Oxysterol-binding protein like 7 deficiency leads to ER stress mediated apoptosis in podocytes and proteinuria.

Chronic kidney disease (CKD) is associated with renal lipid dysmetabolism among a variety of other pathways. We recently demonstrated that oxysterol-binding protein like 7 (OSBPL7) modulates the expression and function of ATP Binding Cassette Subfamily A Member 1 (ABCA1) in podocytes, a specialized type of cell essential for kidney filtration. Drugs that target OSBPL7 lead to improved renal outcomes in several experimental models of CKD. However, the role of OSBPL7 in podocyte injury remains unclear. Employing mouse models and cellular assays, we investigated the influence of OSBPL7 deficiency on podocytes. We demonstrated that reduced renal OSBPL7 levels as observed in two different models of experimental CKD are linked to increased podocyte apoptosis, primarily mediated by heightened endoplasmic reticulum (ER) stress. While as expected the absence of OSBPL7 also resulted in lipid dysregulation (increased lipid droplets and triglycerides content), OSBPL7-deficiency related lipid dysmetabolism did not contribute to podocyte injury. Similarly, we demonstrated that the decreased autophagic flux we observed in OSBPL7-deficient podocytes was not the mechanistic link between OSBPL7-deficiency and apoptosis. In a complementary zebrafish model, osbpl7 knockdown was sufficient to induce proteinuria and morphological damage to the glomerulus, underscoring its physiological relevance. Our study shed new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthen the role of OSBPL7 as a novel therapeutic target.

Cost-effectiveness of open versus laparoscopic pancreatectomy: A nationwide, population-based study.

BACKGROUND: Laparoscopic pancreatic resection is comparable to open pancreatic resection; however, cost-effectiveness analyses of laparoscopic pancreatic resection are scarce. The authors performed a population-based study investigating the cost-effectiveness of laparoscopic pancreatic resection versus open pancreatic resection. METHODS: Data from 9,256 patients who received pancreaticoduodenectomy (66.8%) and distal pancreatectomy (33.2%) from 2016 to 2018 were retrieved from the Korean National Health Insurance Service. Events after pancreatectomy were categorized as no complication, complication, and death. Probabilities of each event and average cost during index admission and 1 year were utilized to calculate incremental cost-effectiveness ratio, the cost difference between two interventions divided by quality-adjusted life year. Quality-adjusted life year, a function of length and quality of life, was measured with utility values determined by researching literature. RESULTS: Laparoscopic pancreatic resection was performed in 12.4% of pancreaticoduodenectomies and 53.4% of distal pancreatectomies. For pancreaticoduodenectomy, laparoscopic pancreatic resection was associated with an increase of 0.0022 quality-adjusted life years for index admission and 0.0023 quality-adjusted life years for 1 year compared with open pancreatic resection. The incremental cost was $321 for index admission and -$1,414 for 1 year, leading to an incremental cost-effectiveness ratio of $147,429 per quality-adjusted life year gained for index admission and -$614,965 per quality-adjusted life year gained for 1 year. For distal pancreatectomy, laparoscopic pancreatic resection improved 0.0131 quality-adjusted life years for index admission and 0.0285 quality-adjusted life years for index admission. The incremental cost was -$1,240 for index admission and -$5,875 for 1 year, leading to an incremental cost-effectiveness ratio of -$94,519 per quality-adjusted life year gained for index admission and -$206,351 for 1 year. CONCLUSION: laparoscopic pancreatic resection was a cost-effective alternative to open pancreatic resection for pancreaticoduodenectomy and distal pancreatectomy, except for the higher cost of index admission for pancreaticoduodenectomy.

Metabolic Analysis and Renal Protective Effects of Linagliptin and Empagliflozin in Alport Syndrome.

BACKGROUND: We previously demonstrated that Empagliflozin (Empa), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduces intrarenal lipid accumulation and slows kidney function decline in experimental Alport syndrome (AS). In this study, we aimed to evaluate the renal protective benefits of Linagliptin (Lina), a dipeptidyl peptidase-4 (DPP4) inhibitor in AS and compare it to Empa. METHODS: Metabolite distribution in kidney cortices was assessed using mass spectrometry imaging. We examined albuminuria and histological changes in kidneys from AS mice treated with Lina and/or Empa or vehicle. RESULTS: Several metabolites, including adrenic acid (AdA) and glucose, were increased in renal cortices of AS mice when compared to wildtype (WT) mice, while eicosapentaenoic acid (EPA) levels were decreased. In addition, a redistribution of AdA from the glomerular compartment in WT mice to the tubulointerstitial compartment in AS mice was observed. Both Lina and Empa treatments were found to reduce albuminuria, to extend the survival of AS mice for about 10 days, and to decrease glomerulosclerosis and tubulointerstitial fibrosis compared to WT mice. There were no significant differences with regard to the renal phenotype observed between Empa and Lina treated AS mice, and the combination of Lina and Empa was not superior to individual treatments. In vitro experiments revealed that DPP4 is expressed in podocytes and tubular cells derived from both AS and WT mice. Differently from what we have reported for Empa, Lina treatment was found to reduce glucose-driven respiration in AS tubular cells, but not in AS podocytes. CONCLUSIONS: Renal expression patterns and spatial distribution of several metabolites differ in AS compared to WT mice. While Lina and Empa treatments similarly partially slow the progression of kidney disease in AS, the metabolic mechanisms conferring the protective effect may be different.

Hyaluronic acid stimulation of stem cells for cardiac repair: a cell-free strategy for myocardial infarct.

BACKGROUND: Myocardial infarction (MI), a representative form of ischemic heart disease, remains a huge burden worldwide. This study aimed to explore whether extracellular vesicles (EVs) secreted from hyaluronic acid (HA)-primed induced mesenchymal stem cells (HA-iMSC-EVs) could enhance the cardiac repair after MI. RESULTS: HA-iMSC-EVs showed typical characteristics for EVs such as morphology, size, and marker proteins expression. Compared with iMSC-EVs, HA-iMSC-EVs showed enhanced tube formation and survival against oxidative stress in endothelial cells, while reduced reactive oxygen species (ROS) generation in cardiomyocytes. In THP-1 macrophages, both types of EVs markedly reduced the expression of pro-inflammatory signaling players, whereas HA-iMSC-EVs were more potent in augmenting anti-inflammatory markers. A significant decrease of inflammasome proteins was observed in HA-iMSC-EV-treated THP-1. Further, phospho-SMAD2 as well as fibrosis markers in TGF-ß1-stimulated cardiomyocytes were reduced in HA-iMSC-EVs treatment. Proteomic data showed that HA-iMSC-EVs were enriched with multiple pathways including immunity, extracellular matrix organization, angiogenesis, and cell cycle. The localization of HA-iMSC-EVs in myocardium was confirmed after delivery by either intravenous or intramyocardial route, with the latter increased intensity. Echocardiography revealed that intramyocardial HA-iMSC-EVs injections improved cardiac function and reduced adverse cardiac remodeling and necrotic size in MI heart. Histologically, MI hearts receiving HA-iMSC-EVs had increased capillary density and viable myocardium, while showed reduced fibrosis. CONCLUSIONS: Our results suggest that HA-iMSC-EVs improve cardiac function by augmenting vessel growth, while reducing ROS generation, inflammation, and fibrosis in MI heart.

Microscopic tumor mapping of post-neoadjuvant therapy pancreatic cancer specimens to predict post-surgical recurrence: A prospective cohort study.

BACKGROUND: Although various pathological grading systems are available for evaluating the response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant therapy (NAT), their prognostic value has not been thoroughly validated. This study examined whether microscopic tumor mapping of post-NAT specimens could predict tumor recurrence. METHODS: This prospective study enrolled 52 patients who underwent pancreaticoduodenectomy after NAT for PDAC between 2019 and 2021. Microscopic mapping was performed to identify residual tumor loci within the tumor bed using 4 mm2 pixels. Patients were divided into small extent (SE; n = 26) and large extent (LE; n = 26) groups using a cutoff value of 226 mm2. The diagnostic performance for predicting tumor recurrence was evaluated using receiver operating characteristic (ROC) curves. RESULTS: Carbohydrate antigen 19-9 levels were normalised after NAT in more patients in the SE group (SE 21 [80.8%] vs. LE 13 [50.0%]; P = 0.041). Tumor size (P < 0.001), T stage (P < 0.001), positive lymph node yield (P = 0.024), and perineural invasion rate (P = 0.018) were significantly greater in the LE group. The 3-year disease-free survival rate was significantly lower in the LE group (SE 83.3% vs. LE 50.0%, P = 0.004). The area under the ROC curve for mapping extent was 0.743, which was greater than that of the other tumor response scoring systems. CONCLUSIONS: Microscopic tumor mapping of the residual tumor in post-NAT specimens is a significant predictor of post-surgical recurrence, and offers better prognostic performance than the current grading systems.

Versatile human cardiac tissues engineered with perfusable heart extracellular microenvironment for biomedical applications.

Engineered human cardiac tissues have been utilized for various biomedical applications, including drug testing, disease modeling, and regenerative medicine. However, the applications of cardiac tissues derived from human pluripotent stem cells are often limited due to their immaturity and lack of functionality. Therefore, in this study, we establish a perfusable culture system based on in vivo-like heart microenvironments to improve human cardiac tissue fabrication. The integrated culture platform of a microfluidic chip and a three-dimensional heart extracellular matrix enhances human cardiac tissue development and their structural and functional maturation. These tissues are comprised of cardiovascular lineage cells, including cardiomyocytes and cardiac fibroblasts derived from human induced pluripotent stem cells, as well as vascular endothelial cells. The resultant macroscale human cardiac tissues exhibit improved efficacy in drug testing (small molecules with various levels of arrhythmia risk), disease modeling (Long QT Syndrome and cardiac fibrosis), and regenerative therapy (myocardial infarction treatment). Therefore, our culture system can serve as a highly effective tissue-engineering platform to provide human cardiac tissues for versatile biomedical applications.

Developing an Online Health Community Platform for Facilitating Empowerment in Chronic Disease Prevention and Health Promotion.

This study aimed to develop an online health community platform for facilitating the empowerment of people with chronic diseases dwelling in the community regarding disease prevention and health promotion. The user-centered design approach included four main steps: (1) identifying the health problems and needs of target users, (2) developing the content of the platform, (3) constructing the platform, and (4) pilot testing, refinement, and finalization. An online health community platform available both in a mobile application and a Web-enabled application has been launched to facilitate empowerment and self-management by people with chronic conditions. The main components of the application comprised (1) screening for chronic diseases and health problems, (2) setting personal goals for health promotion and action planning to achieve the goals themselves, (3) offering an online health community with shared group goals that help users engage with their peers to attain their goals, and (4) creating one's own online health community and inviting others to participate. The platform has the potential to encourage people with chronic conditions to proactively engage in their own health promotion. Future studies are needed to determine the impact of the application on self-management and empowerment for its users.

Achieving Textbook Outcomes after Laparoscopic Resection in Posterosuperior Segments of the Liver: The Impact of the Learning Curve.

Achieving textbook outcomes (TOs) improves the short-term and long-term performance of a hospital. Our objective was to assess TOs in the laparoscopic liver resection (LLR) of tumors in the PS (posterosuperior) section of the liver and identify the impact of the learning curve. We conducted a retrospective cohort study analyzing patients who underwent LLR for lesions located in the PS segments. Patients were divided into a TO and no-TO group. TOs were defined as negative margins, no transfusion, no readmission, no major complications, no 30-day mortality, and a length of stay ≤ 50th percentile. Patients' outcomes were assessed in two study periods before and after 2015. TOs were achieved in 47.6% (n = 117). In multivariable analysis, obesity (p = 0.001), shorter operation time (p < 0.001), less blood loss (p < 0.001), normal albumin (p = 0.003), and minor resection (p = 0.046) were significantly associated with achieving TOs. Although the 5-year recurrence-free survival rate (p = 0.096) was not significantly different, the 5-year overall survival rate was significantly greater in the TO group (p = 0.001). Body mass index > 25 kg/m2 (p = 0.020), age > 65 years (p = 0.049), and achievement of TOs (p = 0.024) were independently associated with survival. The proportion of patients who achieved a TO was higher after 2015 than before 2015 (52.3% vs. 36.1%; p = 0.022). TOs are important markers not only for assessing hospital and surgeon performance but also as predictors of overall survival. As the number of surgeons who achieve the learning curve increases, the number of patients with TOs will gradually increase with a subsequent improvement in overall survival.

CM1, a Chrysin Derivative, Protects from Endotoxin-Induced Lethal Shock by Regulating the Excessive Activation of Inflammatory Responses.

Sepsis, a leading cause of death worldwide, is a harmful inflammatory condition that is primarily caused by an endotoxin released by Gram-negative bacteria. Effective targeted therapeutic strategies for sepsis are lacking. In this study, using an in vitro and in vivo mouse model, we demonstrated that CM1, a derivative of the natural polyphenol chrysin, exerts an anti-inflammatory effect by inducing the expression of the ubiquitin-editing protein TNFAIP3 and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Interestingly, CM1 attenuated the Toll-like receptor 4 (TLR4)-induced production of inflammatory cytokines by inhibiting the extracellular-signal-regulated kinase (ERK)/MAPK and nuclear factor kappa B (NF-κB) signalling pathways. In addition, CM1 induced the expression of TNFAIP3 and SIRT1 on TLR4-stimulated primary macrophages; however, the anti-inflammatory effect of CM1 was abolished by the siRNA-mediated silencing of TNFAPI3 or by the genetic or pharmacologic inhibition of SIRT1. Importantly, intravenous administration of CM1 resulted in decreased susceptibility to endotoxin-induced sepsis, thereby attenuating the production of pro-inflammatory cytokines and neutrophil infiltration into the lung compared to control mice. Collectively, these findings demonstrate that CM1 has therapeutic potential for diverse inflammatory diseases, including sepsis.

Association between Unplanned Conversion and Patient Survival after Laparoscopic Liver Resection for Hepatocellular Carcinoma: A Propensity Score Matched Analysis.

Unplanned conversion (UPC) is considered to be a predictor of poor postoperative outcomes. However, the effects of UPC on the survival of patients with hepatocellular carcinoma (HCC) remain controversial. The aim of this study is to compare the outcomes between patients who underwent laparoscopic liver resection (LLR) and those who underwent UPC for HCC. Among 1029 patients with HCC who underwent hepatectomy between 2004 and 2021, 251 were eligible for the study. Of 251 patients who underwent hepatectomy for HCC in PS segments, 29 (26.0%) required UPC, and 222 underwent LLR. After 1:5 PSM, 25 patients were selected for the UPC group and 125 for the LLR group. Blood loss, transfusion rate, hospital stay, and postoperative complication were higher in the UPC group. Regarding oncologic outcomes, although the 5-year overall survival rate was similar in both groups (p = 0.544), the recurrence-free survival rate was lower in the UPC group (p < 0.001). UPC was associated with poor short-term as well as inferior long-term outcomes compared with LLR for HCC in PS segments. Therefore, surgeons must carefully select patients and consider early conversion if unexpected bleeding occurs to maintain safety and oncologic outcomes.

A Prospective Analysis of the Effects of a Powder-Type Hemostatic Agent on the Short-Term Outcomes after Liver Resection.

Background and Objectives: Postoperative bleeding is a significant cause of morbidity and mortality following liver resection. Therefore, it is crucial to minimize bleeding during liver resection and effectively manage it when it occurs. Arista® AH (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) is a microporous polysaccharide hemosphere (MPH), a new plant-derived polysaccharide powder hemostat that can be applied to the entire surgical field. This study prospectively assessed the effectiveness of Arista for bleeding control when applied intraoperatively to the liver resection surface. Materials and Methods: Data were collected at Seoul National University Bundang Hospital for patients who underwent liver resection owing to malignant hepatocellular carcinoma or benign liver diseases. We compared the outcomes between 45 patients managed with Arista® AH (data were prospectively collected between September 2022 and May 2023) and 156 patients managed without the use of Arista® AH (data were retrospectively collected between January 2021 and December 2021). Results: There were no significant differences in patient characteristics between the two groups. The estimated blood loss (EBL) was significantly lower in the Arista® AH group compared with the control group (495.56 ± 672.7 mL vs. 691.9 ± 777.5 mL, p = 0.049). The mean postoperative hospital stay was significantly shorter in the Arista® AH group (5.93 ± 1.88 days vs. 6.94 ± 4.17 days, p = 0.024). The time to Jackson-Pratt drain removal was also significantly shorter in the Arista® AH group (4.64 ± 1.31 days vs. 5.30 ± 2.87 days, p = 0.030). The patient subgroup was divided into four categories based on the type of resection and the presence or absence of cirrhosis. Within the subgroup of major resections in non-cirrhotic patients, the Arista® AH group demonstrated significantly better outcomes compared to the control group, showed lower EBL, reduced need for blood transfusions, decreased volume of drain fluid collected within 48 h, earlier removal of drains, and shorter hospital stays. In contrast, for the other subgroups such as minor resection (both non-cirrhotic and cirrhotic) and major resection with cirrhosis, the differences between the Arista® AH and control groups in various parameters like EBL, blood transfusion rates, drain fluid volume, time to drain removal, and duration of hospital stay were not statistically significant. Conclusions: Arista® AH significantly improved intraoperative blood management and postoperative recovery in patients undergoing liver resection, particularly in non-cirrhotic patients who underwent major resection.

Decision aids for promoting shared decision-making: A review of systematic reviews.

In the context of shared decision-making (SDM), experts have advocated the use of validated decision aids (DAs) as valuable tools for facilitating SDM in various healthcare scenarios. This comprehensive review attempts to analyze a vast corpus of DA research by performing thorough searches across four prominent databases (PubMed, CINAHL, Embase, and Web of Science). Independent reviewers selected relevant reviews, extracted data, and assessed review quality using the AMSTAR II tool. A total of 34 systematic reviews were identified and evaluated in this review, encompassing a wide range of outcomes associated with using DAs. These outcomes include patient knowledge, patient involvement in SDM, decision conflict, decision regret, satisfaction, and adherence. In addition, DAs positively affect healthcare provider outcomes by increasing satisfaction, reducing decision conflicts, and lengthening clinical consultations. This review highlights the need for additional research in specific contexts such as long-term care, mental health, and reproductive health to better understand the benefits and challenges of implementing DAs in these settings. Such research can contribute to the improvement of SDM practices and patient-centered care.

The artificial amino acid change in the sialic acid-binding domain of the hemagglutinin neuraminidase of newcastle disease virus increases its specificity to HCT 116 colorectal cancer cells and tumor suppression effect.

BACKGROUND: Oncolytic viruses are being studied and developed as novel cancer treatments. Using directed evolution technology, structural modification of the viral surface protein increases the specificity of the oncolytic virus for a particular cancer cell. Newcastle disease virus (NDV) does not show specificity for certain types of cancer cells during infection; therefore, it has low cancer cell specificity. Hemagglutinin is an NDV receptor-binding protein on the cell surface that determines host cell tropism. NDV selectivity for specific cancer cells can be increased by artificial amino acid changes in hemagglutinin neuraminidase HN proteins via directed evolution, leading to improved therapeutic effects. METHODS: Sialic acid-binding sites (H domains) of the HN protein mutant library were generated using error-prone PCR. Variants of the H domain protein were screened by enzyme-linked immunosorbent assay using HCT 116 cancer cell surface molecules. The mutant S519G H domain protein showed the highest affinity for the surface protein of HCT 116 cells compared to that of different types of cancer cells. This showed that the S519G mutant H domain protein gene replaced the same part of the original HN protein gene, and S519G mutant recombinant NDV (rNDV) was constructed and recovered. S519G rNDV cancer cell killing effects were tested using the MTT assay with various cancer cell types, and the tumor suppression effect of the S519G mutant rNDV was tested in a xenograft mouse model implanted with cancer cells, including HCT 116 cells. RESULTS: S519G rNDV showed increased specificity and enhanced killing ability of HCT 116 cells among various cancer cells and a stronger suppressive effect on tumor growth than the original recombinant NDV. Directed evolution using an artificial amino acid change in the NDV HN (S519G mutant) protein increased its specificity and oncolytic effect in colorectal cancer without changing its virulence. CONCLUSION: These results provide a new methodology for the use of directed evolution technology for more effective oncolytic virus development.

Establishment and Characterization of Immortalized Human Dermal Papilla Cells Expressing Human Papillomavirus 16 E6/E7.

Primary human dermal papilla cells (HDPCs) are often preferred in studies on hair growth and regeneration. However, primary HDPCs are limited by their reduced proliferative capacity, decreased hair induction potential, and extended doubling times at higher passages. To overcome these limitations, pTARGET vectors containing human papillomavirus16 (HPV16) E6/E7 oncogenes were transfected into HDPCs and selected using G-148 to generate immortalized cells here. HPV16 E6/E7 oncogenes were efficiently transfected into primary HDPCs. Immortalized HDPC showed higher proliferative activity than primary HDPC, confirming an increased proliferation rate. Expression of p53 and pRb proteins was downregulated by E6 and E7, respectively. E6/E7 expressing HDPC cells revealed that cyclin-dependent kinase (CDK) inhibitor p21 expression was decreased, while cell cycle-related genes and proteins (CDK2 and cyclin E) and E2F family genes were upregulated. Immortalized HDPCs maintained their responsiveness to Wnt/ß-catenin pathway and hair follicle formation capability, as indicated by their aggregative properties and stemness. E6/E7 immortalized HDPCs may facilitate in vitro hair growth and regeneration studies.

Modulatory effects of point-mutated IL-32θ (A94V) on tumor progression in triple-negative breast cancer cells.

Breast cancer is a frequently diagnosed cancer and the leading cause of death among women worldwide. Tumor-associated macrophages stimulate cytokines and chemokines, which induce angiogenesis, metastasis, proliferation, and tumor-infiltrating immune cells. Although interleukin-32 (IL-32) has been implicated in the development and modulation of several cancers, its function in breast cancer remains elusive. Mutation of interleukin-32θ (IL-32θ) in the tissues of patients with breast cancer was detected by Sanger sequencing. RT-qPCR was used to detect the mRNA levels of inflammatory cytokines, chemokines, and mediators. The secreted proteins were detected using respective enzyme-linked immunosorbent assays. Evaluation of the inhibitory effect of mutant IL-32θ on proliferation, migration, epithelial-mesenchymal transition (EMT), and cell cycle arrest in breast cancer cells was conducted using MTS assays, migration assays, and Western blotting. A point mutation (281C>T, Ala94Val) was detected in IL-32θ in both breast tumors and adjacent normal tissues, which suppressed the expression of pro-inflammatory factors, EMT factors, and cell cycle related factors. Mutated IL-32θ inhibited the expression of inflammatory factors by regulating the NF-κB pathway. Furthermore, mutated IL-32θ suppressed EMT markers and cell cycle related factors through the FAK/PI3K/AKT pathway. It was inferred that mutated IL-32θ modulates breast cancer progression. Mutated IL-32θ (A94V) inhibited inflammation, EMT, and proliferation in breast cancer by regulating the NF-κB (p65/p50) and FAK-PI3K-GSK3 pathways.

Selectivity of Electrochemical Reactions Based on Adsorption at Nanoporous Electrodes.

Enhancing selectivity is a pivotal area of research when electrodes are utilized as catalysts or sensors. Nanoporous electrodes are representative electrode materials for diverse applications, such as catalysts and sensors. Selectivity arising from nanoporous structures has been applied to systems involving nonfaradaic reactions such as capacitive deionization, electrochemical supercapacitors, and conductometry. Since selectivity in faradaic reactions has primarily been explored based on reactivity and molecular charge and size, we propose that the surface adsorption of reactant molecules can be considered as another crucial factor in achieving selectivity. Our observations reveal that the nonadsorptive reaction of 2-propanol and 2-butanol experienced a more pronounced enhancement compared to the adsorptive reaction of 1-propanol and 1-butanol at nanoporous Pt electrodes, owing to the nanoconfinement effect. Even within the same molecule with a mixture of adsorptive and nonadsorptive reactions, the degree of influence of the nanostructure depends on the adsorptive capacity of the reaction, which affects the overall selectivity. Moreover, the size effect of the reactants in the nanoporous electrode is also dependent on the degree of adsorption. These findings provide valuable insights into the effective utilization of nanoporous materials as catalysts or sensors.

Vascular regeneration and skeletal muscle repair induced by long-term exposure to SDF-1α derived from engineered mesenchymal stem cells after hindlimb ischemia.

Despite recent progress in medical and endovascular therapy, the prognosis for patients with critical limb ischemia (CLI) remains poor. In response, various stem cells and growth factors have been assessed for use in therapeutic neovascularization and limb salvage in CLI patients. However, the clinical outcomes of cell-based therapeutic angiogenesis have not provided the promised benefits, reinforcing the need for novel cell-based therapeutic angiogenic strategies to cure untreatable CLI. In the present study, we investigated genetically engineered mesenchymal stem cells (MSCs) derived from human bone marrow that continuously secrete stromal-derived factor-1α (SDF1α-eMSCs) and demonstrated that intramuscular injection of SDF1α-eMSCs can provide long-term paracrine effects in limb ischemia and effectively contribute to vascular regeneration as well as skeletal muscle repair through increased phosphorylation of ERK and Akt within the SDF1α/CXCR4 axis. These results provide compelling evidence that genetically engineered MSCs with SDF-1α can be an effective strategy for successful limb salvage in limb ischemia.

Salvage Hepatectomy for Recurrent Hepatocellular Carcinoma after Radiofrequency Ablation: A Retrospective Cohort Study with Propensity Score-Matched Analysis.

BACKGROUND AND OBJECTIVES: Although radiofrequency ablation (RFA) is a well-established locoregional treatment modality for hepatocellular carcinoma (HCC), the optimal strategy to handle local recurrence after ablation is still debated. This study aims to investigate the role of salvage hepatectomy (SH) as a rescue therapy for recurrent HCC after RFA. MATERIALS AND METHODS: Between January 2004 and December 2020, 1161 patients were subject to surgical resection for HCC. Among them, 47 patients who underwent SH for local recurrence after ablation were retrospectively analyzed and compared to a propensity score-matched group of controls (n = 47) who received primary hepatectomy (PH). Short-term and long-term outcomes were analyzed between the two groups. RESULTS: After matching, operation time, intraoperative blood loss, postoperative hospital stay, and postoperative morbidity rates showed no statistically significant difference. Tumors in the SH group were associated with poor differentiation (SH 9 (19.1%) vs. PH 1 (2.1%), p < 0.001). The 5-year disease-free survival rates (31.6% vs. 73.4%, p < 0.001) and overall survival rates (80.3% vs. 94.2%, p = 0.047) were significantly lower in the SH group. In multivariable analysis, less extensive resection compared to the initial plan (hazard ratio (HR) 4.68, p = 0.024), higher grade (HR 5.38, P < 0.001), negative but close (<0.1 cm) resection margin (HR 22.14, p = 0.007), and R1 resection (HR 3.13, p = 0.006) were significant predictors for recurrence. CONCLUSIONS: SH for recurrent tumors after ablation showed safety and effectiveness equivalent to primary resection. As recurrent tumors show a higher grade and more aggressive behavior, more extensive resections with wide surgical margins are necessary to prevent recurrence.

Core-Shell Droplet-Based Angiogenic Patches for the Treatment of Ischemic Diseases: Ultrafast Processability, Physical Tunability, and Controlled Delivery of an Angiogenic Cocktail.

The patch-based delivery system has been a promising therapeutic approach for treating various vascular diseases. However, conventional methods face several challenges, including labor-intensive and time-consuming processes associated with patch fabrication or factor incorporation, inadequate physical properties, and uncontrolled release of factors. These limitations restrict the potential applications in clinical settings. To overcome these issues, we propose a novel core-shell-shaped droplet patch system called an angiogenic patch (AP). Our system offers several distinct advantages over conventional patches. It enables a rapid and straightforward fabrication process utilizing only two biodegradable ingredients [alginate and ε-poly(l-lysine)], ensuring minimal toxicity. Moreover, the AP exhibits excellent physical integrity to match and withstand physiological mechanics and allows for customizable patch dimensions tailored to individual patients' pathological conditions. Notably, the AP enables facile loading of angiogenic cytokines during patch fabrication, allowing sustained release at a controlled rate through tunable network cross-linking. Subsequently, the AP, delivering a precisely formulated cocktail of angiogenic cytokines (VEGF, bFGF, EGF, and IGF), demonstrated significant effects on endothelial cell functions (migration and tubule formation) and survival under pathological conditions simulating ischemic injury. Likewise, in in vivo experiments using a mouse model of hindlimb ischemia, the AP encapsulating the angiogenic cocktail effectively restored blood flow following an ischemic insult, promoting muscle regeneration and preventing limb loss. With its simplicity and rapid processability, user-friendly applicability, physical tunability, and the ability to efficiently load and control the delivery of angiogenic factors, the AP holds great promise as a therapeutic means for treating patients with ischemic diseases.