Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA.

Multi-cancer early detection remains a key challenge in cell-free DNA (cfDNA)-based liquid biopsy. Here, we perform cfDNA whole-genome sequencing to generate two test datasets covering 2125 patient samples of 9 cancer types and 1241 normal control samples, and also a reference dataset for background variant filtering based on 20,529 low-depth healthy samples. An external cfDNA dataset consisting of 208 cancer and 214 normal control samples is used for additional evaluation. Accuracy for cancer detection and tissue-of-origin localization is achieved using our algorithm, which incorporates cancer type-specific profiles of mutation distribution and chromatin organization in tumor tissues as model references. Our integrative model detects early-stage cancers, including those of pancreatic origin, with high sensitivity that is comparable to that of late-stage detection. Model interpretation reveals the contribution of cancer type-specific genomic and epigenomic features. Our methodologies may lay the groundwork for accurate cfDNA-based cancer diagnosis, especially at early stages.

Perioperative management of living donor liver transplantation: Part 2 - Donors.

Living donor liver transplantation was first developed to mitigate the limited access to deceased donor organs in Asia in the 1990s. This alternative liver transplantation method has become a widely practiced and established transplantation option for adult patients suffering with end-stage liver disease, and it has successfully helped address the shortage of deceased donors. The Society for the Advancement of Transplant Anesthesia and the Korean Society of Transplantation Anesthesiologists jointly reviewed published studies on the perioperative management of adult live liver donors undergoing donor hemi-hepatectomy. The goal of the review is to offer transplant anesthesiologists and critical care physicians a comprehensive overview of the perioperative management of adult live donors. We featured the current status, donor selection process, outcomes and complications, surgical procedure, anesthetic management, Enhanced Recovery After Surgery protocols, avoidance of blood transfusion, and considerations for emergency donation. Recent surgical advances, including laparoscopic donor hemi-hepatectomy and robotic laparoscopic donor surgery, are also addressed.

Protective effects of non-thermal plasma on triethylene glycol dimethacrylate-induced damage in odontoblast-like MDPC-23 cells.

AIM: To evaluate whether the use of non-thermal plasma (NTP) could reduce triethylene glycol dimethacrylate (TEGDMA)-mediated damage in MDPC-23 cells. METHODOLOGY: The effects of NTP and TEGDMA on MDPC-23 cell proliferation were tested using WST-1 assays after pretreatment with NTP for 1 min and exposure to TEGDMA. Live/Dead assays were used to visualize cell death. To monitor the effects of NTP and TEGDMA on the cell cycle and apoptotic cell death, flow cytometry was performed. Western blotting was used to assess changes in protein levels mediated by NTP and TEGDMA treatment, and enzyme-linked immunosorbent assays were performed to evaluate the effects of NTP and TEGDMA on prostaglandin E2 (PGE2 ) expression. One-way analysis of variance and Duncan's post hoc tests were used for statistical analysis. RESULTS: NTP treatment effectively protected cells from TEGDMA-mediated cell damage and blocked TEGDMA-mediated cell growth inhibition (p < .05). NTP appeared to protect cells from death (p < .05) and blocked TEGDMA-mediated apoptotic cell death. Additionally, NTP reduced TEGDMA-mediated apoptotic activation of poly (ADP) ribose polymerase-1 and caspase-3 (p < .05). Furthermore, NTP effectively reduced TEGDMA-mediated expression of cyclooxygenase-2 and PGE2 proteins by inhibiting nuclear factor-κB protein expression (p < .05). CONCLUSIONS: NTP alleviated TEGDMA-mediated adverse effects by reducing cytotoxicity and inflammatory reactions in cells exposed to TEGDMA.

In Situ Hydrogel-Forming/Nitric Oxide-Releasing Wound Dressing for Enhanced Antibacterial Activity and Healing in Mice with Infected Wounds.

The eradication of bacteria from wound sites and promotion of healing are essential for treating infected wounds. Nitric oxide (NO) is desirable for these purposes due to its ability to accelerate wound healing and its broad-spectrum antibacterial effects. We developed an in situ hydrogel-forming/NO-releasing powder dressing (NO/GP), which is a powder during storage and forms a hydrogel when applied to wounds, as a novel NO-releasing formulation to treat infected wounds. An NO/GP fine powder (51.5 µm) was fabricated by blending and micronizing S-nitrosoglutathione (GSNO), alginate, pectin, and polyethylene glycol (PEG). NO/GP remained stable for more than four months when stored at 4 or 37 °C. When applied to wounds, NO/GP absorbed wound fluid and immediately converted to a hydrogel. Additionally, wound fluid triggered a NO release from NO/GP for more than 18 h. The rheological properties of hydrogel-transformed NO/GP indicated that NO/GP possesses similar adhesive properties to marketed products (Vaseline). NO/GP resulted in a 6-log reduction in colony forming units (CFUs) of methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, which are representative drug-resistant gram-positive and -negative bacteria, respectively. The promotion of wound healing by NO/GP was demonstrated in mice with full-thickness wounds challenged with MRSA and P. aeruginosa. Thus, NO/GP is a promising formulation for the treatment of infected wounds.

Increment of growth factors in mouse skin treated with non-thermal plasma.

Non-thermal plasma (NTP) has several beneficial effects, and can be applied as a novel instrument for skin treatment. Recently, many types of NTP have been developed for potential medical or clinical applications, but their direct effects on skin activation remain unclear. In this study, the effect of NTP on the alteration of mouse skin tissue was analyzed. After NTP treatment, there were no signs of tissue damage in mouse skin, whereas significant increases in epidermal thickness and dermal collagen density were detected. Furthermore, treatment with NTP increased the expression of various growth factors, including TGF-α, TGF-ß, VEGF, GM-CSF, and EGF, in skin tissue. Therefore, NTP treatment on skin induces the expression of growth factors without causing damage, a phenomenon that might be directly linked to epidermal expansion and dermal tissue remodeling.

Selective Killing of Melanoma Cells With Non-Thermal Atmospheric Pressure Plasma and p-FAK Antibody Conjugated Gold Nanoparticles.

Melanomas are fast growing high-mortality tumors, and specific treatments for melanomas are needed. Melanoma cells overexpress focal adhesion kinase (FAK) compared to normal keratinocytes, and we sought to exploit this difference to create a selectively lethal therapy. We combined gold nanoparticles (GNP) with antibodies targeting phosphorylated FAK (p-FAK). These conjugates (p-FAK-GNP) entered G361 melanoma cells and bound p-FAK. Treatment with p-FAK-GNP decreased the viability of G361 cells in a time dependent manner by inducing apoptosis. To maximize the preferential killing of G361 cells, non-thermal atmospheric pressure plasma was used to stimulate the GNP within p-FAK-GNP. Combined treatment with plasma and p-FAK-GNP showed much higher lethality against G361 cells than HaCaT keratinocyte cells. The p-FAK-GNP induced apoptosis over 48 hours in G361 cells, whereas plasma and p-FAK-GNP killed G361 cells immediately. This study demonstrates that combining plasma with p-FAK-GNP results in selective lethality against human melanoma cells.

Sensory and rheological characteristics of thickened liquids differing concentrations of a xanthan gum-based thickener.

The objectives of this study were to develop and compare sensory characteristics of beverages and soups thickened with different concentrations of a xanthan gum-based thickener, and to examine, using rheological measurement, whether the viscosity of the thickened liquids conformed to the recommendations of the National Dysphagia Diet (NDD) Task Force. Beverages tested included water, apple juice, orange juice, soymilk, and Yakult. The thickening agent was added to samples at concentrations of 1, 2, or 3%. Addition of the thickening agent had a significant effect on the appearance, texture, and starchy flavor, which were evaluated by descriptive sensory evaluation. The reference standards of viscosity used in sensory descriptive analysis could be useful to practitioners who have to make dysphagia diets and need to learn to make them properly. In rheological measurement, viscosity of thickened liquids in stationary state would be perceived as higher compared to that while swallowing, because of the shear thinning property. This could lead to noncompliance of the medical advice or malnutrition. It is necessary to determine optimal proportion of xanthan gum-based thickener or uncover alternatives, which have shear thinning properties lower than those of xanthan gum, for the acceptance of dysphagia patients. There was no pudding-like viscosity as classified by NDD, when prepared following instructions. Future studies should include higher concentrations of thickener to find out the concentration of the thickener resulting in pudding-like viscosity as recommended by NDD. PRACTICAL APPLICATIONS: When a manufacturer modifies or develops a xanthan gum-based thickener, findings from this study can be utilized to understand sensory and rheological characteristics of thickened liquid. For practitioners who have to make dysphagia diets, the reference standards of viscosity used in sensory descriptive analysis could be helpful for deciding the viscosity level of thickened liquids based only on visual evaluation. This study suggests manufacturers should provide clear direction for viscosity range and thickener concentration. Medical doctors should pay close attention to the risk of aspiration when prescribing pudding-like viscosity. Dietitians should understand the variability in achieving different levels of viscosity and should educate preparers who are responsible for making dysphagia meals.

Carbopol-incorporated thermoreversible gel for intranasal drug delivery.

The present study describes the preparation and evaluation of a poloxamer 407 (P407)-based thermoreversible gel using Carbopol 934P (C934P) as a mucoadhesive polymer and hydroxypropyl-ß-cyclodextrin (HP-ß-CD) for enhancing the aqueous solubility and intranasal absorption of fexofenadine hydrochloride (FXD HCl). The prepared gels were characterized by gelation temperature, viscoelasticity, and drug release profile. Thermoreversibility of P407/C934P gel was demonstrated by rheological studies. The incorporation of carbopol into P407 gel also reduced the amounts of drug released from the gel formulations (p < 0.05). In vivo pharmacokinetic results of the prepared gel formulations in rabbits (at 0.5 mg/kg dose) showed that the relative bioavailability of drug from P407/C934P gel was 11.3 and 2.7-fold higher than those of drug solution and P407 gel group, respectively. These findings suggested that developed thermoreversible gels could be used as promising dosage forms to improve intranasal drug absorption.

Dose-Volume Analysis of Lung and Heart according to Respiration in Breast Cancer Patients Treated with Breast Conserving Surgery.

PURPOSE: Adjuvant radiotherapy of breast cancer using a photon tangential field incurs a risk of late heart and lung toxicity. The use of free breathing (FB), expiration breath hold (EBH), and deep inspiration breath hold (DIBH) during tangential breast radiotherapy as a means of reducing irradiated lung and heart volume was evaluated. METHODS: In 10 women with left-sided breast cancer (mean age, 44 years) post-operative computed tomography (CT) scanning was done under different respiratory conditions using FB, EBH, and DIBH in 3 CT scans. For each scan, an optimized radiotherapy plan was designed with 6 MV photon tangential fields encompassing the clinical target volume after breast-conserving surgery. RESULTS: The results of dose-volume histograms were compared using three breathing pattern techniques for the irradiated volume and dose to the heart. A significant reduction dose to the irradiated heart volume for the DIBH breathing technique was compared to FB and EBH breathing techniques (p<0.05). CONCLUSION: This study demonstrated that the irradiated heart volume can be significantly reduced in patients with left-sided breast cancer using the DIBH breathing technique for tangential radiotherapy.

Lithium-induced supramolecular hydrogel.

We describe a novel anisotropic supramolecular gel made of cyclodextrin-dye, in which physical gelation is completed by lithium salt. Rheological experiment reveals the elastic behaviors of the hydrogel, and high ionic conductivity represents a good mobility of ions inside the gel matrix.

Poloxamer/cyclodextrin/chitosan-based thermoreversible gel for intranasal delivery of fexofenadine hydrochloride.

To enhance permeation and solubility of an intranasal delivery system of fexofenadine hydrochloride (FXD HCl), a new formulation using poloxamer 407 (P407)/hydroxypropyl-ß-cyclodextrin (HP-ß-CD)-based thermoreversible gels with chitosan, was developed. Prepared gels were characterized by gelation temperature, viscosity, viscoelasticity, and drug release profile. The in vitro permeation study was performed in primary human nasal epithelial cell monolayers cultured by air-liquid interface method. The addition of chitosan caused the slight elevation of gelation temperature and viscosity-enhancing effect. Viscosity enhancement by the incorporation of chitosan caused the retardation of drug release from P407 gels in in vitro release test. The in vitro permeation profile showed that the increase in chitosan content (0.1% and 0.3%, w/v) significantly enhanced the permeation of FXD HCl. After intranasal administration of P407/HP-ß-CD-based thermoreversible gels containing 0.1% and 0.3% of chitosan in rabbits at 0.5 mg/kg dose, plasma concentrations of FXD HCl were significantly higher than those of nasal solutions (p < 0.05). In particular, the bioavailability of the optimized thermoreversible gel containing 0.3% chitosan was about 18-fold higher than that of the solution type. These results suggested the feasibility that thermosensitive gels could be used as an effective dosage form to enhance the nasal absorption of FXD HCl.

Rheological evaluation of petroleum jelly as a base material in ointment and cream formulations: steady shear flow behavior.

The objective of the present study is to systematically characterize a nonlinear rheological behavior of petroleum jelly (petrolatum) in steady shear flow fields correspondent to the spreading condition onto the human body. With this aim, using a strain-controlled rheometer, the steady shear flow properties of commercially available petroleum jelly have been measured at 37 degrees C (body temperature) over a wide range of shear rates. In this article, the shear rate dependence of steady shear flow behavior was reported from the experimentally obtained data. In particular, the existence of a yield stress and a non-Newtonian flow behavior were discussed in depth with a special emphasis on their importance in actual application onto the human body. In addition, several inelastic-viscoplastic flow models including a yield stress parameter were employed to make a quantitative description of the steady shear flow behavior, and then the applicability of these models was examined in detail. Main findings obtained from this study can be summarized as follows: (1) Petroleum jelly exhibits a finite magnitude of yield stress. The appearance of a yield stress is attributed to its three-dimensional network structure that can show a resistance to flow and plays an important role in determining a storage stability and sensory feature of the product. (2) Petroleum jelly demonstrates a pronounced non-Newtonian shear-thinning flow behavior which is well described by a power-law equation and may be interpreted by the disruption of a crystalline network under the influence of mechanical shear deformation. This rheological feature enhances sensory qualities of pharmaceutical and cosmetic products in which petroleum jelly is used as a base material during their actual usage. (3) The Casson, Mizrahi-Berk, Heinz-Casson and Herschel-Bulkley models are all applicable and have almost an equivalent ability to quantitatively describe the steady shear flow behavior of petroleum jelly whereas the Bingham model does not give a good validity. Among these flow models, the Herschel-Bulkley model provides the best applicability.

Toward 300 liver transplants a year.

The technical success of cadaveric whole-size liver transplantation and better immunosuppressive drugs has extended the application of this life-saving procedure to include patients with irreversible acute and chronic liver diseases. However, because of the scarcity of cadaveric liver grafts, living-donor liver transplantation (LDLT) has emerged as an alternative to cadaveric-donor liver transplantation (CDLT), especially in Asia. In Korea, 8% of the population are hepatitis B virus (HBV) carriers, and the resultant HBV cirrhosis, with or without hepatocellular carcinoma (HCC), is common in the 40- to 60-year-old generation. Accordingly, many patients require orthotopic liver transplantation (OLT). In 1992, we started performing CDLTs in the Asan Medical Center. In 1994, the first successful pediatric LDLT was performed in Korea, on a 9-monthold infant with biliary atresia. In 1997, the first successful adult LDLT was performed in our department, using a left lobe, on a 37-year-old patient with HBV cirrhosis associated with HCC. Even after the first successful right-lobe LDLT, we faced the obstacle of anterior segment congestion of a right-lobe graft, and initiated reconstruction of the middle hepatic venous tributaries of a right-lobe graft in 1998. In 1999, we performed more than 100 OLTs a year. Insufficient graft size has hindered the expansion of adult LDLT, when the remaining left-lobe of potential donors is too small to assure donor safety. Dual two-left-lobe graft LDLT (transplanting from two donors into one recipient) was developed in 2000 to solve graft-size insufficiency and minimize donor risk. More than 200 OLTs a year have been performed since 2004, while broadening the indications for adult LDLT to near complete obstruction of the portal vein, with the application of intraoperative portography (IOP) and portal vein stenting. In 2007, 320 LTs were performed, including 276 adult LDLTs, 10 pediatric LDLTs, and 34 CDLTs (including 7 adult and 1 pediatric split-liver transplant). There has been no donor mortality in LDLT. With technical refinement and advanced perioperative care, the in-hospital mortality of recipients has dropped to 4%: attributed to the dedication of our liver transplantation team members.

Clinical analysis of right anterior segmentectomy for hepatic malignancy.

BACKGROUND/AIMS: Combined resection of segments 5 and 8, or right anterior segmentectomy, is one of the most difficult hepatic resections because of the danger of bleeding from the two major hepatic veins, the middle and right hepatic veins, during hepatectomy. We describe here the operative procedure and clinical analysis of right anterior segmentectomy in 35 patients with hepatic malignancy. METHODOLOGY: Between March 1993 and December 2004, 35 patients underwent right anterior segmentectomy for hepatic malignancy. The technique used was based on the extraglissonian approach and parenchymal Kelly crushing, during which the two major hepatic veins were almost fully exposed. RESULTS: Thirty-three patients had hepatocellular carcinoma, one had peripheral cholangiocellular carcinoma, and one had primary hepatic sarcoma. The mean operation time was 331 +/- 73 minutes and the mean transfusion of packed RBC was 1.09 +/- 1.57 pints. There was one in-hospital death as a result of sepsis and hepatic failure. The cumulative 1-, 2- and 5-year survival rates were 94%, 72% and 62%, respectively. CONCLUSIONS: For surgeons who accurately know the anatomy of the liver, this procedure is safe and suitable in selected patients with hepatic malignancies and may increase the survival rate.

Approach to anatomic variations of the graft portal vein in right lobe living-donor liver transplantation.

Right lobe living-donor liver transplantation (LDLT) is often not attempted in donors with anomalous portal venous branching (APVB). The authors describe their experience with portal vein (PV) reconstruction in 17 cases of APVB in right lobe LDLT. From July 1997 to December 2001, 214 right liver LDLT were performed at the Asan Medical Center. Seventeen of the donors had APVB and successfully underwent right lobectomy. The APVB were type II (trifurcation) in nine cases, type III (independent posterior segmental branching from main PV trunk) in seven, and unclassified in one. All 17 donors and recipients are alive, with good liver function. In type II APVB, the donor PV branches were obtained with separate openings that were joined as a common orifice at the back table in two, with a discoid-patch single opening in four, and with one common opening in three. In type III APVB, the donor PV were divided with two openings in four and with a discoid-patch single opening in three. The discoid-patch defect in the remnant PV was repaired with a vein patchplasty in two donors and resected with end-to-end anastomosis in five. However, one donor developed portal vein thrombosis (PVT) that was managed successfully by re-exploration and insertion of a metallic vascular stent. Of the four type III APVB obtained with two separate PV openings, the first two liver grafts were each reconstructed as double PV anastomoses. One of them required re-exploration because of PVT. In the two succeeding cases, a Y-graft interposition technique using a cryopreserved cadaveric iliac vein or the recipient's own portal confluence was successfully applied. To minimize the risk of PVT in donors with APVB, discoid-patch excision followed by repair with vein patchplasty or segmental resection should be avoided. Individual division of the PV branches creating two separate openings instead is recommended. To decrease the recipient's risk of PVT, interposition Y-graft venous reconstruction at the back table is superior to double PV anastomoses.

[A Mathematical Approach To The Mode Of Transmission Of Clonorchiasis In The Inhabitants Of Nak-Dong And Han River Basin]

To understand the mode of transmission in clonorchiasis, a survey was made in Kim-hae Goon, South Kyong-sang Do (=Province). The mathematical analysis of the age prevalence was done on the egg positive rates. And another analysis for the comparison was also made to the cited data from two areas, North Kyong-sang Do and Ko-yang Goon, Kyong-gi Do. Some catalytic models of H. Muench (1959) were applied to the observed age prevalence. Because the both parameters, such as force of infection(a) and loss of positivity(b) were considered to be constant for a long period in the surveyed area, the two stage catalytic model by Muench was chosen to the analysis. In the surveyed area, Kim-hae Goon where the egg positive rates were 56.2% and 61.2% (by Kim, 1974), the constant values of 'a' were found to be 0.051 and 0.089 respectively. In other words, the force of infection was 51, 89 per 1,000 susceptibles. The values of 'b' were found to be 0.006 and 0.005. This means that the rates of disappearance from egg positive cases to negative were 6 and 5 per annum per l,000 positive cases in above area. Therefore, the two catalytic curves were expressed by the following equations, y = 1.133 {e(-0.006t) - e(-0.051t)} and y = 1.047 {e(-0.005t) - e(-0.089t)} respectively. In the cases of North Kyong-sang Do and Ko-yang Goon, Kyong-gi Do where the egg positive rates of clonorchis shown as 27.7% and 15.2% by Shin (1964) and Kim (l974), the curves were expressed by y = 1.769 {e(-0.010t) - e(-0.034t)} and y = 2.857 {e(-0.020t) - e(-0.027t)} respectively. From the above mathematical analyses by age prevalence in clonorchiasis, it was considered that the mode of transmission of clonorchiasis in the surveyed area, Kim-hae Goon presented more rapid pattern than those of North Kyong-sang Do and Ko-yang Goon, Kyong-gi Do.