BRCA1/2 Serves as a Biomarker for Poor Prognosis in Breast Carcinoma.

BRCA1/2 are breast cancer susceptibility genes that are involved in DNA repair and transcriptional control. They are dysregulated in breast cancer, making them attractive therapeutic targets. Here, we performed a systematic multiomics analysis to expound BRCA1/2 functions as prognostic biomarkers in breast cancer. First, using different web-based bioinformatics platforms (Oncomine, TIMER 2.0, UALCAN, and cBioportal), the expression of BRCA1/2 was assessed. Then, the R package was used to analyze the diagnostic value of BRCA1/2 in patients. Next, we determined the relationship between BRCA1/2 mRNA expression and prognosis in patients (PrognoScan Database, R2: Kaplan Meier Scanner and Kaplan−Meier Plotter). Subsequently, the association of BRCA1/2 with mutation frequency alteration and copy number alterations in breast cancer was investigated using the cBioportal platform. After that, we identified known and predicted structural genes and proteins essential for BRCA1/2 functions using GeneMania and STRING db. Finally, GO and KEGG pathway enrichment analyses were performed to elucidate the potential biological functions of the co-expression genes of BRCA1/2. The BRCA1/2 mRNA level in breast cancer tissues was considerably higher than in normal tissues, with AUCs of 0.766 and 0.829, respectively. Overexpression of BRCA1/2 was significantly related to the worse overall survival (p < 0.001) and was correlated to clinicopathological characteristics including lymph nodes, estrogen receptors, and progesterone receptors (p < 0.01). The alteration frequencies of both the gens have been checked, and the results show that BRCA1 and BRCA2 show different alteration frequencies. Their mutation sites differ from each other. GO and KEGG showed that BRCA1/2 was mainly enriched in catalytic activity, acting on DNA, chromosomal region, organelle fission, cell cycle, etc. The 20 most frequently changed genes were closely related to BRCA1/2, including PALB2 and RAD51 relatively. Our study provides suggestive evidence of the prognostic role of BRCA1/2 in breast cancer and the therapeutic target for breast cancer. Furthermore, BRCA1/2 may influence BRCA prognosis through catalytic activity, acting on DNA, chromosomal regions, organelle fission, and the cell cycle. Nevertheless, further validation is warranted.

Comprehensive Analysis of Cardiac Xeno-Graft Unveils Rejection Mechanisms.

Porcine heart xenotransplantation is a potential treatment for patients with end-stage heart failure. To understand molecular mechanisms of graft rejection after heart transplantation, we transplanted a 31-day-old alpha-1,3-galactosyltransferase knockout (GTKO) porcine heart to a five-year-old cynomolgus monkey. Histological and transcriptome analyses were conducted on xenografted cardiac tissue at rejection (nine days after transplantation). The recipient monkey's blood parameters were analyzed on days -7, -3, 1, 4, and 7. Validation was conducted by quantitative real-time PCR (qPCR) with selected genes. A non-transplanted GTKO porcine heart from an age-matched litter was used as a control. The recipient monkey showed systemic inflammatory responses, and the rejected cardiac graft indicated myocardial infarction and cardiac fibrosis. The transplanted heart exhibited a total of 3748 differentially expressed genes compared to the non-transplanted heart transcriptome, with 2443 upregulated and 1305 downregulated genes. Key biological pathways involved at the terminal stage of graft rejection were cardiomyopathies, extracellular interactions, and ion channel activities. The results of qPCR evaluation were in agreement with the transcriptome data. Transcriptome analysis of porcine cardiac tissue at graft rejection reveals dysregulation of the key molecules and signaling pathways, which play relevant roles on structural and functional integrities of the heart.

Immune molecular profiling of whole blood drawn from a non-human primate cardiac xenograft model treated with anti-CD154 monoclonal antibodies.

Most studies of xenografts have been carried out with complex immunosuppressive regimens to prevent immune rejection; however, such treatments may be fatal owing to unknown causes. Here, we performed immune molecular profiling following anti-CD154 monoclonal antibody (mAb) treatment in heterotopic abdominal cardiac xenografts from α-1,3-galactosyltransferase-knockout pigs into cynomolgus monkeys to elucidate the mechanisms mediating the undesirable fatal side effects of immunosuppressive agents. Blood samples were collected from healthy monkeys as control and then at 2 days after xenograft transplantation and just before humane euthanasia; 94 genes related to the immune system were analyzed. The basic immunosuppressive regimen included cobra venom factor, anti-thymocyte globulin, and rituximab, with and without anti-CD154 mAbs. The maintenance therapy was followed with tacrolimus, MMF, and methylprednisolone. The number of upregulated genes was initially decreased on Day 2 (-/+ anti-CD154 mAb, 22/13) and then increased before euthanasia in recipients treated with anti-CD154 mAbs (-/+ anti-CD154 mAb, 30/37). The number of downregulated genes was not affected by anti-CD154 mAb treatment. Additionally, the number of upregulated genes increased over time for both groups. Interestingly, treatment with anti-CD154 mAbs upregulated coagulation inducers (CCL2/IL6) before euthanasia. In conclusion, immunosuppressive regimens used for cardiac xenografting affected upregulation of 6 inflammation genes (CXCL10, MPO, MYD88, NLRP3, TNFα, and TLR1) and downregulation of 8 genes (CCR4, CCR6, CD40, CXCR3, FOXP3, GATA3, STAT4, and TBX21).

Prevalence of Malnutrition in Hospitalized Patients: a Multicenter Cross-sectional Study.

BACKGROUND: Malnutrition is associated with many adverse clinical outcomes. The present study aimed to identify the prevalence of malnutrition in hospitalized patients in Korea, evaluate the association between malnutrition and clinical outcomes, and ascertain the risk factors of malnutrition. METHODS: A multicenter cross-sectional study was performed with 300 patients recruited from among the patients admitted in 25 hospitals on January 6, 2014. Nutritional status was assessed by using the Subjective Global Assessment (SGA). Demographic characteristics and underlying diseases were compared according to nutritional status. Logistic regression analysis was performed to identify the risk factors of malnutrition. Clinical outcomes such as rate of admission in intensive care units, length of hospital stay, and survival rate were evaluated. RESULTS: The prevalence of malnutrition in the hospitalized patients was 22.0%. Old age (≥ 70 years), admission for medical treatment or diagnostic work-up, and underlying pulmonary or oncological disease were associated with malnutrition. Old age and admission for medical treatment or diagnostic work-up were identified to be risk factors of malnutrition in the multivariate analysis. Patients with malnutrition had longer hospital stay (SGA A = 7.63 ± 6.03 days, B = 9.02 ± 9.96 days, and C = 12.18 ± 7.24 days, P = 0.018) and lower 90-day survival rate (SGA A = 97.9%, B = 90.7%, and C = 58.3%, P < 0.001). CONCLUSION: Malnutrition was common in hospitalized patients, and resulted in longer hospitalization and associated lower survival rate. The rate of malnutrition tended to be higher when the patient was older than 70 years old or hospitalized for medical treatment or diagnostic work-up compared to elective surgery.

Molecular immunology profiles of monkeys following xenografting with the islets and heart of α-1,3-galactosyltransferase knockout pigs.

Effective immunosuppression strategies and genetically modified animals have been used to prevent hyperacute and acute xenograft rejection; however, the underlying mechanisms remain unknown. In this study, we evaluated the expression of a comprehensive set of immune system-related genes (89 genes, including five housekeeping genes) in the blood of cynomolgus monkeys (~5 yr old) used as graft recipients, before and after the xenografting of the islets and heart from single and double α-1,3-galactosyltransferase (GalT) knockout (KO) pigs (<6 weeks old). The immunosuppressive regimen included administration of cobra venom factor, anti-thymocyte globulin, rituximab, and anti-CD154 monoclonal antibodies to recipients before and after grafting. Islets were xenografted into the portal vein in type 1 diabetic monkeys, and the heart was xenografted by heterotopic abdominal heart transplantation. Genes from recipient blood were analyzed using RT(2) profiler PCR arrays and the web-based RT(2) profiler PCR array software v.3.5. Recipients treated with immunosuppressive agents without grafting showed significant downregulation of CCL5, CCR4, CCR6, CD4, CD40LG, CXCR3, FASLG, CXCR3, FOXP3, GATA3, IGNG, L10, IL23A, TRAF6, MAPK8, MIF, STAT4, TBX21, TLR3, TLR7, and TYK2 and upregulation of IFNGR1; thus, genes involved in protection against viral and bacterial infection were downregulated, confirming the risk of infection. Notably, C3-level control resulted in xenograft failure within 2 days because of a 7- to 11-fold increase in all xenotransplanted models. Islet grafting using single GalT-KO pigs resulted in upregulation of CXCL10 and MX1, early inflammation, and acute rejection-associated signals at 2 days after xenografting. We observed at least 5-fold upregulation in recipients transplanted with islets grafts from single (MX1) or double (C3, CCR8, IL6, IL13, IRF6, CXCL10, and MX1) GalT-KO pigs after 77 days; single GalT-KO incurred early losses owing to immune attacks. Our results suggest that this novel, simple, non-invasive, and time-efficient procedure (requiring only 1.5 ml blood) for evaluating graft success, minimizing immune rejection, and blocking infection.

The 1,470-nm bare-fiber diode laser ablation of the great saphenous vein and small saphenous vein at 1-year follow-up using 8-12 W and a mean linear endovenous energy density of 72 J/cm.

PURPOSE: To demonstrate 1-year outcomes after low-energy endovenous laser ablation (EVLA) of incompetent saphenous veins with linear endovenous energy density (LEED) of 80 J/cm or lower with the use of a 1,470-nm diode laser. MATERIALS AND METHODS: Incompetent saphenous veins in 236 patients (355 limbs; Clinical/Etiology/Anatomy/Pathophysiology classifications of C2-C4) were treated by EVLA with a bare-tipped 1,470-nm laser with LEED no greater than 80 J/cm (mean, 72.4 J/cm) and laser power of 8-12 W. Patients were evaluated clinically and with duplex ultrasonography at 1 week and 1, 3, 6, and 12 months after EVLA to assess the technical and clinical success and complication rates. RESULTS: In the 355 limbs, the technical success rate was 100%. The great saphenous vein (GSV) remained occluded in all 229 limbs (100%) after 1 week, 202 of 203 limbs (99.5%) after 1 month, 157 of 158 limbs after 3 months (99.3%), all 99 limbs after 6 months (100%), and all 41 limbs after 1 year (100%). The small saphenous vein (SSV) remained occluded in all 103 limbs (100%) after 1 week, all 94 limbs (100%) after 1 month, 68 of 69 limbs (98.5%) after 3 months, 40 of 41 limbs (97.5%) after 6 months, and all 14 limbs after 1 year (100%). Two GSVs and two SSVs were recanalized and underwent repeated EVLA. No major complications occurred, although bruising (21% of cases), pain (15%), and paresthesia (4%) were observed. CONCLUSIONS: Low-energy EVLA with the use of a 1,470-nm laser with LEED of 80 J/cm or lower is an effective, safe, and technically successful option for the treatment of incompetent saphenous veins.

A Comparison Between GalT-/-;hCD39;hCD55 and GalT-/-;hCD39;hCD46;hCD55;TBM Pig Kidneys Transplanted in Nonhuman Primates.

Because there is a shortage of donor kidneys, researchers are exploring the possibility of using genetically modified pig kidneys for transplantation. Approaches involving knockout of carbohydrate genes or knockin of protective proteins have been attempted to determine the best gene modifications. In this study, we utilized GalT-/-;hCD39;hCD55 and GalT-/-;hCD39;hCD46;hCD55;thrombomodulin (TBM) pigs for transplantation in nonhuman primates (NHPs). The NHPs survived for 4 weeks after kidney transplantation (4 WAT) from the GalT-/-;hCD39;hCD55 pig and for 6 WAT from the GalT-/-;hCD39;hCD46;hCD55;TBM pig. However, messenger RNA (mRNA) sequencing and immunohistochemistry analysis revealed that the 6 WAT kidney exhibited more severe apoptosis, inflammation, loss of renal function, and renal fibrosis than the 4 WAT kidney. These results indicate that additional knockin of complement regulator (hCD46) and coagulation regulator (TBM) is not enough to prevent renal damage, suggesting that improved immune suppression is needed for more prolonged survival.

CTLA4 expression profiles and their association with clinical outcomes of breast cancer: a systemic review.

Purpose: The cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is involved in the progression of various cancers, but its biological roles in breast cancer (BRCA) remain unclear. Therefore, we performed a systematic multiomic analysis to expound on the prognostic value and underlying mechanism of CTLA4 in BRCA. Methods: We assessed the effect of CTLA4 expression on BRCA using a variety of bioinformatics platforms, including Oncomine, GEPIA, UALCAN, PrognoScan database, Kaplan-Meier plotter, and R2: Kaplan-Meier scanner. Results: CTLA4 was highly expressed in BRCA tumor tissue compared to normal tissue (P < 0.01). The CTLA4 messenger RNA levels in BRCA based on BRCA subtypes of Luminal, human epidermal growth factor receptor 2, and triple-negative BRCA were considerably higher than in normal tissues (P < 0.001). However, the overexpression of CTLA4 was associated with a better prognosis in BRCA (P < 0.001) and was correlated with clinicopathological characteristics including age, T stage, estrogen receptors, progesterone receptors, and prediction analysis of microarray 50 (P < 0.01). The infiltration of multiple immune cells was associated with increased CTLA4 expression in BRCA (P < 0.001). CTLA4 was highly enriched in antigen binding, immunoglobulin complexes, lymphocyte-mediated immunity, and cytokine-cytokine receptor interaction. Conclusion: This study provides suggestive evidence of the prognostic role of CTLA4 in BRCA, which may be a therapeutic target for BRCA. Furthermore, CTLA4 may influence BRCA prognosis through antigen binding, immunoglobulin complexes, lymphocyte-mediated immunity, and cytokine-cytokine receptor interaction. These findings help us understand how CTLA4 plays a role in BRCA and set the stage for more research.

Clinical outcomes of endovascular treatments for critical limb ischemia with chronic total occlusive lesions limited to below-the-knee arteries.

BACKGROUND: Diabetes mellitus tends to have the greatest impact on the smaller vessels and contributes significantly to occlusive disease from the popliteal artery distally. PURPOSE: To evaluate the clinical outcomes after a balloon angioplasty with or without stent placement in diabetic patients with critical limb ischemia (CLI) by chronic total occlusion (CTO) limited to below-the-knee (BTK) arteries. MATERIAL AND METHODS: From August 2005, patients who presented CLI and CTO limited to the BTK arteries, and who underwent endovascular treatment, were included in this study. The primary endpoints evaluated were technical success, limb salvage, and primary patency. The secondary endpoints evaluated were 30-day access site, intervention site, and systemic complications. Patency and limb salvage were evaluated using the Kaplan-Meier method and compared using Fisher's exact test. RESULTS: The BTK endovascular treatment (EVT) was performed on 64 limbs. Technical success rate was 93.8% and limb salvage rate was 90.6%. Three of four limbs with technical failure and three of 60 limbs with technical success underwent BTK amputation and the comparison of these rates were significantly different (75% vs. 5%, P = 0.002). Primary patency rates for the limbs were 75% and 59.1% at 6-month and 12-month follow-up, respectively. Minor complications disappeared through the follow-up periods and there was no 30-day complication or systemic adverse events for the treated vessel. CONCLUSION: Even though EVT for CLI in patients with diabetes and CTO in isolated BTK arteries does not have comparable primary patency, it can lead to a very high rate of limb salvage. This result can accentuate the importance of more blood flow to the foot by means of successful revascularization using EVT rather than long-term patency in CTO of isolated BTK arteries.

Comparison of Graft Survival Between Full-Thickness and Lamellar Pig-to-Monkey Corneal Xenotransplantation from the Same Genetically Engineered Pig Model with Minimal Immunosuppression.

BACKGROUND: The graft survival rate of full-thickness corneal xenotransplantation (XTP) with minimal immunosuppression in genetically engineered pigs is unknown, whereas lamellar corneal XTP shows satisfactory results. We compared graft survival between full-thickness and lamellar transplantations in the same genetically engineered pig. METHODS: Six pig-to-monkey corneal transplantations were performed on 3 transgenic pigs. Two corneas harvested from 1 pig were transplanted into 2 monkeys using full-thickness and lamellar corneal xenotransplantation. The transgenic donor pigs used were α1,3-galactosyltransferase gene-knockout + membrane cofactor protein (GTKO+CD46) in one recipient and GTKO+CD46+ thrombomodulin (TBM) in the other. RESULTS: The graft survival time for GTKO+CD46 XTP was 28 days. With the addition of TBM, the survival differences between lamellar and full-thickness XTP were 98 days versus 14 days and >463 days (ongoing) versus 21 days, respectively. An excessive number of inflammatory cells was observed in failed grafts, but none were in the recipient's stromal bed. CONCLUSIONS: Unlike full-thickness corneal XTP, lamellar xenocorneal transplantation does not exhibit surgical complications, such as retrocorneal membrane or anterior synechia. The graft survival of lamellar XTP in this study was not as good as in our previous experiments, although the survival period was superior to that of full-thickness XTP. The difference in graft survival based on transgenic type is not definitive. Further studies using transgenic pigs and minimal immunosuppression need to focus on improving graft survival of lamellar XTP and using a larger sample size to determine the potential of full-thickness corneal XTP.

Current Status of Genetically Engineered Pig to Monkey Kidney Xenotransplantation in Korea.

BACKGROUND: In South Korea, pig-to-nonhuman primate trials of solid organs have only been performed recently, and the results are not sufficiently satisfactory to initiate clinical trials. Since November 2011, we have performed 30 kidney pig-to-nonhuman primate xenotransplantations at Konkuk University Hospital. METHODS: Donor αGal-knockout-based transgenic pigs were obtained from 3 institutes. The knock-in genes were CD39, CD46, CD55, CD73, and thrombomodulin, and 2-4 transgenic modifications with GTKO were done. The recipient animal was the cynomolgus monkey. We used the immunosuppressants anti-CD154, rituximab, anti-thymocyte globulin, tacrolimus, mycophenolate mofetil, and steroids. RESULTS: The mean survival duration of the recipients was 39 days. Except for a few cases for which survival durations were <2 days because of technical failure, 24 grafts survived for >7 days, with an average survival duration of 50 days. Long-term survival was observed 115 days after the removal of the contralateral kidney, which is currently the longest-recorded graft survival in Korea. We confirmed functioning grafts for the surviving transplanted kidneys after the second-look operation, and no signs of hyperacute rejection were observed. CONCLUSIONS: Although our survival results are relatively poor, they are the best-recorded results in South Korea, and the ongoing results are improving. With the support of government funds and the volunteering activities of clinical experts, we aim to further improve our experiments and contribute to the commencement of clinical trials of kidney xenotransplantation in Korea.

Comparative transcriptome analysis between long- and short-term survival after pig-to-monkey cardiac xenotransplantation reveals differential heart failure development.

Cardiac xenotransplantation is the potential treatment for end-stage heart failure, but the allogenic organ supply needs to catch up to clinical demand. Therefore, genetically-modified porcine heart xenotransplantation could be a potential alternative. So far, pig-to-monkey heart xenografts have been studied using multi-transgenic pigs, indicating various survival periods. However, functional mechanisms based on survival period-related gene expression are unclear. This study aimed to identify the differential mechanisms between pig-to-monkey post-xenotransplantation long- and short-term survivals. Heterotopic abdominal transplantation was performed using a donor CD46-expressing GTKO pig and a recipient cynomolgus monkey. RNA-seq was performed using samples from POD60 XH from monkey and NH from age-matched pigs, D35 and D95. Gene-annotated DEGs for POD60 XH were compared with those for POD9 XH (Park et al. 2021). DEGs were identified by comparing gene expression levels in POD60 XH versus either D35 or D95 NH. 1,804 and 1,655 DEGs were identified in POD60 XH versus D35 NH and POD60 XH versus D95 NH, respectively. Overlapped 1,148 DEGs were annotated and compared with 1,348 DEGs for POD9 XH. Transcriptomic features for heart failure and inhibition of T cell activation were observed in both long (POD60)- and short (POD9)-term survived monkeys. Only short-term survived monkey showed heart remodeling and regeneration features, while long-term survived monkey indicated multi-organ failure by neural and hormonal signaling as well as suppression of B cell activation. Our results reveal differential heart failure development and survival at the transcriptome level and suggest candidate genes for specific signals to control adverse cardiac xenotransplantation effects.

Randomized clinical trial comparing two methods for endovenous laser ablation of incompetent perforator veins in thigh and great saphenous vein without evidence of saphenofemoral reflux.

BACKGROUND: Percutaneous ablation of incompetent perforators has been introduced as a safe and efficacious alternative. OBJECTIVE: To compare two methods of treating incompetent thigh perforator and great saphenous veins (GSV). MATERIALS AND METHODS: Patients with varicose veins of CEAP C2 and C3 with incompetent perforating veins (IPVs) in the thigh without evidence of saphenofemoral reflux and with obvious venous reflux from IPVs into the GSV distal to IPVs were included. Endovenous laser ablation was done using two methods (IPV ablation (IPVA) versus GSV ablation: GSVA). Their technical success rate, clinical success rate, and complications were compared at 1 week, and 1, 3, 6, and 12 months. RESULTS: Sixty-nine consecutive patients were randomized to IPVA (n = 34) or GSVA (n = 35). Technical success was significantly lower with IPVA than GSVA (p = .002). Clinical success, defined as continued closure of treated veins, was similar with IPVA and GSVA (96.1% vs 100% at 1 week, 100% vs 97.1% at 1 month, and 100% for both at 3, 6, and 12 months, respectively). CONCLUSION: IPVA has clinical results and complications similar to those of GSVA in individuals with C2 and C3 chronic venous disease with IPVs in the thigh combined with incompetent GSV, but its higher technical failure rate makes it difficult to choose it as the primary treatment method.

Vitamin D receptor (VDR) mRNA overexpression is associated with poor prognosis in breast carcinoma.

Purpose: The prognostic value of vitamin D receptor gene (VDR) expression in breast cancer development is unclear. Here, we aimed to investigate whether VDR expression can be used as a prognostic indicator of breast cancer. Methods: We used various public bioinformatics platforms: Oncomine, GEPIA, UALCAN, Kaplan-Meier plotter, UCSC XENA, bc-GenExMiner, WebGestalt, and STRING database. Results: We found that VDR was upregulated in breast cancer in comparison to normal tissues. Overexpression of VDR was significantly associated with worse overall survival in breast cancer. The expression of VDR was related to age, TNM stages, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, basal-like (PAM 50) status, triple-negative breast cancer (TNBC) status, and basal-like (PAM 50) & TNBC status (P < 0.05). Increased VDR expression in breast cancer was significantly associated with older age. The 5 hub genes for VDR were NCOA1, EP300, CREBBP, and RXRA. Conclusion: Our investigation offers hints about the prognostic role of VDR in breast cancer. The findings suggest that VDR expression might be used as a marker to determine a breast cancer patient's prognosis. Nevertheless, further validation is warranted.

Transcatheter arterial embolization for hemoperitoneum: unusual manifestation of iatrogenic injury to abdominal muscular arteries.

PURPOSE: To evaluate the etiology of unusual manifestation of hemoperitoneum and the efficacy of transcatheter arterial embolization (TAE). MATERIALS AND METHODS: A retrospective review of patients at three hospitals was performed. A total of 12 patients (M:F = 5:7, mean age: 48) had massive hemoperitoneum without evidence of an intramuscular hematoma on CT (n = 10) or US (n = 2) after injury to the abdominal wall. The patients underwent TAE. The etiology of iatrogenic injury to the abdominal muscular arteries and the effectiveness of embolization were evaluated. RESULTS: Among 12 patients, 11 patients had injuries to the inferior epigastric artery (IEA) and one patient had an injury to the deep circumflex iliac artery (DCIA). The causes of the injuries were: paracentesis (n = 6), open laparotomy (n = 4), removal of a CAPD catheter (n = 1), and surgical drain (n = 1). The TAE was successfully performed in all patients. Over 10 days of follow-up after the embolization, all patients were stabilized hemodynamically. CONCLUSION: Injury to the IEA or DCIA should be considered as a possible source of hemoperitoneum even in patients with no evidence of an intramuscular hematoma after injury to the superficial arteries of the abdominal wall. In addition, such injuries can be treated successfully using TAE.

Early Interferon-Gamma Response in Nonhuman Primate Recipients of Solid-Organ Xenotransplantation.

BACKGROUND: To understand changes in biological responses in nonhuman primate (NHP) recipients of xenotransplantation (XTP), we retrospectively investigated chronological changes in cytokine profiles of NHP recipients after solid-organ XTP. METHODS: Plasma samples were collected from 7 NHP recipients of pig heart or kidney XTP with α-1,3-galactosyltransferase gene knockout (GTKO) under anti-CD154-based immune suppression at the following time points: immediately before; 2 hours, 3 days, and 7 days after XTP; and weekly thereafter until the graft failed. The plasma levels of the following cytokines were measured: interleukin (IL)-1α, IL-1ß, IL-6, IL-12p70, IL-8, IL-10, IL-15, tumor necrosis factor, interferon gamma (IFN-γ), D-dimer, C3a, and histone-complexed DNA fragments. For in vitro experiments, human natural killer (NK) cells were cocultured with wild-type porcine endothelial cells (PECs), GTKO-PECs, and human umbilical vein endothelial cells, with or without anti-CD154 antibody. IFN-γ levels in the culture supernatants were compared. RESULTS: IFN-γ levels peaked on day 7 or 10 of XTP and then decreased to basal levels, whereas proinflammatory cytokine levels increased along with the elevation of histone-complexed DNA fragments and were sustained until xenograft failure. In vitro, human NK cells produced more IFN-γ when in contact with wild-type PECs than with human umbilical vein endothelial cells, which was not reduced by the use of GTKO-PECs or addition of anti-CD154 antibody to the mixture. CONCLUSIONS: In NHP recipients of XTP, the early peak of IFN-γ priming subsequent inflammatory responses may be attributed to NK cell activation in response to xenografts.

Improving self-sufficiency in organ transplantation in Korea.

After attaining a qualified medical capacity in organ transplantation, Korea has been struggling to increase the number of deceased organ transplants to reach self-sufficiency. As one of these efforts, Korea revised the organ transplantation law in 2010 by adding three articles the mandatory reporting based on the recommendation of the 3rd Global Consultation on Organ Transplantation of Madrid in 2010. Along with the new constitution, considerable efforts have been initiated to upgrade the deceased organ transplantation system while maintaining the virtues of fairness, justice, and transparency. The Korean Society of Transplantation played a critical role in revising the law as well as in establishing organizations such as the Korean Organ Donation Agency (KODA; 2009), the Vitallink (2009), and the Korean Organ Transplantation Registry (KOTRY; 2010). By the activities of these professional organizations, Korea could implement fundamental programs such as mandatory reporting and could develop various education programs for organ donation for students and the general population. As a result, the number of deceased donors increased from 1.08 p.m.p. (2000) to 9.23 p.m.p.(2020). Further efforts are needed to increase the number of organ donor cardholders and family consent rates by well-designed, target-specific education programs to overcome traditional negative cultural barriers toward organ donation. The community atmosphere of honoring and thanking donors and their families should be nurtured by national and regional activities of life-sharing weeks linked with organ donor memorial parks.

Prognostic Significance of Prostaglandin-Endoperoxide Synthase-2 Expressions in Human Breast Carcinoma: A Multiomic Approach.

Prostaglandin-endoperoxide synthase-2 (PTGS2) plays a pivotal role in inflammation and carcinogenesis in human breast cancer. Our aim of the study is to find the prognostic value of PTGS2 in breast cancer. We conducted a multiomic analysis to determine whether PTGS2 functions as a prognostic biomarker in human breast cancer. We explored PTGS2 mRNA expressions using different public bioinformatics portals. Oncomine, Serial Analysis of Gene Expression (SAGE), GEPIA, ULCAN, PrognoScan database, Kaplan-Meier Plotter, bc-GenExMiner, USC XENA, and Cytoscape/STRING DB were used to identify the prognostic roles of PTGS2 in breast cancer. Based on the clinicopathological analysis, decreased PTGS2 expressions correlated positively with older age, lymph node status, the human epidermal growth factor receptor 2 (HER2) status (P < .0001), estrogen receptor (ER+) expression (P < .0001) Luminal A (P < .0001), and Luminal B (P < .0001). Interestingly, progesterone receptor (PR) (P < .0001) negative showed a high expression of PTGS2. Prostaglandin-endoperoxide synthase-2 was downregulated in breast cancer tissues than in normal tissues. In the PrognoScan database and, Kaplan-Meier Scanner, downregulated expressions of PTGS2 associated with poor overall survival (OS), relapse-free survival (RFS), and distant metastasis-free survival. The methylation levels were significantly higher in the Luminal B subtype. Through oncomine coexpressed gene analysis, we found a positive correlation between PTGS2 and interleukin-6 (IL-6) expression in breast cancer tissues. These results indicate that downregulated expressions of PTGS2 can be used as a promising prognostic biomarker and Luminal B hyper methylation may play an important role in the development of breast cancers. However, to clarify our results, extensive study is required.

Moderate-to-severe early-onset hyperuricaemia: a prognostic marker of long-term kidney transplant outcome.

BACKGROUND: Hyperuricaemia commonly occurs in renal transplant recipients (RTRs), but the effects of post-transplant hyperuricaemia on kidney transplant outcome have not been clearly established. This work was designed to explore the impact of hyperuricaemia on renal transplant outcome. METHODS: The authors examined this issue by analysing the clinical outcome of 281 RTRs. Hyperuricaemia (defined as UA > 7.0 mg/dl in men and >6.0 mg/dl in women for at least two consecutive tests, n = 121) was classified as early onset (within 1 year of transplant, n = 90) or late onset (n = 31). Graft function was estimated using the MDRD Study Equation 7 (eGFR(MDRD)). RESULTS: As late-onset hyperuricaemia was found to be induced by a progressive decline in the graft function (P < 0.01), data from early-onset hyperuricaemic recipients were used. Early-onset moderate-to-severe hyperuricaemia (defined as UA >or= 8.0 mg/dl) was found to be a significant risk factor for chronic allograft nephropathy (P = 0.035) and a poorer graft survival (P = 0.026) by multivariate analysis, whereas mild hyperuricaemia was not. The impact of moderate-to-severe hyperuricaemia on renal transplant survival was dependent on the duration of exposure. Likewise, the detrimental effect of early-onset hyperuricaemia on the graft function was dependent on UA levels and exposure time. After control of the baseline graft function by analysis of only recipients with a good graft function at 1 year post-transplantation (eGFR(MDRD) > 60 ml/min), moderate-to-severe early-onset hyperuricaemia was also found to be a marker of long-term graft dysfunction and failure. CONCLUSION: Moderate-to-severe early-onset hyperuri- caemia may be a prognostic marker of the long-term graft outcome in RTRs, which needs further investigation.

Fluoroscopy-guided endovenous foam sclerotherapy using a microcatheter in varicose tributaries followed by endovenous laser treatment of incompetent saphenous veins: technical feasibility and early results.

OBJECTIVES: To evaluate the technical feasibility and preliminary results of endovenous foam sclerotherapy using a microcatheter in varicose tributaries followed by endovenous laser treatment (EVLT) of incompetent saphenous veins. MATERIALS AND METHODS: From July 2005 to August 2006, 312 patients (M:F=139:173, mean age 45.8) who presented with varicose veins with reflux in the saphenofemoral, saphenopopliteal junction or tributaries were enrolled. Under ultrasound or fluoroscopy guidance, selective microcatheterization and endovenous foam slcerotherapy were first performed in varicose tributaries, followed by EVLT (980 nm) of incompetent saphenous veins. Follow-up at 1-week and 1-, 3-, and 6-month intervals was done. RESULTS: Technical success was seen in 410 of 411 limbs (99%). Continued closure of the saphenous veins and the complete sclerosis of varicose tributaries were noted in 332 of 373 limbs (89%) at the 1-month follow-up, all 307 limbs (100%) at the 3-month follow-up, and all 274 limbs (100%) at the 6-month follow-up. No serious complication was noted. CONCLUSION: Endovenous foam sclerotherapy using a microcatheter in varicose tributaries followed by EVLT in incompetent saphenous veins is a safe, effective, and technically feasible treatment for varicose veins. It not only reduces additional sclerotherapy and technical failure, but also makes multiple therapeutic sessions unnecessary.