) is a new target of PC-NVs in this process, demonstrating that PC-NVs exert their angiogenic and nerve-regeneration effects by activating MAP kinase and PI3K/Akt and suppressing P53 signaling pathway in an Lcn2-dependent manner. Our findings provide new conclusive evidence that PC-NVs can promote neurovascular regeneration and recovery of erectile function under diabetic conditions via an Lcn2-dependent mechanism. Thus, local administration of PC-NVs may be a promising treatment strategy for the treatment of diabetic ED., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia, which causes endothelial dysfunction and peripheral neuropathy, ultimately leading to multiple complications. One prevalent complication is diabetic erectile dysfunction (ED), which is more severe and more resistant to treatment than nondiabetic ED. The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1) is a modulator of TGF-β-mediated angiogenesis and has been proposed as a biomarker for a variety of diseases, including DM. Here, we found that the adhesion GPCR latrophilin-2 (LPHN2) is a TGF-β-independent receptor of LRG1. By interacting with LPHN2, LRG1 promotes both angiogenic and neurotrophic processes in mouse tissue explants under hyperglycemic conditions. Preclinical studies in a diabetic ED mouse model showed that LRG1 administration into the penile tissue, which exhibits significantly increased LPHN2 expression, fully restores erectile function by rescuing vascular and neurological abnormalities. Further investigations revealed that PI3K, AKT, and NF-κB p65 constitute the key intracellular signaling pathway of the LRG1/LPHN2 axis, providing important mechanistic insights into LRG1-mediated angiogenesis and nerve regeneration in DM. Our findings suggest that LRG1 can be a potential new therapeutic option for treating aberrant peripheral blood vessels and neuropathy associated with diabetic complications, such as diabetic ED., (© 2022. The Author(s).)

Purpose: To investigate the efficacy, safety, and tolerability of oro-dispersible film (ODF) formulation of mirodenafil 50 mg and 100 mg for the treatment of patients with erectile dysfunction (ED) in Korea., Materials and Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 129 subjects was performed. Subjects were randomized to either placebo or mirodenafil ODF 50 mg or 100 mg to be taken in an "on demand" manner for 8 weeks. The primary efficacy variable was the International Index of Erectile Dysfunction (IIEF)-5 questionnaire. The secondary efficacy variables comprised Sexual Encounter Profile questions 2 and 3 (SEP2 and SEP3), the Global Assessment Question (GAQ), and the Life Satisfaction Checklist (LSC)., Results: IIEF-5 was significantly increased in all groups after treatment. However, compared to the placebo group, only the mirodenafil ODF 100 mg group showed a significant difference. SEP2 and SEP3 were increased in both mirodenafil groups; however, the increase was not statistically significant for SEP2. In terms of GAQ and LSC, the mirodenafil ODF groups showed significant increases compared with the baseline. Most treatment-associated adverse events were mild and resolved spontaneously., Conclusions: Mirodenafil ODF is an effective and well-tolerated agent for the treatment of patients with ED in Korea., Competing Interests: The authors have nothing to disclose., (Copyright © 2022 Korean Society for Sexual Medicine and Andrology.)

Objective: Two follow-up studies (exp. 1 and 2) were conducted to determine the effects of L-glutamine (L-Gln) supplementation on degradation and rumen fermentation characteristics in vitro., Methods: First, rumen liquor from three cannulated cows was used to test L-Gln (50 mM) degradation rate and ammonia-N production at 6, 12, 24, 36, and 48 h after incubation (exp. 1). Second, rumen liquor from two cannulated steers was used to assess the effects of five levels of L-Gln including 0% (control), 0.5%, 1%, 2%, and 3% at 0, 3, 6, 12, 24, 36, and 48 h after incubation on fermentation characteristics, gas production, and degradability of nutrients (exp. 2)., Results: In exp. 1, L-Gln degradation rate and ammonia-N concentrations increased over time (p<0.001). In exp. 2, pH was reduced significantly as incubation time elapsed (p<0.001). Total gas production tended to increase in all groups as incubation time increased. Acetate and propionate tended to increase by increasing glutamine (Gln) levels, whereas levels of total volatile fatty acids (VFAs) were the highest in 0.5% and 3% Gln groups (p<0.001). The branched-chain VFA showed both linear and quadratic effects showing the lowest values in the 1% Gln group particularly after 6 h incubation (p<0.001). L-Gln increased crude protein degradability (p<0.001), showing the highest degradability in the 0.5% Gln group regardless of incubation time (p<0.05). Degradability of acid detergent fiber and neutral detergent fiber showed a similar pattern showing the highest values in 0.5% Gln group (p<0.10)., Conclusion: Although L-Gln showed no toxicity when it was supplemented at high dosages (2% to 3% of DM), 0.5% L-Gln demonstrated the positive effects on main factors including VFAs production in-vitro. The results of this study need to be verified in further in-vivo study.

Pericyte‑derived extracellular vesicle‑mimetic nanovesicles (PC‑NVs) play an important role in the improvement of erectile function after cavernous nerve injury. However, the impact of PC‑NVs on the peripheral nervous system (PNS), such as the sciatic nerve, is unclear. In this study, PC‑NVs were isolated from mouse cavernous pericytes (MCPs). A sciatic nerve transection (SNT) model was established using 8‑week‑old C57BL/6J mice. The sciatic nerve was harvested 5 and 14 days for immunofluorescence and western blot studies. Function studies were evaluated by performing the rotarod test and walking track analysis. The results demonstrated that PC‑NVs could stimulate endothelial cells, increase neuronal cell content, and increase macrophage and Schwann cell presence at the proximal stump rather than the distal stump in the SNT model, thereby improving angiogenesis and nerve regeneration in the early stage of sciatic nerve regeneration. In addition, PC‑NVs also increased the expression of neurotrophic factors (brain‑derived nerve growth factor, neurotrophin‑3 and nerve growth factor) and the activity of the cell survival signaling pathway (PI3K/Akt signaling), and reduced the activity of the JNK signaling pathway. Additionally, after 8 weeks of local application of PC‑NVs in SNT model mice, their motor and sensory functions were significantly improved, as assessed by performing the rotarod test and walking track analysis. In conclusion, the present study showed that the significant improvement of neurovascular regeneration in mice following treatment with PC‑NVs may provide a favorable strategy for promoting motor and sensory regeneration and functional recovery of the PNS.

This special edition is based on the revelation that "the lessons learned and unlearned during COVID-19 grant us an unparalleled opportunity to reflect." Here, we reflect on lessons learned related to teacher adaptiveness. We examined how the COVID-19 pandemic demonstrated the adaptiveness necessary for teachers to knowledge generation approaches aligned with the Next Generation Science Standards. First, we outline a three-year professional development program focused on knowledge generation approaches. We present findings from teachers' experiences teaching science from 2019 to 2021, collected through consecutive form explanatory mixed-methods analysis involving written responses to vignettes ( n  = 474) and classroom observations ( n  = 58). Then, using an individual teacher case study, we explore how the shift to virtual teaching was supported by adaptiveness. Results suggest a significant relationship between teacher adaptiveness and the use of knowledge generation approaches. We conclude with implications for elementary science teacher professional development and present questions for further research on adaptiveness., Supplementary Information: The online version contains supplementary material available at 10.1186/s43031-022-00052-3., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022, corrected publication 2022.)

Purpose: This study aimed to determine the urodynamic characteristics of refractory enuresis and explored whether those characteristics can be managed through differential endoscopic injections with botulinum toxin., Methods: In total, 27 patients with nonmonosymptomatic enuresis who showed no response after conservative treatment for more than 12 months were included. The patients then underwent a videourodynamic study and received a differential endoscopic injection of botulinum toxin on the same day. Reduced capacity, detrusor overactivity, and bladder neck widening were the 3 major abnormal findings assessed during the filling phase, while sphincter hyperactivity was the only abnormality assessed during the emptying phase. An intravesical or intrasphincteric injection of botulinum toxin was attempted according to the videourodynamic study findings. Follow-up was conducted at 1, 3, 6, and 12 months after treatment., Results: The median age was 10 years (range, 7-31 years). Although 19 and 8 patients had a preoperative diagnosis of overactive bladder or dysfunctional voiding, respectively, the urodynamic diagnosis was different in more than half of the patients. Those showing detrusor overactivity benefited from intravesical botulinum toxin injection, whereas those with only sphincter hyperactivity benefited from both intravesical and intrasphincteric injections. Treatment resistance to botulinum toxin seemed to be attributable to bladder neck widening. Time had no apparent effect on efficacy, which persisted 6 months after the injection. More than 80% of the patients maintained the benefits of the injection after 1 year., Conclusion: Videourodynamic studies were useful for identifying the reasons underlying refractory nonmonosymptomatic enuresis and helpful for determining the appropriate site of botulinum toxin injection.

Background: Peyronie's disease (PD) is a severe fibrotic disease of the tunica albuginea that causes penis curvature and leads to penile pain, deformity, and erectile dysfunction. The role of pericytes in the pathogenesis of fibrosis has recently been determined. Extracellular vesicle (EV)-mimetic nanovesicles (NVs) have attracted attention regarding intercellular communication between cells in the field of fibrosis. However, the global gene expression of pericyte-derived EV-mimetic NVs (PC-NVs) in regulating fibrosis remains unknown. Here, we used RNA-sequencing technology to investigate the potential target genes regulated by PC-NVs in primary fibroblasts derived from human PD plaque., Methods: Human primary fibroblasts derived from normal and PD patients was cultured and treated with cavernosum pericytes isolated extracellular vesicle (EV)-mimetic nanovesicles (NVs). A global gene expression RNA-sequencing assay was performed on normal fibroblasts, PD fibroblasts, and PD fibroblasts treated with PC-NVs. Reverse transcription polymerase chain reaction (RT-PCR) was used for sequencing data validation., Results: A total of 4135 genes showed significantly differential expression in the normal fibroblasts, PD fibroblasts, and PD fibroblasts treated with PC-NVs. However, only 91 contra-regulated genes were detected among the three libraries. Furthermore, 20 contra-regulated genes were selected and 11 showed consistent changes in the RNA-sequencing assay, which were validated by RT-PCR., Conclusion: The gene expression profiling results suggested that these validated genes may be good targets for understanding potential mechanisms and conducting molecular studies into PD., (© 2021. The Author(s).)

Background: Presently, there are no national screening programs for cancer in Vietnam. This study aimed to analyze the cost-effectiveness of an annual colorectal cancer (CRC) screening program from the healthcare service provider's perspective for the Vietnamese population. Methods: The economic model consisted of adecision tree and aMarkov model. Adecision tree was constructed for comparing two strategies, including ascreening group with aguaiac-based fecal occult blood test ( g FOBT) and ano-screening group in general populations, aged 50 years and above. The Markov model projected outcomes over a25-year horizon. The cost-effectiveness outcome was the incremental cost-effectiveness ratio (ICER) represented by costs per quality-adjusted life-years (QALYs). Results: When compared with no screening, ICER was $1,388per QALY with an increased cost of $ 43.98 and again of 0.032 QALY (Willingness to pay $2,590). The uptake rate of gFOBT, cost of colonoscopy, and the total cost of screening contributed to the largest impact on the ICER. PSA showed that results were robust to variation in parameter estimates, with annual screening remaining cost-effective compared with no screening. Conclusion: Our screening strategy could be considered cost-effective compared to ano screening strategy. Our findings could be potentially used to develop aCRC national screening program.

Purpose: To determine the prognostic indicators for hematopoietic stem cell transplantation (HSCT)-associated neurological complications, the clinical characteristics and brain magnetic resonance imaging (MRI) lesions in pediatric HSCT recipients were reviewed., Methods: This retrospective study included 51 patients who had underwent a brain MRI due to newly developed neurological symptoms or infection signs during chemotherapy or HSCT. We reviewed the demographics, received treatments, treatment-related morbidities, laboratory findings and brain MRI findings, which were compared between good and poor neurologic outcome groups., Results: Thirty-seven patients (72.5%) fully recovered from the neurologic deficits and fourteen (27.5%) persisted or aggravated. The children with an underlying malignant disease had significantly poorer neurological outcomes ( p = 0.015). The neurologic complications associated with infection were more frequent in the poor outcome group ( p = 0.038). In the neuroimaging findings, the extent of the white matter lesions was significantly higher in the poor outcome group, as was that of abnormal enhancement, ventriculomegaly, cortical change, deep gray matter abnormalities and cerebellar abnormalities., Conclusion: Most children with neurologic complications and neuroimaging abnormalities during HSCT had recovered. However, children with neurologic complications associated with infectious causes, malignant disease or severe brain MRI abnormalities should be more carefully monitored during HSCT.

Sleep-disordered breathing (SDB) causes hypoxic stress and can trigger uric acid (UA) overproduction. We comprehensively investigated whether SDB, interacting with components of metabolic syndrome, hepatic and renal dysfunctions, low physical fitness, sedentary lifestyle, disrupted sleep, and chronic systemic inflammation (CSI), is directly associated with hyperuricaemia. In 528 community-based males (mean [SD] age 46.2 [7.4] years), we cross-sectionally analysed measures of anthropometry; self-reported lifestyle habits; overnight sleep polysomnography data; cardiopulmonary exercise tests; and biomarkers of cardiometabolic, hepatic, and renal functions; and CSI, using structural equation modelling. Objective disrupted sleep, C-reactive protein, low physical fitness, and sedentary lifestyle were not related to UA levels in univariate analysis and were excluded. The latent variables (with corresponding manifest variables) obesity (body mass index, waist-hip ratio), hypertension (post-sleep systolic, diastolic blood pressure), dyslipidaemia (total cholesterol, triglyceride/high-density lipoprotein cholesterol), hepatic dysfunction (alanine aminotransferase, aspartate transaminase), and renal dysfunction (blood urea nitrogen, serum creatinine) were positively; and hyperglycaemia (fasting glucose, glycated haemoglobin) was negatively associated with hyperuricaemia (serum UA), except for SDB (Apnea-Hypopnea Index, percentage of oxygen saturation <90% period against total sleep time, oxygen desaturation index) in the one-stage influence model. In the two-stage model, SDB, closely interacting with obesity, was positively indirectly associated with hyperuricaemia through directly linked renal dysfunction and obesity-linked hypertension, inverse hyperglycaemia, dyslipidaemia, and hepatic dysfunction. In conclusion, structural equation modelling reveals that SDB closely interacts with obesity and is positively but indirectly related to hyperuricaemia in males. This suggests that urinary UA excretion modulates and obesity confounds the SDB-hyperuricaemia relationship., (© 2020 European Sleep Research Society.)

The diagnosis of inherited platelet function disorders (IPFDs) is challenging owing to the unavailability of essential testing methods, including light transmission aggregometry and flow cytometry, in several medical centers in Korea. This study, conducted by the Korean Pediatric Hematology Oncology Group from March 2017 to December 2020, aimed to identify the causative genetic variants of IPFDs in Korean patients using next-generation sequencing (NGS). Targeted exome sequencing, followed by whole-genome sequencing, was performed for diagnosing IPFDs. Of the 11 unrelated patients with suspected IPFDs enrolled in this study, 10 patients and 2 of their family members were diagnosed with Glanzmann thrombasthenia (GT). The variant c.1913+5G>T of ITGB3 was the most common, followed by c.2333A>C (p.Gln778Pro) of ITGB2B . Known variants of GT, including c.917A>C (p.His306Pro) of ITGB3 and c.2975del (p.Glu992Glyfs*), c.257T>C (p.Leu86Pro), and c.1750C>T (p.Arg584*) of ITGA2B , were identified. Four novel variants of GT, c.1451G>T (p.Gly484Val) and c.1595G>T (p.Cys532Phe) of ITGB3 and c.1184G>T (p.Gly395Val) and c.2390del (p.Gly797Valfs*29) of ITGA2B , were revealed. The remaining patient was diagnosed with platelet type bleeding disorder 18 and harbored two novel RASGRP2 variants, c.1479dup (p.Arg494Alafs*54) and c.813+1G>A. We demonstrated the successful application of NGS for the accurate and differential diagnosis of heterogeneous IPFDs.

Background: Prognostic factors in hepatoblastoma need to be reevaluated considering the advances in treatment modalities. The study aimed to evaluate current outcomes of hepatoblastoma and reappraise the association of prognostic factors, including pre-treatment extent of tumor (PRETEXT) stage with annotation factors and Children's Hepatic tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system, with survival outcomes., Methods: We evaluated 103 consecutive patients with hepatoblastoma retrospectively according to the treatment period based on the introduction of a liver transplantation program., Results: The 5-year overall survival (OS), event-free survival (EFS), and transplant-free survival rates were 80.2%, 74.2%, and 61.8%, respectively. EFS and OS were improved significantly from 58.6% to 81.6% (P = 0.024) and from 58.6% to 90.8% (P < 0.001), respectively, in the late period (N = 74) compared with the early period (N = 29). The PRETEXT stage was significant or marginally significant for EFS and OS in the early period but not in the late period. The P, F, R, and C factors were significant for OS and EFS in the early period. However, in the late period, only the P factor was significant for OS, and the F and M factors were significant for EFS. The CHIC-HS system was significant or marginally significant for EFS in both the early and late periods; however, it was significant for OS only in the early period., Conclusion: Survival rates were significantly improved in children with hepatoblastoma, especially in those with advanced PRETEXT stages with positive annotation factors and in a high-risk CHIC-HS group. Prognostic factors had different clinical implications with evolved treatment modalities., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder caused by the clonal expansion of myeloid precursors that differentiate into CD1a+/CD207+ cells in the lesion. Advances in genomic sequencing techniques have improved our understanding of the pathophysiology of LCH. Activation of the mitogen-activated protein kinase (MAPK) pathway is a key molecular mechanism involved in the development of LCH. Recurrent BRAF mutations and MAP2K1 mutations are the major molecular alterations involved in the activation of the MAPK pathway. Recent studies have supported the "misguided myeloid differentiation model" of LCH, where the extent of disease is defined by the differentiation stage of the cell in which the activating somatic MAPK mutation occurs, suggesting LCH. Several studies have advocated the efficacy of targeted therapy using BRAF inhibitors with a high response rate, especially in patients with high-risk or refractory LCH. However, the optimal treatment scheme for children remains unclear. This review outlines recent advances in LCH, focusing on understanding the molecular pathophysiology, emerging targeted therapy options, and their clinical implications.

Background: B- and T-lymphocyte attenuator (BTLA) and programmed cell death-1 (PD-1) inhibit γδ T cell homeostasis and activation. This study aimed to determine whether BTLA and PD-1 signaling pathways were convergent or independent in human peripheral blood γδ T cells. Herein we demonstrate that the signalings of BTLA and PD-1 regulated proliferation and cytotoxicity of human γδ T cells, respectively., Methods: Human peripheral blood γδ T cells were cultured with inactivated Jurkat cells in the presence of interleukin-2 and zoledronate (Zol) for 14 days. Flow cytometry was performed to evaluate the phenotypes and functions of γδ T cells., Results: The proliferation of the γδ T cells was increased when PBMCs were cocultured with inactivated herpes virus entry mediator (HVEM) low Jurkat cells. The cytotoxicity of the expanded γδ T cells was not affected by coculture with inactivated HVEM low Jurkat cells and was further increased in the presence of anti-PD-L1 mAb. These results suggest that the inactivation of the BTLA signaling pathway during expansion could help produce more γδ T cells without compromising γδ T cell function. The inhibition of BTLA or PD-1 signaling repressed phosphorylation of the src homology region 2-containing protein tyrosine phosphatase 2 and increased the phosphorylation of protein kinase B in γδ T cells. However, there were no synergistic or additive effects by a combination of BTLA and PD-1 blockade., Conclusion: These results suggest that BTLA signaling is crucial in regulating γδ T cell proliferation and function and that the BTLA and PD-1 signaling pathways act independently on the proliferation and cytotoxicity of human peripheral γδ T cells., (© 2020 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background/aims: Inhibitors of the renin-angiotensin system, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), reportedly have anti-inflammatory effects. This study assessed the association of prior use of ACE inhibitors and ARBs with sepsis-related clinical outcomes., Methods: A population-based observational study was conducted using the Health Insurance Review and Assessment Service claims data. Among the adult patients hospitalized with new onset of sepsis in 2012, patients who took ARBs or ACE inhibitors at least 30 days prior to hospitalization were analyzed. Generalized linear models and logistic regression were used to examine the relation between the prior use of medication and clinical outcomes, such as in-hospital mortality, mechanical ventilation, and length of stay., Results: Of a total of 27,628 patients who were hospitalized for sepsis, the ACE inhibitor, ARB, and non-user groups included 1,214 (4.4%), 3,951 (14.4%), and 22,463 (82.1%) patients, respectively. As the patients in the ACE inhibitor and ARB groups had several comorbid conditions, higher rates of intensive care unit admission, hemodialysis, and mechanical ventilation were observed. However, after covariate adjustment, the use of ACE inhibitor (odds ratio [OR], 0.752; 95% confidence interval [CI], 0.661 to 0.855) or ARB (OR, 0.575; 95% CI, 0.532 to 0.621) was significantly associated with a lower rate of in-hospital mortality., Conclusion: Pre-hospitalization use of ACE inhibitors or ARBs for sepsis was an independent factor for a lower rate of in-hospital mortality.

Neovascularization of the erectile tissue emerges as a beneficial curative approach to treat erectile dysfunction (ED). Here we for the first time report the unexpected role of vasohibin-1 (VASH1), mainly known as an anti-angiogenic factor, in restoring erectile function in diabetic mice. A diabetic patient has lower cavernous VASH1 expression than in the potent man. VASH1 was mainly expressed in endothelial cells. There were significant decreases in cavernous endothelial cell and pericyte contents in VASH1 knockout mice compared with those in wild-type mice, which resulted in impairments in erectile function. Intracavernous injection of VASH1 protein successfully restored erectile function in the diabetic mice (~ 90% of control values). VASH1 protein reinstated endothelial cells, pericytes, and endothelial cell-cell junction proteins and induced phosphorylation of eNOS (Ser1177) in the diabetic mice. The induction of angiogenic factors, such as angiopoietin-1 and vascular endothelial growth factor, is responsible for cavernous angiogenesis and the restoration of erectile function mediated by VASH1. Altogether, these findings suggest that VASH1 is proangiogenic in diabetic penis and is a new potential target for diabetic ED.

Background: Radical prostatectomy for prostate cancer can not only induce cavernous nerve injury (CNI), but also causes cavernous hypoxia and cavernous structural changes, which lead to a poor response to phosphodiesterase 5 inhibitors., Aim: To investigate the therapeutic effect of oral administration of LM11A-31, a small molecule p75 neurotrophin receptor (p75 NTR ) ligand and proNGF antagonist, in a mouse model of bilateral CNI, which mimics nerve injury-induced erectile dysfunction after radical prostatectomy., Methods: 8-week-old male C57BL/6 mice were divided into sham operation and CNI groups. Each group was divided into 2 subgroups: phosphate-buffered saline and LM11A-31 (50 mg/kg/day) being administered once daily starting 3 days before CNI via oral gavage. 2 weeks after CNI, we measured erectile function by electrical stimulation of the bilateral cavernous nerve. The penis was harvested for histologic examination and Western blot analysis. The major pelvic ganglia was harvested and cultured for assays of ex vivo neurite outgrowth., Outcomes: Intracavernous pressure, neurovascular regeneration in the penis, in vivo or ex vivo functional evaluation, and cell survival signaling were measured., Results: Erectile function was decreased in the CNI group (44% of the sham operation group), while administration of LM11A-31 led to a significant improvement of erectile function (70% of the sham operation group) in association with increased neurovascular content, including cavernous endothelial cells, pericytes, and neuronal processes. Immunohistochemical and Western blot analyses showed significantly increased p75 NTR expression in the dorsal nerve of CNI mice, which was attenuated by LM11A-31 treatment. Protein expression of active PI3K, AKT, and endothelial nitric oxide synthase was increased, and cell death and c-Jun N-terminal kinase signaling was significantly attenuated after LM11A-31 treatment. Furthermore, LM11A-31 promoted neurite sprouting in cultured major pelvic ganglia after lipopolysaccharide exposure., Clinical Implications: LM11A-31 may be used as a strategy to treat erectile dysfunction after radical prostatectomy or in men with neurovascular diseases., Strengths & Limitations: Unlike biological therapeutics, such as proteins, gene therapies, or stem cells, the clinical application of LM11A-31 would likely be relatively less complex and low cost. Our study has some limitations. Future studies will assess the optimal dosing and duration of the compound. Given its plasma half-life of approximately 1 hour, it is possible that dosing more than once per day will provide added efficacy., Conclusion: Specific inhibition of the proNGF-p75 NTR degenerative signaling via oral administration of LM11A-31 represents a novel therapeutic strategy for erectile dysfunction induced by nerve injury. Yin GN, Ock J, Limanjaya A, et al. Oral Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Improves Erectile Function in a Mouse Model of Cavernous Nerve Injury. J Sex Med 2021;18:17-28., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Penile erection requires integrative interactions between vascular endothelial cells, pericytes, smooth muscle cells, and autonomic nerves. Furthermore, the importance of the role played by pericytes in the pathogenesis of angiopathy has only recently been appreciated. However, global gene expression in pericytes in diabetes mellitus-induced erectile dysfunction (DMED) remains unclear. We aimed to identify potential target genes related to DMED in mouse cavernous pericytes (MCPs)., Materials and Methods: Mouse cavernous tissue was allowed to settle under gravity in collagen I-coated dishes, and sprouted cells were subcultivated for experiments. To imitate diabetic conditions, MCPs were treated with normal-glucose (NG, 5 mM) or high-glucose (HG, 30 mM) media for 3 days. Microarray technology was used to evaluate gene expression profiles, and RT-PCR was used to validate sequencing data. Histological examinations and Western blot were used to validate final selected target genes related to DMED., Results: Decreased tube formation and increased apoptosis were detected in MCPs exposed to the HG condition. As shown by microarray analysis, the gene expression profiles of MCPs exposed to the NG or HG condition differed. A total of 2,523 genes with significantly altered expression were classified into 15 major gene categories. After further screening based on gene expression and RT-PCR and histologic results, we found that Hebp1 gene expression was significantly diminished under the HG condition and in DM mice., Conclusions: This gene profiling study provides new potential targets responsible for diabetes in MCPs. Validation studies suggest that Hebp1 may be a suitable biomarker for DMED., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association, 2021.)

Background: Radical prostatectomy induces some degree of cavernous nerve injury (CNI) and causes denervation-induced pathologic changes in cavernous vasculature, regardless of the advances in surgical techniques and robotic procedures. The precursor for nerve growth factor (proNGF) is known to be involved in neuronal cell apoptosis and microvascular dysfunction through its receptor p75 NTR ., Objectives: To determine the expression of proNGF/p75 NTR and the efficacy of proNGF neutralizing antibody (anti-proNGF-Ab) in a mouse model of ED induced by CNI., Materials and Methods: Age-matched 12-week-old C57BL/6 mice were distributed into three groups: sham group and bilateral CNI group treated with intracavernous injections of PBS (20 μL) or of anti-proNGF-Ab (20 µg in 20 μL of PBS) on days -3 and 0. Two weeks after treatment, erectile function was measured by electrical stimulation of cavernous nerve. Penis tissues from a separate group of animals were harvested for further analysis. We also determined the efficacy of anti-proNGF-Ab on neural preservation in major pelvic ganglion (MPG) ex vivo., Results: We observed increased penile expression of proNGF and p75 NTR after CNI. Intracavernous administration of anti-proNGF-Ab increased nNOS and neurofilament expression probably by enhancing the production of neurotrophic factors, such as neurotrophin-3, NGF, and brain-derived neurotrophic factor. Anti-proNGF-Ab preserved the integrity of cavernous sinusoids, such as pericytes, endothelial cells, and endothelial cell-to-cell junctions, possibly by controlling angiogenic factors (angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor) and induced endogenous eNOS phosphorylation in CNI mice. And finally, treatment with anti-proNGF-Ab rescued erectile function in CNI mice. Anti-proNGF-Ab also enhanced neurite sprouting from MPG exposed to lipopolysaccharide., Discussion and Conclusion: The preservation of damaged cavernous neurovasculature through inhibition of the proNGF/p75 NTR pathway may be a novel strategy to treat radical prostatectomy-induced erectile dysfunction., (© 2020 American Society of Andrology and European Academy of Andrology.)

Purpose: Proper functional and structural integrity of nervous and vascular system in urinary bladder plays an important role in normal bladder function and the disruption of these structures is known to be related to lower urinary tract symptoms. Here, we present an immunohistochemical staining method that delineates neurovascular structures in the mouse urinary bladder by using immunohistochemical staining with three-dimensional reconstruction., Materials and Methods: The urinary bladder was harvested from 8-week-old C57BL/6 male mouse. Lamina propria and detrusor muscle layer were dissected for whole mount staining, and thick-cut (60-μm) sections were prepared for full-thickness bladder staining. Immunofluorescent staining of bladder tissue was performed with antibodies against CD31 (an endothelial cell marker), smooth muscle α-actin (a smooth muscle cell marker), NG2 (a pericyte marker), and βIII-tubulin (a neuronal marker). We reconstructed three-dimensional images of bladder neurovascular system from stacks of two-dimensional images., Results: Three-dimensional images obtained from thick-cut sections clearly provided good anatomic information about neurovascular structures in the three layers of bladder, such as urothelium, lamina propria, and detrusor muscle layer. Whole mount images of lamina propria and detrusor muscle layer also clearly delineated spatial relationship between nervous and vascular systems. The microvessel density was higher in the lamina propria than in the detrusor muscle layer. Nerve fibers were evenly innervated into the lamina propria and detrusor muscle., Conclusions: This study provides comprehensive insight into three-dimensional neurovascular structures of mouse urinary bladder. Our technique may constitute a standard tool to evaluate pathologic changes in a variety of urinary bladder diseases., Competing Interests: The authors have nothing to disclose., (Copyright © 2021 Korean Society for Sexual Medicine and Andrology.)

Purpose: To investigate potential target genes associated with the diabetic condition in mouse cavernous endothelial cells (MCECs) for the treatment of diabetes-induced erectile dysfunction (ED)., Materials and Methods: Mouse cavernous tissue was embedded into Matrigel, and sprouted cells were subcultivated for other studies. To mimic diabetic conditions, MCECs were exposed to normal-glucose (NG, 5 mmoL) or high-glucose (HG, 30 mmoL) conditions for 72 hours. An RNA-sequencing assay was performed to evaluate gene expression profiling, and RT-PCR was used to validate the sequencing data., Results: We isolated MCECs exposed to the two glucose conditions. MCECs showed well-organized tubes and dynamic migration in the NG condition, whereas tube formation and migration were significantly decreased in the HG condition. RNA-sequencing analysis showed that MCECs had different gene profiles in the NG and HG conditions. Among the significantly changed genes, which we classified into 14 major gene categories, we identified that aging-related (9.22%) and angiogenesis-related (9.06%) genes were changed the most. Thirteen genes from the two gene categories showed consistent changes on the RNA-sequencing assay, and these findings were validated by RT-PCR., Conclusions: Our gene expression profiling studies showed that Cyp1a1 , Gclm , Igfbp5 , Nqo1 , Il6 , Cxcl5 , Olr1 , Ctgf , Hbegf , Serpine1 , Cyr61 , Angptl4 , and Loxl2 may play a critical role in diabetes-induced ED through aging and angiogenesis signaling. Additional research is necessary to help us understand the potential mechanisms by which these genes influence diabetes-induced ED., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association, 2021.)

Background: Lymphoblastic lymphoma (LBL) is the second most common subtype of pediatric non-Hodgkin lymphoma. Modified treatments derived from the LSA2-L2 regimen resulted in encouraging survival, but toxicities and long-term sequelae have been problematic. At present, the acute lymphoblastic leukemia (ALL)-type protocol has demonstrated efficacy in LBL. We analyzed the outcomes of children and adolescents with LBL treated with various regimens., Methods: From 1991‒2018, this study enrolled 63 patients diagnosed with LBL at Asan Medical Center. Medical records were retrospectively analyzed., Results: Among 63 patients, most patients (38.1%) presented with stage IV at diagnosis, and two had central nervous system (CNS) involvement. At a median follow-up of 160 months, the 5-year event free survival (EFS), overall survival (OS), and relapse free survival (RFS) were 68.8%, 79.3%, and 71.3%, respectively. Among 61 patients who received chemotherapy, 27 patients (44.3%) received the NY protocol, and 14 (23.0%) received the ALL-type protocol. There was no significant difference in 5-yr OS (85.2%/78.6%), EFS (73.5%/78.6%), and RFS (73.5%/78.6%) between the NY and ALL protocol groups, regardless of immunophenotype. Thirteen patients (21.3%) received prophylactic cranial radiotherapy with no difference in the incidence of CNS relapse based on irradiation., Conclusion: This study showed no difference in outcome between the NY and ALL-type protocols, regardless of stage or immunophenotype. In addition to improving the effectiveness of treatment, it is necessary to continuously appraise the appropriate chemotherapy regimen, considering toxicities and long-term prognosis, for pediatric LBL.

The incidence and mortality of colorectal cancer (CRC) has increased rapidly in Vietnam, but the economic burden of this disease has never been estimated. We estimate the direct and indirect cost of CRC patients in Vietnam in 2018 using a prevalence-based approach and human capital method. The total economic cost of CRC was VND 3041.88 billion (~$132.9 million), representing 0.055% of the 2018 gross domestic product. Notably, indirect costs comprised 83.58 % of the total cost, 82.61% of which is future income loss, because CRC occurs during productive years. The economic burden of CRC in Vietnam is substantial. The medical cost for CRC diagnosis and treatment is higher for younger patients and for those in advanced stages. Strategies to decrease the economic burden of CRC at the patient and national level, such as screening programs, should be developed and implemented in Vietnam.

Background/aim: This study was conducted to evaluate the clinical usefulness of panel next-generation sequencing (NGS) and to investigate the spectrum of genetic alterations and their clinical implications in neuroblastoma., Patients and Methods: Formalin-fixed, paraffin-embedded archival samples from 41 cases of neuroblastoma were used for targeted sequencing., Results: A total of 145 somatic mutations were identified, including 51 synonymous, 86 missense, 3 nonsense, 2 frameshift deletion, 2 splice-site, and 1 in-frame deletion mutations. The most frequently mutated gene was ALK (9 missense mutations). The common copy number variations (CNVs) were amplification at 2p24.2 and deletion at 11q22.3 and 1p36.21. ALK mutations were more frequent in patients with stage 4 or 4S (0% vs. 33.3%, p=0.017). Among 27 patients with high-risk disease, the 5-year overall survival was inferior in patients with ALK mutations to those without (25.0% vs. 67.0%, p=0.009)., Conclusion: Genetic analysis using targeted NGS was feasible and helpful in detecting point mutations and CNVs in neuroblastoma. Targeted NGS could predict prognosis and be used to find molecular target-based therapies for neuroblastoma., (Copyright © 2020 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)