Selection of Catechin Biosynthesis-Related Genes and Functional Analysis from Chromosome-Level Genome Assembly in C. sinensis L. Variety 'Sangmok'.

Camellia is an important plant genus that includes well-known species such as C. sinensis, C. oleifera, and C. japonica. The C. sinensis cultivar 'Sangmok', one of Korea's standard types of tea landraces, is a small evergreen tree or shrub. Genome annotation has shown that Korean tea plants have special and unique benefits and superior components, such as catechin. The genome of Camellia sinensis cultivar 'Sangmok' was assembled on the chromosome level, with a length of 2678.62 Mbp and GC content of 38.16%. Further, 15 chromosome-scale scaffolds comprising 82.43% of the assembly (BUSCO completeness, 94.3%) were identified. Analysis of 68,151 protein-coding genes showed an average of 5.003 exons per gene. Among 82,481 coding sequences, the majority (99.06%) were annotated by Uniprot/Swiss-Prot. Further analysis revealed that 'Sangmok' is closely related to C. sinensis, with a divergence time of 60 million years ago. A total of 3336 exclusive gene families in 'Sangmok' were revealed by gene ontology analysis to play roles in auxin transport and cellular response mechanisms. By comparing these exclusive genes with 551 similar catechin genes, 17 'Sangmok'-specific catechin genes were identified by qRT-PCR, including those involved in phytoalexin biosynthesis and related to cytochrome P450. The 'Sangmok' genome exhibited distinctive genes compared to those of related species. This comprehensive genomic investigation enhances our understanding of the genetic architecture of 'Sangmok' and its specialized functions. The findings contribute valuable insights into the evolutionary and functional aspects of this plant species.

PD-1 inhibitor plus oncolytic vaccinia virus is a safe and effective treatment option for metastatic renal cell carcinoma.

BACKGROUND: Although a combination of immune checkpoint inhibitors (ICIs) is recommended as the first line treatment option for metastatic renal cell carcinoma (mRCC), several immune-related adverse events (irAEs) occur, especially hepatitis. We explored the therapeutic benefits and safety profile of combining oncolytic vaccinia virus, JX-594, with a programmed cell death protein-1 (PD-1) inhibitor. METHODS: We used early-stage and advanced-stage orthotopic murine mRCC models developed by our group. PD-1 inhibitor monotherapy or a PD-1 inhibitor combined with either JX-594 or a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor were systemically injected through the peritoneum. An immunofluorescence analysis was performed to analyze the tumor immune microenvironment (TIME). irAEs were assessed in terms of hepatitis. RESULTS: In the early-stage mRCC model mice, the combination of JX-594 and a PD-1 inhibitor significantly decreased the primary tumor size and number of lung nodules, compared with the ICI combination, but the JX-594 and PD-1 inhibitor combination and ICI combination did not differ significantly in the advanced-stage mRCC model mice. The JX-594 and PD-1 inhibitor combination induced tumor-suppressing TIME changes in both the early- and advanced-stage mRCC models. Furthermore, mice treated with the ICI combination had significantly greater hepatic injuries than those treated with the JX-594 and PD-1 inhibitor combination which was evaluated in early-stage mRCC model. CONCLUSIONS: The JX-594 and PD-1 inhibitor combination effectively reduced primary tumors and the metastatic burden, similar to ICI combination therapy, through dynamic remodeling of the TIME. Furthermore, hepatitis was significantly decreased in the JX-594 and PD-1 inhibitor combination group, suggesting the potential benefit of that combination for reducing ICI-induced toxicity.

CCIDB: a manually curated cell-cell interaction database with cell context information.

Cell-cell interaction (CCI) is a crucial event in the development and function of multicellular organisms. The development of CCI databases is beneficial for researchers who want to analyze single-cell sequencing data or study CCI through molecular experiments. CCIs are known to act differently according to cellular and biological contexts such as cell types, gene mutations or disease status; however, previous CCI databases do not completely provide this contextual information pertaining to CCIs. We constructed a cell-cell interaction database (CCIDB) containing the biological and clinical contexts involved in each interaction. To build a database of cellular and tissue contexts, we collected 38 types of context features, which were categorized into seven categories, including 'interaction', 'cell type', 'cofactor', 'effector', 'phenotype', 'pathology' and 'reference'. CCIs were manually retrieved from 272 studies published recently (less than 6 years ago). In the current version of CCIDB, 520 CCIs and their 38 context features have been manually collected and curated by biodata engineers. We suggest that CCIDB is a manually curated CCI resource that is highly useful, especially for analyzing context-dependent alterations in CCIs. Database URL https://ccidb.sysmed.kr/.

Efficacy of Asymmetric siRNA Targeting Androgen Receptors for the Treatment of Androgenetic Alopecia.

Asymmetric small interfering RNAs (asiRNAs) that mediate RNA interference have been investigated for therapeutic use in various tissues, including skin tissue. Androgenetic alopecia (AGA) is caused by a combination of genetic factors, resulting in sensitivity to dihydrotestosterone (DHT), which binds to the androgen receptor (AR) to mediate a series of biomolecular changes leading to hair loss. This study aimed to evaluate the therapeutic potential of a cell-penetrating, AR-targeting asiRNA (cp-asiAR) for AGA treatment, which was designed to silence the AR gene. AGA mouse models were developed by stimulation with DHT, and ex vivo human scalp tissues were also used for analysis. Cp-asiAR-mediated changes in mRNA expression and protein levels of AR were assessed along with the examination of phenotypic improvements in mouse model of AGA. We also assessed downstream signaling associated with AR in primary human dermal papilla (DP) cells. Several cp-asiARs were screened for selecting the optimal sequence of AR using cell lines in vitro. A cholesterol-conjugated, chemically modified cp-asiAR candidate was optimized under passive uptake conditions in vitro. Intradermal cp-asiAR injection efficiently reduced mRNA and protein levels corresponding to AR in mouse models. Moreover, cp-asiAR injection promoted hair growth in mouse models with DHT-induced AGA. In ex vivo human hair follicle culture, the proportion of telogen hair decreased, and the mean hair bulb diameter increased in the cp-asiAR-treated group. In isolated primary human DP cells, AR expression was effectively downregulated by cp-asiAR. Furthermore, cp-asiAR attenuated DHT-mediated increases in interleukin-6, transforming growth factor-ß1, and dickkopf-1 levels. No significant toxicity was observed in DP cells after cp-asiAR treatment. Cp-asiAR treatment showed effective downregulation of AR expression and prevention of DHT-mediated alterations in the hair cycle and hair diameter, indicating its potential as a novel therapeutic option for AGA.

CD47 mediates the progression of colorectal cancer by inducing tumor cell apoptosis and angiogenesis.

CD47 is an immunoregulatory protein that is found on the cell surface and plays significant roles in cellular functions such as proliferation, apoptosis, migration, and immune homeostasis. CD47 is overexpressed in various human cancers and is associated with tumor development, progression, and poor prognosis. In this study, we analyzed the expression of CD47 to determine whether it affected the oncogenic behavior of colorectal cancer (CRC) and investigated the prognostic value of CD47 expression in patients with CRC. We investigated 468 patients with CRC who underwent curative surgery and examined the expression of CD47 in tumor and lymph node tissues by performing RT-PCR and immunohistochemistry. Apoptosis, proliferation, angiogenesis, and lymphangiogenesis were determined via a TUNEL assay and immunohistochemical staining for Ki-67, CD34, and D2-40. CD47 expression was increased in human CRC tumors and metastatic lymph nodes compared with normal colorectal mucosa and non-metastatic lymph node tissues. CD47 expression was significantly associated with perineural invasion, lymphovascular invasion, cell differentiation, cancer stage, depth of invasion, lymph node metastasis, distant metastasis, and poor survival. The mean apoptotic index and microvessel density value of CD47-positive tumors were significantly higher than those of CD47-negative tumors. However, no significant difference was observed between CD47 expression and Ki-67 labeling index or lymphatic vessel density. These results indicate that CD47 mediated the progression of CRC by inducing tumor cell apoptosis and angiogenesis.

Smart Homes Supporting the Wellness of One or Two-Person Households.

The reduction in face-to-face contact and the increase in time spent at home during the ongoing coronavirus disease pandemic have resulted in increasing interest and demand for smart homes. Further, the rapid increase in the number of one-person and two-person households in Korea recently has led to these becoming representative household types. This study identifies the wellness characteristics of such households and proposes a direction for smart home development to help them lead healthy, happy lives. It focuses on mapping residents' perceptions and experiences to scenarios and on identifying the functions required in smart homes and the technologies needed to provide these functions. It uses data from a survey to investigate and analyze the wellness characteristics of one- and two-person households in five dimensions and develops five scenarios of representative household types. By analyzing the developed scenarios, this study proposes smart homes that support the wellness of such households in six categories: exercise/sports, hobby/entertainment, social communications, occupation/work, self-development/education, and energy conservation. These households are exposed to digital environments from an early age and are familiar with the internet and technologies. Therefore, they are likely to adopt innovative technologies in housing. Thus, the smart home development proposed in this study is a promising strategic approach to housing planning.

Engulfment and Cell Motility 1 (ELMO1) Regulates Tumor Cell Behavior and Predicts Prognosis in Colorectal Cancer.

BACKGROUND/AIM: Engulfment and cell motility 1 (ELMO1) plays a crucial role in the process of migration, chemotaxis, and metastasis of tumor cells. ELMO1 has been implicated in the pathogenesis of various cancers. However, the distinct function of ELMO1 in colorectal cancer (CRC) is unclear. We determined whether ELMO1 affects the oncogenic behavior of CRC cells and investigated its prognostic value in CRC patients. MATERIALS AND METHODS: We investigated the impact of ELMO1 on tumor cell behavior using small interference RNA (siRNA) in CRC cell lines, including SW480 and DLD1. The expression of ELMO1 was investigated by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) in cancer tissues and sera obtained from CRC patients. RESULTS: ELMO1 knockdown suppressed tumor cell proliferation in SW480 and DLD1 cells. ELMO1 knockdown-induced apoptosis through up-regulation of caspase-3, -7, and PARP activities and down-regulation of the anti-apoptotic Mcl-1 protein. ELMO1 knockdown-induced cell-cycle arrest by decreasing cyclin D1, cyclin-dependent kinase 2, 4 and 6, and the 25C cell division cycle (CDC25C). ELMO1 knockdown suppressed tumor cell invasion and migration. The expression of E-cadherin was increased, while that of Vimentin and Claudin 1 decreased following ELMO1 knockdown. The phosphorylation levels of PDK1, Akt, and GSK-3ß and were down-regulated after ELMO1 knockdown. The expression of ELMO1 was found up-regulated in cancer tissues and sera taken from CRC patients. ELMO1 expression was significantly associated with tumor stage, lymph node metastasis, distant metastases, and poor survival. CONCLUSION: ELMO1 mediates tumor progression by increasing tumor cell motility and inhibiting apoptosis in human CRC.

Resource for FRET-Based Biosensor Optimization.

After the development of Cameleon, the first fluorescence resonance energy transfer (FRET)-based calcium indicator, a variety of FRET-based genetically encoded biosensors (GEBs) have visualized numerous target players to monitor their cell physiological dynamics spatiotemporally. Many attempts have been made to optimize GEBs, which require labor-intensive effort, novel approaches, and precedents to develop more sensitive and versatile biosensors. However, researchers face considerable trial and error in upgrading biosensors because examples and methods of improving FRET-based GEBs are not well documented. In this review, we organize various optimization strategies after assembling the existing cases in which the non-fluorescent components of biosensors are upgraded. In addition, promising areas to which optimized biosensors can be applied are briefly discussed. Therefore, this review could serve as a resource for researchers attempting FRET-based GEB optimization.

Clinical relevance of serum-derived exosomal messenger RNA sequencing in patients with non-Hodgkin lymphoma.

Background: The clinical utility of mRNA cargo in exosomes is unclear, although exosomes have potential as non-invasive biomarkers. This study aimed to investigate the feasibility of exosomal mRNA sequencing for monitoring disease status and predicting outcomes in non-Hodgkin lymphoma (NHL) patients. Methods: Exosomes were isolated from archived serum samples of 33 patients with NHL who were registered into our prospective cohort: diffuse large B-cell lymphoma (DLBCL, n = 17), intravascular B-cell lymphoma (IVL, n = 1), primary mediastinal large B-cell lymphoma (PMBL, n = 4), follicular lymphoma (FL, n = 3), mantle cell lymphoma (MCL, n = 3), and extranodal NK/T-cell lymphoma (ENKTL, n = 5). Exosomal mRNA sequencing was performed, and its concordance with clinical course was analyzed and compared with those of circulating tumor DNA (ctDNA) mutations. Results: Exosomal mRNA sequencing was performed successfully in 26 cases (79%, 26/33), whereas the remaining seven cases were not completed due to their small amount of RNA. The exosomal mRNA sequencing of DLBCL showed gene expression profiles consistent with activated B-cell-like and germinal center type. The longitudinal assessment of exosomal mRNA sequencing results in accordance with the clinical course showed that the post-treatment changes of exosomal mRNA expression were more consistent with treatment outcome than were those of ctDNA mutations. In particular, the exosomal mRNA expression of genes such as BCL2 and BCL6 was increased at the time of disease progression in DLBCL and FL patients. Conclusions: This study demonstrated the feasibility of exosomal mRNA expression profiles as a biomarker for NHL patients. Our results might provide the rationale for studies to explore the potential of exosomal mRNA as a biomarker in NHL patients.

Gene Expression Analysis of Aggressive Adult Xp11.2 Translocation Renal Cell Carcinoma at Clinical Stage T1N0M0 to Identify Potential Prognostic and Therapeutic Biomarkers.

Xp11.2 translocation renal cell carcinoma (tRCC), involving transcription factor E3 (TFE3) gene fusions, is a rare and aggressive RCC variant when present in adults and has been recently recognized as a unique entity in RCC. Biomarkers and treatment guidelines do not exist for patients with aggressive Xp11.2 tRCC. The aim was to identify and evaluate therapeutic biomarkers for aggressive Xp11.2 tRCC. RNA sequencing was performed using formalin-fixed, paraffin-embedded tissues from 11 adult patients with clinical T1N0M0 Xp11.2 tRCC, including three patients with aggressive characteristics (recurrence or cancer-specific death after nephrectomy). Thirty genes were differentially expressed between the aggressive and non-aggressive groups, even after adjustment, and were associated with KEGG pathways related to the aggressiveness of Xp11.2 tRCC. PIK3R2, involved in various KEGG pathways, including the PI3K/AKT/mTOR pathway, was overexpressed in the Xp11.2 tRCC cell lines UOK120 and UOK146. The PI3K pathway inhibitor LY294002 showed a significant therapeutic benefit. This study provides the first candidate biomarker, PIK3R2, for aggressive clinical T1N0M0 Xp11.2 tRCC. Furthermore, this study is the first to recommend a targeted drug, LY294002, for aggressive Xp11.2 tRCC based on the molecular pathophysiology.

Systemic Injection of Oncolytic Vaccinia Virus Suppresses Primary Tumor Growth and Lung Metastasis in Metastatic Renal Cell Carcinoma by Remodeling Tumor Microenvironment.

Immune checkpoint inhibitors and tyrosine kinase inhibitors are the first-line treatment for metastatic renal cell carcinoma (mRCC), but their benefits are limited to specific patient subsets. Here, we aimed to evaluate the therapeutic efficacy of JX-594 (pexastimogene devacirepvec, Pexa-vec) monotherapy by systemic injection in comparison with sunitinib monotherapy in metastatic orthotopic RCC murine models. Two highly metastatic orthotopic RCC models were developed to compare the treatment efficacy in the International Metastatic RCC Database Consortium favorable-risk and intermediate- or poor-risk groups. JX-594 was systemically injected through the peritoneum, whereas sunitinib was orally administered. Post-treatment, tumor microenvironment (TME) remodeling was determined using immunofluorescence analysis. Systemic JX-594 monotherapy injection demonstrated therapeutic benefit in both early- and advanced-stage mRCC models. Sunitinib monotherapy significantly reduced the primary tumor burden and number of lung metastases in the early-stage, but not in the advanced-stage mRCC model. Systemic JX-594 delivery remodeled the primary TME and lung metastatic sites by increasing tumor-infiltrating CD4/8+ T cells and dendritic cells. Systemic JX-594 monotherapy demonstrated significantly better therapeutic outcomes compared with sunitinib monotherapy in both early- and advanced-stage mRCCs by converting cold tumors into hot tumors. Sunitinib monotherapy effectively suppressed primary tumor growth and lung metastasis in early-stage mRCC.

Discovery of GCC5694A: A potent and selective sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes.

Sodium-dependent glucose co-transporter 2 (SGLT2) has emerged as a promising drug target for the treatment of type 2 diabetes, and recently, several SGLT2 inhibitors have been approved for clinical use. A series of molecules with a C-aryl glucoside scaffold was designed and synthesized for biological evaluation. Among the molecules tested, a dihydrobenzofuran-containing analog, 14g (GCC5694A), exhibited excellentin vitro activity against SGLT2 (IC50 = 0.460 nM), good selectivity for SGLT1, and good metabolic stability. Data from further evaluation of the compound in animal models showed that this molecule is a promising candidate for development as an anti-diabetic agent.

Case report of gastric syphilis in Korea: Clinical features, pathology, management, and prognosis.

RATIONALE: Syphilis is a contagious infectious disease caused by Treponema pallidum. Gastric involvement of syphilis is rare and has nonspecific gastrointestinal symptoms and endoscopic findings. To date, 16 cases have been reported in Korea. Here, we report 2 additional cases of gastric syphilis in men in their 30 second. PATIENTS CONCERNS: Two 35- and 33-year-old men presented with epigastric pain. DIAGNOSIS: The serum venereal disease research laboratory and fluorescent treponemal antibody absorption tests were positive. Esophagogastroduodenoscopy showed multiple variable-sized flat elevated lesions and geographic ulcers with whitish exudates in the antrum and body. Warthin-Starry silver staining of endoscopic biopsy specimens confirmed gastric syphilis. INTERVENTIONS: The patients were treated with an intramuscular injection of 2.4 million units of benzathine penicillin once a week for 3 weeks. OUTCOMES: Clinical symptoms and gastric lesions were completely resolved. LESSONS: First, gastric syphilis, despite its rarity and nonspecific symptoms and endoscopic findings, should be considered in a rare extracutaneous presentation of syphilis. Second, a high index of clinical suspicion and an accurate diagnosis based on a combination of clinical, radiological, endoscopic, serologic, and histopathologic findings provide an opportunity to identify and treat patients with gastric syphilis.

Effect of the Nanotube Radius and the Volume Fraction on the Mechanical Properties of Carbon Nanotube-Reinforced Aluminum Metal Matrix Composites.

By using the advantages of carbon nanotubes (CNTs), such as their excellent mechanical properties and low density, CNT-reinforced metal matrix composites (MMCs) are expected to overcome the limitations of conventional metal materials, i.e., their high density and low ductility. To understand the behavior of composite materials, it is necessary to observe the behavior at the molecular level and to understand the effect of various factors, such as the radius and content of CNTs. Therefore, in this study, the effect of the CNT radius and content on the mechanical properties of CNT-Al composites was observed using a series of molecular dynamics simulations, particularly focusing on MMCs with a high CNT content and large CNT diameter. The mechanical properties, such as the strength and stiffness, were increased with an increasing CNT radius. As the CNT content increased, the strength and stiffness increased; however, the fracture strain was not affected. The behavior of double-walled carbon nanotubes (DWNTs) and single-walled carbon nanotubes (SWNTs) was compared through the decomposition of the stress-strain curve and observations of the atomic stress field. The fracture strain increased significantly for SWNT-Al as the tensile force was applied in the axial direction of the armchair CNTs. In the case of DWNTs, an early failure was initiated at the inner CNTs. In addition, the change in the elastic modulus according to the CNT content was predicted using the modified rule of mixture. This study is expected to be useful for the design and development of high-performance MMCs reinforced by CNTs.

Predictors of clinical outcomes of self-expandable metal stent treatment for malignant colorectal obstruction: A Honam Association for the Study of Intestinal Disease (HASID) multicenter study.

ABSTRACT: There has been increased use of self-expandable metal stents (SEMS) in treating malignant colorectal obstruction (MCO). The aim of this study was to investigate factors that are associated with the outcomes of SEMS placement for MCO.Clinical data from patients who underwent SEMS placement for MCO at 6 hospitals in Honam province of South Korea between 2009 and 2018 were reviewed retrospectively. Eight hundred two patients were identified and their data were analyzed. Technical success, clinical success, complications, and predictors of outcome were included as main outcome measures.Technical and clinical success rates were 98.8% (792/802) and 90.1% (723/802), respectively. Complications including stent migration, stent occlusion due to tumor ingrowth and outgrowth, perforation, bacteremia/fever, and bleeding occurred in 123 (15.3%) patients. In multivariate regression analyses, procedure time was significantly associated with the technical success of SEMS placement (P = .001). Longer length of obstruction, the use of covered stent, and longer procedure time were significant independent predictive factors for the clinical success of SEMS placement (odds ratio [OR] 0.974 (95% confidence interval [CI] 0.950-0.990); P = .043, OR 0.255 (95% CI 0.138-0.471); P < .001, and OR 0.957 (95% CI 0.931-0.984); P = .002, respectively). Stage IV colorectal cancer and the use of covered stent were significant independent predictive factors for the development of complications after SEMS placement (OR 2.428 (95% CI 1.407-4.188); P = .001 and OR 3.329 (95% CI 2.060-5.378); P < .001, respectively).Longer length of obstruction, the use of covered stent, and longer procedure time were associated with lower clinical success rates. Having stage IV colorectal cancer and the use of covered stents were associated with an increased risk of complications.

The DEAD/DEAH Box Helicase, DDX11, Is Essential for the Survival of Advanced Clear Cell Renal Cell Carcinoma and Is a Determinant of PARP Inhibitor Sensitivity.

Genes associated with the DEAD-box helicase DDX11 are significant biomarkers of aggressive renal cell carcinoma (RCC), but their molecular function is poorly understood. We analyzed the molecular pathways through which DDX11 is involved in RCC cell survival and poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity. Immunohistochemistry and immunoblotting determined DDX11 expression in normal kidney tissues, benign renal tumors, and RCC tissues and cell lines. Quantitative polymerase chain reaction validated the downregulation of DDX11 in response to transfection with DDX11-specific small interfering RNA. Proliferation analysis and apoptosis assays were performed to determine the impact of DDX11 knockdown on RCC cells, and the relevant effects of sunitinib, olaparib, and sunitinib plus olaparib were evaluated. DDX11 was upregulated in high-grade, advanced RCC compared to low-grade, localized RCC, and DDX11 was not expressed in normal kidney tissues or benign renal tumors. DDX11 knockdown resulted in the inhibition of RCC cell proliferation, segregation defects, and rapid apoptosis. DDX11-deficient RCC cells exhibited significantly increased sensitivity to olaparib compared to sunitinib alone or sunitinib plus olaparib combination treatments. Moreover, DDX11 could determine PARP inhibitor sensitivity in RCC. DDX11 could serve as a novel therapeutic biomarker for RCC patients who are refractory to conventional targeted therapies and immunotherapies.

Exosomal miR-1305 in the oncogenic activity of hypoxic multiple myeloma cells: a biomarker for predicting prognosis.

Background: Exosomes have emerged as important mediators of tumor progression, and a prognostic role for serum exosomal miRNAs has been suggested in multiple myeloma (MM). Given the association of hypoxia with tumor aggressiveness, including cancer stem cell-like phenotypes, we explored exosomal miRNAs from MM cells under hypoxic conditions and analyzed their diverse roles both in promoting oncogenic activity and in predicting prognosis. Methods: The human MM cell line, RPMI 8226, was cultured under hypoxic conditions and their exosome production and exosomal miRNA profiles were compared with those of normoxic parental cells. The survival outcome of myeloma patients was compared using serum levels of exosomal miRNAs, and the effects of exosomal miRNAs on the target genes of MM cells and adjacent immune cells were analyzed. Results: Increased expression of stem cell markers and exosome production were observed in hypoxic MM cells. Exosome miRNA analysis identified a higher expression of miR-1305 in exosomes isolated from hypoxic MM cells than in those of normoxic parental cells. The overall survival of patients with high exosomal miR-1305 was poorer than it was in patients with low exosomal miR-1305. In hypoxic MM cells, an increase of exosomal miR-1305 led to a decrease of cellular miR-1305 and increased expression of the miR-1305 target genes, MDM2, IGF1 and FGF2 resulted in the promotion of oncogenic activity of MM. Exosomal miR-1305 was also transferred from MM cells to macrophages, and miR-1305-transferred macrophages showed tumor-promoting, M2-macrophage phenotypes. Conclusions: Exosome-mediated secretion of miR-1305 in MM cells promoted oncogenic activity of hypoxic MM cells and high serum levels of exosomal miR-1305.

Development of a highly pulmonary metastatic orthotopic renal cell carcinoma murine model.

The incidence of renal cell carcinoma (RCC) is high, and its outcomes remain poor. Mortality is attributable largely to metastatic disease and a dearth of effective therapeutic interventions. The lungs are the most common metastatic site. To elucidate the biological mechanisms underlying pulmonary metastasis and identify superior therapeutic strategies, we developed a novel and clinically relevant murine RCC model exhibiting enhanced pulmonary metastasis. Mice underwent intrarenal implantation using luciferase-expressing Renca, a murine renal adenocarcinoma cell line. Primary renal tumor progression and development of metastatic lung lesions were monitored in live mice using bioluminescent imaging, followed by post-mortem organ assessment. Cells were isolated from pulmonary metastases for reimplantation, followed by repeat monitoring and assessment. This process was repeated once more for a total of two in vivo passages to select for pulmonary metastatic Renca cell subpopulations. However, a single round of in vivo selection was sufficient to produce a near-maximally metastatic subpopulation. Relative to Renca cell-implanted mice, subpopulation-implanted mice exhibited shorter implantation-metastasis intervals (5 days), shorter implantation-moribundity intervals (sacrificed at 18.6±2.9 versus 22.3±1.1 days), a higher number of metastatic lung lesions at 23 days (183.9±39.0 versus 172.6±38.2) and poorer survival. Implantation of cells derived from the second round of in vivo selection produced no further significant differences in the above metrics. This model consistently and efficiently recapitulates RCC pulmonary metastasis while allowing in vivo monitoring of tumor progression, thereby facilitating elucidation of the molecular mechanisms underlying pulmonary metastasis and evaluation of therapeutic modalities.

Association between ALDH2 polymorphism and esophageal cancer risk in South Koreans: a case-control study.

BACKGROUND: Alcohol consumption is a major risk factor for esophageal cancer; however, a high incidence of esophageal cancer is observed particularly among Eastern Asians, although they consume relatively less alcohol, presumably due to the high frequency of aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphisms. Nevertheless, the association between ALDH2 polymorphisms and esophageal cancer remains under debate. In the present study, we evaluated the association between ALDH2 rs671 polymorphisms and the risk of esophageal cancer in the South Korean population. METHODS: This study included 783 hospital based-cases and 8732 population-based controls. Information on smoking history and alcohol consumption was obtained from the medical records or interview questionnaires. Age-adjusted logistic regression analysis was performed to assess the association between ALDH2 rs671 polymorphisms and esophageal cancer. RESULTS: Odds ratios (ORs) for esophageal cancer in men with GA and AA genotypes were 2.75 (95% confidence interval [CI]: 2.34-3.23) and 0.08 (95% CI: 0.00-0.35), respectively; whereas, in women, these ratios were 2.99 (95% CI: 1.43-6.34) and 6.18 (95% CI: 1.40-19.62), respectively, taking subjects with the ALDH2 GG genotype as a reference. In men, the association between ALDH2 polymorphisms and esophageal cancer was modified by alcohol consumption. CONCLUSION: In Eastern Asians, ALDH2 rs671 polymorphisms are associated with esophageal cancer, which may be linked to acetaldehyde accumulation.

Target-mediated drug disposition modeling of an anti-TFPI antibody (MG1113) in cynomolgus monkeys to predict human pharmacokinetics and pharmacodynamics.

BACKGROUND: MG1113 is a human monoclonal antibody of tissue factor pathway inhibitor (TFPI) under development for prophylaxis for hemophilia patients with or without inhibitors against factor VIII products, which have been used for the treatment of hemophilia. Because TFPI is a negative regulator in the extrinsic coagulation pathway, neutralization of TFPI function by MG1113 can potentially increase coagulation activity by bypassing the intrinsic coagulation pathway, which factor VIII activates. OBJECTIVES: This study aims to determine the correlation between pharmacokinetics (PK) and pharmacodynamics (PD) after administering MG1113 to monkeys and to predict the PK and PD of MG1113 in humans by the Target-Mediated Drug Disposition (TMDD) model using the results from monkeys. METHODS: The PK profile of MG1113 and the PD effect on the free TFPI level were evaluated after intravenous (IV) and subcutaneous (SC) administrations of MG1113 (2.5, 5, and 10 mg/kg) to male cynomolgus monkeys. After setting up the PK/PD model on monkeys, PK parameters on humans were calculated using allometric scaling, and then clinically effective doses were predicted applying the TMDD model. RESULTS AND CONCLUSIONS: MG1113 showed nonlinear PK after both IV and SC administrations at the dosing range from 2.5 to10 mg/kg. The concentrations of MG1113 versus TFPI could be characterized a dose-response relationship using a TMDD model. The TMDD modeling and simulation built in this study were used to simulate various dosage regimens of MG1113 to apply to the first-in-human study design, and moreover expected to be referred to establish the dose for further clinical trials.