Intranodal Lymphangiography and Embolization for the Treatment of Early Postoperative Lymphatic Leaks after Pelvic Surgery.

PURPOSE: To assess outcome and predictors of outcome after lymphatic embolization (LE) for early postoperative lymphatic leak after pelvic surgery. MATERIAL AND METHODS: Lymphangiography (LG) procedures performed between May 2015 and February 2020 for postoperative intraperitoneal lymphatic leaks after pelvic surgery were reviewed. Treatment indication was lymphatic drainage of >500 mL/d persisting for >1 week. LE was performed by injecting glue into the iliac lymph node. Fisher exact and Wilcoxon rank-sum tests were used for comparative analysis, and logistic regression was used to assess predictors of outcome. RESULTS: LG was performed in 71 patients. A leak was demonstrated in 69 patients who underwent LE. The mean drainage was 1,329 mL/d ± 773. Catheters were removed in 49 (69.0%) patients after 1 procedure and in 69 (97.2%) patients after a mean of 1.3 procedures. The mean drainage at the time of catheter removal was 157 mL/d ± 100. Failure occurred in 12 (16.9%) cases, including 2 (2.8%) cases of unsuccessful catheter removal and 10 (14.1%) cases of catheter reinsertion owing to recurrent ascites (n = 3) and lymphoceles (n = 7). Older age and drainage of >1,500 mL/d were associated with failure (P = .004). Drainage of >1,500 mL/d was associated with a post-LE catheter dwell time of longer than 1 week (P = .024). Minor adverse events were noted in 4 (5.6%) patients who presented with transient leg swelling. CONCLUSIONS: LE was effective for treating pelvic surgery-related lymphatic leaks. Reintervention may be required. Drainage of >1,500 mL/d was associated with clinical failure and a post-LE catheter dwell time of longer than 1 week.

Nicotinamide (niacin) supplement increases lipid metabolism and ROS-induced energy disruption in triple-negative breast cancer: potential for drug repositioning as an anti-tumor agent.

Metabolic dysregulation is an important hallmark of cancer. Nicotinamide (NAM), a water-soluble amide form of niacin (vitamin B3), is currently available as a supplement for maintaining general physiologic functions. NAM is a crucial regulator of mitochondrial metabolism and redox reactions. In this study, we aimed to identify the mechanistic link between NAM-induced metabolic regulation and the therapeutic efficacy of NAM in triple-negative breast cancer (TNBC). The combined analysis using multiomics systems biology showed that NAM decreased mitochondrial membrane potential and ATP production, but increased the activities of reverse electron transport (RET), fatty acid ß-oxidation and glycerophospholipid/sphingolipid metabolic pathways in TNBC, collectively leading to an increase in the levels of reactive oxygen species (ROS). The increased ROS levels triggered apoptosis and suppressed tumour growth and metastasis of TNBC in both human organoids and xenograft mouse models. Our results showed that NAM treatment leads to cancer cell death in TNBC via mitochondrial dysfunction and activation of ROS by bifurcating metabolic pathways (RET and lipid metabolism); this provides insights into the repositioning of NAM supplement as a next-generation anti-metabolic agent for TNBC treatment.

The complete chloroplast genome of Bupleurum euphorbioides, a traditional medicinal plant.

Bupleurum euphorbioides is a rare native plant attributed with analgesic, gallbladder-supportive, and other functions in China and the Republic of Korea. However, the complete chloroplast genome sequence of the native plant B. euphorbioides has not been determined. In this study, we sequenced the complete chloroplast genome sequence, and examined the molecular phylogeny and genetic information of B. euphorbioides. The total chloroplast genome of B. euphorbioides was 154,871 bp in length with a large single-copy region (85,089 bp), small single-copy region (17,714 bp), and pair of inverted repeats regions (26,034 bp). The chloroplast genome encoded a total of 176 genes, including 131 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. The phylogenetic tree indicated that B. euphorbioides was most closely related to B. latissimum.

The complete chloroplast genome of Bupleurum euphorbioides, a traditional medicinal plant.

Bupleurum euphorbioides is a rare native plant attributed with analgesic, gallbladder-supportive, and other functions in China and the Republic of Korea. However, the complete chloroplast genome sequence of the native plant B. euphorbioides has not been determined. In this study, we sequenced the complete chloroplast genome sequence, and examined the molecular phylogeny and genetic information of B. euphorbioides. The total chloroplast genome of B. euphorbioides was 154,871 bp in length with a large single-copy region (85,089 bp), small single-copy region (17,714 bp), and pair of inverted repeats regions (26,034 bp). The chloroplast genome encoded a total of 176 genes, including 131 protein-coding genes, 37 tRNA genes, and eight rRNA genes. The phylogenetic tree indicated that B. euphorbioides was the most closely related to B. latissimum.

The current state of patient access to new drugs in South Korea under the positive list system: evaluation of the changes since the new review pathways.

Objective: This study aims to provide an up-to-date analysis of the current state of patient access to new drugs in South Korea, focusing on the effect of new review pathways for reimbursement. Methods: We analyzed patients' access to new drugs, listing rate and lead time until listing from marketing authorization. New pathways were defined as 'price negotiation waiver,' 'risk-sharing agreements,' and 'pharmacoeconomic evaluation exemption.' Results: The listing rate for drugs increased after the introduction of the new pathways (93.7% vs. 77.9%, p < 0.001). Before the new pathways, the median lead time for listing was 21.0 months (95% CI: 16.9-25.0), while afterward it was shortened to 10.9 months (95% CI: 10.2-11.7) (p < 0.001). Conclusion: Although it has strengthened national health insurance coverage by positively impacting the rate and lead time, the lead time for the oncology and orphan drugs is substantially longer as compared to other drugs. Expanding the eligibility criteria to include non-life-threatening but rare or intractable diseases, and resolving the system's operational issues are still necessary.

Stability of 3-deoxyanthocyanin pigment structure relative to anthocyanins from grains under microwave assisted extraction.

Sorghum derived 3-deoxyanthocyanin (DXA) pigments are stable relative to their anthocyanin analogs, and are of growing interest in food applications. However, the 3DXA are poorly extractable from grain tissue. This work aimed to determine the relative stability and extractability of sorghum 3-DXA vs anthocyanins from maize and cowpea under microwave-assisted extraction (MAE). UV-Vis and UPLC-MS/MS spectrometry were used to characterize the properties. The 3-DXA remained structurally stable to MAE conditions up to 1200 W/100 °C/30 min. MAE increased sorghum 3-DXA yield 100% versus control (3100 vs 1520 mg/g). On the other hand, both maize and cowpea anthocyanins were unstable and rapidly degraded under MAE. Cell wall-derived ferulate esters were detected in sorghum and maize MAE extracts, indicating cell wall degradation occurred during MAE. Thus the enhanced extraction of 3-DXA under MAE was due to their structural stability, along with improved diffusion from cell matrix due to microwave-induced sorghum cell wall disruption.

Characterization of the complete chloroplast genome of Liriope platyphylla (Asparagaceae: Nolinoideae) isolated in Korea.

Liriope platyphylla is used as an important medicinal plant for fatigue, cough, and inflammation in South Korea. Here, we report the complete chloroplast genome of L. platyphylla. The total genome size of the chloroplast is 157,076 bp with a large single-copy region (LSC: 85,374 bp), a small single-copy region (SSC: 18,748 bp), and inverted repeat regions (IRa and IRb: 26,477 bp). The GC content of the L. platyphylla chloroplast was 37.6%. The cp genome encoded a set of 129 genes, including 83 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. The phylogenetic tree analysis indicated that L. platyphylla is closely related to L. spicata.

Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.

Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.

Noninvasive identification of viable cell populations in docetaxel-treated breast tumors using ferritin-based magnetic resonance imaging.

BACKGROUND: Cancer stem cells (CSCs) are highly tumorigenic and are responsible for tumor progression and chemoresistance. Noninvasive imaging methods for the visualization of CSC populations within tumors in vivo will have a considerable impact on the development of new CSC-targeting therapeutics. METHODOLOGY/PRINCIPAL FINDINGS: In this study, human breast cancer stem cells (BCSCs) transduced with dual reporter genes (human ferritin heavy chain [FTH] and enhanced green fluorescence protein [EGFP]) were transplanted into NOD/SCID mice to allow noninvasive tracking of BCSC-derived populations. No changes in the properties of the BCSCs were observed due to ferritin overexpression. Magnetic resonance imaging (MRI) revealed significantly different signal intensities (R(2)* values) between BCSCs and FTH-BCSCs in vitro and in vivo. In addition, distinct populations of pixels with high R(2)* values were detected in docetaxel-treated FTH-BCSC tumors compared with control tumors, even before the tumor sizes changed. Histological analysis revealed that areas showing high R(2)* values in docetaxel-treated FTH-BCSC tumors by MRI contained EGFP+/FTH+ viable cell populations with high percentages of CD44+/CD24- cells. CONCLUSIONS/SIGNIFICANCE: These findings suggest that ferritin-based MRI, which provides high spatial resolution and tissue contrast, can be used as a reliable method to identify viable cell populations derived from BCSCs after chemotherapy and may serve as a new tool to monitor the efficacy of CSC-targeting therapies in vivo.

Induction of apoptotic cell death by Pharbitis nil extract in HER2-overexpressing MCF-7 cells.

AIM OF THE STUDY: We performed this study to investigate the anti-cancer activity of Pharbitis nil (PN) ethanol extract which has been used for herbal medicinal treatment against diseases in East Asia. MATERIALS AND METHODS: We analyzed the effects of PN extract on proliferation of breast cancer cell lines, MCF-7 control vector (vec) and MCF-7 human epidermal growth factor receptor 2 (HER2) cells engineered to overexpress oncogenic HER2 via retroviral infection. We performed the proliferation assay to measure the growth rate of the cells. FACS analysis was used to analyze the cell cycle. Western blot analysis was used to investigate the effect of PN on the level and activation of intracellular molecules. RESULTS: We found that PN extract inhibited the proliferation of both MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with the increase of sub G0/G1 apoptotic fractions. When we check the efficiency of PN on the level of intracellular signaling molecules, we found that PN extract induced the inhibition of phosphorylation of HER2 and its downstream effectors, Akt and extracellular signal-regulated kinases (ERK). Active forms of both Akt and ERK were gradually decreased in PN-treated MCF-7 vec and MCF-7 HER2 cells suggesting that the growth suppressive activity of PN is related to signaling pathway. The level of cyclin D also diminished in PN-treated both cells suggesting that PN may inhibit the growth of MCF-7 vec and MCF-7 HER2 cells by perturbing cell cycle progression. It should be noted that PN decreased the growth rate of both MCF-7 vec and MCF-7 HER2 cells without changing the level and activation of p53. CONCLUSION: PN extract suppressed the proliferation rate of HER-2 overexpressing MCF-7 breast cancer cells inducing apoptotic cell death in vitro. Our data demonstrates that PN extracts contain useful anti-tumor activity especially against HER2 overexpressing breast cancer.

Berberine inhibits growth of the breast cancer cell lines MCF-7 and MDA-MB-231.

The effects of berberine on the behavior of breast tumors have not yet been established. To determine whether this compound is useful in the treatment of breast cancer, we analyzed the impact of berberine on the human breast cancer cell lines MCF-7 and MDA-MB-231 cells. Berberine was added to proliferating MCF-7 and MDA-MB-231 cells in culture. Following treatment, changes in cell growth characteristics such as proliferation, cell cycle duration, and the degree of apoptosis were assayed. Following berberine treatment, a time-dependent reduction in proliferation was observed in both cell lines at differing concentrations: 20 microM for MCF-7 and 10 microM for MDA-MB-231 cells. Annexin V staining showed an increase in apoptosis in both cell lines of 31 % in MCF-7 and 12 % in MDA-MB-231 cells compared to their respective controls. In addition, 12 % of the MCF-7 cells were arrested at G0/G1, compared to 62 % of control cells. These results demonstrate that treatment with berberine inhibits growth in both MDA-MB-231 and MCF-7 cells. In addition, they show that this partly occurs through the induction of apoptosis in MDA-MB-231 cells, and through both cell cycle arrest and induction of apoptosis in MCF-7 cells. Thus, berberine may be a novel therapeutic drug for breast cancer.

Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity.

Cyclooxygenase-2 (COX-2) is a major contributor to the elevation of spinal prostaglandin E2, which augments the processing of nociceptive stimuli following peripheral inflammation, and dynorphin has been shown to have an important role in acute and chronic pain states. Moreover, the transcription factor, nuclear factor-kappa B (NF-kB), regulates the expressions of both COX-2 and dynorphin. To elucidate the role of spinal NF-kB in the induction of inflammatory pain hypersensitivity, we examined whether activated NF-kB affects pain behavior and the expressions of the mRNAs of COX-2 and prodynorphin following peripheral inflammation. Intrathecal pretreatment with different NF-kB inhibitors, namely, NF-kB decoy or pyrrolidine dithiocarbamate, significantly reduced mechanical allodynia and thermal hyperalgesia following unilateral hindpaw inflammation evoked by complete Freund's adjuvant (CFA). These NF-kB inhibitors also suppressed the activation of spinal NF-kB and the subsequent remarkable elevation of spinal COX-2 mRNA, but not that of prodynorphin mRNA. In addition, the activation of spinal NF-kB following CFA injection was inhibited by intrathecal pretreatments with interleukin-1 beta receptor antagonist or caspase-1 inhibitor. In view of the fact that interleukin-1 beta (IL-1 beta) is the major inducer of spinal COX-2 upregulation following CFA injection, our results suggest that IL-1 beta-induced spinal COX-2 upregulation and pain hypersensitivity following peripheral inflammation are mediated through the activation of the NF-kB-associated pathways.