Monocyte-to-lymphocyte ratio as a determinant of survival in patients with gastric cancer undergoing gastrectomy: A cohort study.

The monocyte-to-lymphocyte ratio (MLR) is an important prognostic determinant of various malignancies. However, the prognostic role of MLR in patients with gastric cancer undergoing gastrectomy remains unclear. Patients with stage I to III gastric cancer who underwent curative-intent gastric resection were enrolled in this study. Cox regression analysis was used to determine the independent variables for overall survival (OS) and disease-free survival (DFS). The established models were validated internally. Inter-model comparisons were performed using the integrated area under the receiver operating characteristic curve and the concordance index. Multivariate Cox regression analysis revealed that age, tumor-node-metastasis (TNM) stage, perineural invasion, serum albumin level, and MLR were prognostic factors for OS and DFS and constituted the full model. The full model was internally validated using calibration curves and decision curve analysis. The integrated area under the curve and concordance index of the full model outperformed those of TNM stage. The full model was a significant determinant of OS and DFS. Additionally, the full model was suggested to outperform TNM stage in predicting patient survival outcomes.

Programming inactive RNA-binding small molecules into bioactive degraders.

Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded RNA structures. Mapping these interaction landscapes across the human transcriptome defined structure-activity relationships. Although RNA-binding compounds that bind to functional sites were expected to elicit a biological response, most identified interactions were predicted to be biologically inert as they bind elsewhere. We reasoned that, for such cases, an alternative strategy to modulate RNA biology is to cleave the target through a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L1. Overlay of the substrate specificity for RNase L with the binding landscape of small molecules revealed many favourable candidate binders that might be bioactive when converted into degraders. We provide a proof of concept, designing selective degraders for the precursor to the disease-associated microRNA-155 (pre-miR-155), JUN mRNA and MYC mRNA. Thus, small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function.

Effect of Fermented Red Ginseng Concentrate Intake on Stool Characteristic, Biochemical Parameters, and Gut Microbiota in Elderly Korean Women.

Fermented red ginseng (FRG) has been used as a general stimulant and herbal medicine for health promotion in Asia for thousands of years. Few studies have investigated the effects of FRG containing prebiotics on the gut microbiota. Here, 29 Korean women aged ≥ 50 years were administered FRG for three weeks to determine its effect on stool characteristics, biochemical parameters, and gut microbiome. Gut microbial DNA was subjected to 16S rRNA V3-V4 region sequencing to assess microbial distribution in different stages. Additionally, the stool consistency, frequency of bowel movements, and biochemical parameters of blood were evaluated. We found that FRG intake improved stool consistency and increased the frequency of bowel movements compared to before intake. Biochemical parameters such as glucose, triglyceride, cholesterol, low-density lipoprotein cholesterol, creatinine, alkaline phosphatase, and lactate dehydrogenase decreased and high-density lipoprotein cholesterol increased with FRG intake. Gut microbiome analysis revealed 20 specific bacteria after three weeks of FRG intake. Additionally, 16 pathways correlated with the 20 specific bacteria were enhanced after red ginseng intake. In conclusion, FRG promoted health in elderly women by lowering blood glucose levels and improving bowel movement frequency. The increase in bacteria observed with FRG ingestion supports these findings.

Citizen science projects in freshwater monitoring. From individual design to clusters?

Citizen science projects spring up in freshwater monitoring, with an increasing number of projects in river, lake, and groundwater monitoring around the globe. Citizen science scholars assume that these projects have different designs, including diverse characteristics of citizens, institutions, and forms of interactions, potentially affecting the outcomes of these projects. Given the strong focus on case studies or reviews in the field, there is, however, little comparative evidence of the different types of citizen science projects in freshwater monitoring. Based on a global survey, this study provides a systematic comparative analysis of the design of 85 citizen science projects in the field of freshwater monitoring. Descriptive statistics reveal how projects differ along 45 literature-based design variables raised in the survey. Factor analysis based on 31 of these variables yields ten key design factors, and cluster analysis, based on these design factors, allows to identify seven distinguished clusters of citizen science projects. While these clusters are rather heterogeneous, they reveal differences between groups of projects regarding institutional motivation, citizen characteristics, and interaction forms. These results significantly add to a systematic comparison of citizen science projects in freshwater monitoring and enable a more effective involvement of citizens in environmental management.

Cell-penetrating, amphipathic cyclic peptoids as molecular transporters for cargo delivery.

Here we describe the design, synthesis, and biological evaluation of cell-penetrating, amphipathic cyclic peptoids as a novel class of molecular transporters. We demonstrated that macrocyclization, along with the introduction of hydrophobic residues, greatly enhanced cellular uptake of polyguanidine linear peptoids. The amphipathic cyclic peptoids showed an order of magnitude more efficient intracellular delivery ability, compared to a commonly used polyarginine cell-penetrating peptide, representing one of the best molecular transporters reported to date. Given the excellent cell-permeability, proteolytic stability, and ease of synthesis, the amphipathic cyclic peptoids would be broadly applicable to a wide range of clinical and biological applications.

Individual Identification with Short Tandem Repeat Analysis and Collection of Secondary Information Using Microbiome Analysis.

Forensic investigation is important to analyze evidence and facilitate the search for key individuals, such as suspects and victims in a criminal case. The forensic use of genomic DNA has increased with the development of DNA sequencing technology, thereby enabling additional analysis during criminal investigations when additional legal evidence is required. In this study, we used next-generation sequencing to facilitate the generation of complementary data in order to analyze human evidence obtained through short tandem repeat (STR) analysis. We examined the applicability and potential of analyzing microbial genome communities. Microbiological supplementation information was confirmed for two of four failed STR samples. Additionally, the accuracy of the gargle sample was confirmed to be as high as 100% and was highly likely to be classified as a body fluid sample. Our experimental method confirmed that anthropological and microbiological evidence can be obtained by performing two experiments with one extraction. We discuss the advantages and disadvantages of using these techniques, explore prospects in the forensic field, and highlight suggestions for future research.

Intake of MPRO3 over 4 Weeks Reduces Glucose Levels and Improves Gastrointestinal Health and Metabolism.

Human gut microbiota are involved in different metabolic processes, such as digestion and nutrient synthesis, among others. For the elderly, supplements are a major means of maintaining health and improving intestinal homeostasis. In this study, 51 elderly women were administered MPRO3 (n = 17), a placebo (n = 16), or both (MPRO3: 1 week, placebo: 3 weeks; n = 18) for 4 weeks. The fecal microbiota were analyzed by sequencing the 16S rRNA gene V3-V4 super-variable region. The dietary fiber intake increased, and glucose levels decreased with 4-week MPRO3 intake. Reflux, indigestion, and diarrhea syndromes gradually improved with MPRO3 intake, whereas constipation was maintained. The stool shape also improved. Bifidobacterium animalis, B. pseudolongum, Lactobacillus plantarum, and L. paracasei were relatively more abundant after 4 weeks of MPRO3 intake than in those subjects after a 1-week intake. Bifidobacterium and B. longum abundances increased after 1 week of MPRO3 intake but decreased when the intake was discontinued. Among different modules and pathways, all 10 modules analyzed showed a relatively high association with 4-week MPRO3 intake. The mineral absorption pathway and cortisol biosynthesis and secretion pathways correlated with the B. animalis and B. pseudolongum abundances at 4 weeks. Therefore, 4-week MPRO3 intake decreased the fasting blood glucose level and improved intestinal health and metabolism.

Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway.

Aberrantly elevated steroid receptor coactivator-1 (SRC-1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC-1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N-degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC-1 in cells through the N-degron pathway. Importantly, given the ubiquitous expression of the UBR protein in most cells, PROTACs targeting the UBR box could degrade a protein of interest regardless of cell types. We also showed that the SRC-1 degrader significantly suppressed cancer cell invasion and migration in vitro and in vivo. Together, these results demonstrate that the SRC-1 degrader can be an invaluable chemical tool in the studies of SRC-1 functions. Moreover, our findings suggest PROTACs based on the N-degron pathway as a widely useful strategy to degrade disease-relevant proteins.

Bridged α-helix mimetic small molecules.

Herein, we report a strategy for generating conformationally restricted α-helix mimetic small molecules by introducing covalent bridges that limit rotation about the central axis of α-helix mimetics. We demonstrate that the bridged α-helix mimetics have enhanced binding affinity and specificity to the target protein due to the restricted conformation as well as extra interaction of the bridge with the protein surface.

A solid-phase method for synthesis of dimeric and trimeric ligands: Identification of potent bivalent ligands of 14-3-3σ.

Multivalent protein-protein interactions including bivalent and trivalent interactions play a critical role in mediating a wide range of biological processes. Hence, there is a significant interest in developing molecules that can modulate those signaling pathways mediated by multivalent interactions. For example, multimeric molecules capable of binding to a receptor protein through a multivalent interaction could serve as modulators of such interactions. However, it is challenging to efficiently generate such multimeric ligands. Here, we have developed a facile solid-phase method that allows for the rapid generation of (homo- and hetero-) dimeric and trimeric protein ligands. The feasibility of this strategy was demonstrated by efficiently synthesizing fluorescently-labeled dimeric peptide ligands, which led to dramatically increased binding affinities (~400-fold improvement) relative to a monomeric 14-3-3σ protein ligand.

A Forkhead Box Protein†C2 Inhibitor: Targeting Epithelial-Mesenchymal Transition and Cancer Metastasis.

The epithelial-mesenchymal transition (EMT) has been suggested as a new target for therapeutic intervention of metastatic cancer. Forkhead box protein C2 (FOXC2) is known to be necessary for initiating and maintaining EMT, and therefore bestows on cancer cells metastatic and cancer stem cell (CSC)-like phenotypes, allowing cells to acquire higher motility, invasiveness, self-renewal, and therapy resistance. Here, we describe the first inhibitor of FOXC2, MC-1-F2. MC-1-F2 was able to induce cadherin switching and reverse EMT through the degradation of FOXC2 and blocking of its nuclear localization. In addition, MC-1-F2 was very effective in inhibiting cancer cell migration and invasion. As the first small-molecule inhibitor of FOXC2 and the first compound targeting EMT-associated transcription factor, MC-1-F2 will pave the way for a new anticancer therapeutic agent targeting metastatic cancer and help to elucidate the network of EMT signaling pathways.

Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction.

The complex formation between transcription factors (TFs) and coactivator proteins is required for transcriptional activity, and thus disruption of aberrantly activated TF/coactivator interactions could be an attractive therapeutic strategy. However, modulation of such protein-protein interactions (PPIs) has proven challenging. Here we report a cell-permeable, proteolytically stable, stapled helical peptide directly targeting nuclear receptor coactivator 1 (NCOA1), a coactivator required for the transcriptional activity of signal transducer and activator of transcription 6 (STAT6). We demonstrate that this stapled peptide disrupts the NCOA1/STAT6 complex, thereby repressing STAT6-mediated transcription. Furthermore, we solved the first crystal structure of a stapled peptide in complex with NCOA1. The stapled peptide therefore represents an invaluable chemical probe for understanding the precise role of the NCOA1/STAT6 interaction and an excellent starting point for the development of a novel class of therapeutic agents.

Skp2 Inhibitors: Novel Anticancer Strategies.

Skp2 is frequently overexpressed in many human cancers and plays a key role in tumorigenesis. As a component of the SCFSkp2ubiquitin E3 ligase complex, Skp2 is responsible for recruiting substrate proteins for their ubiquitination and subsequent degradation by the 26S proteasome. Thus, Skp2 promotes the cell cycle by down-regulating cell cycle proteins such as the tumor suppressor p27. Alternatively, Skp2 suppresses p53-dependent apoptosis by outcompeting p53 for binding to p300, thereby perturbing p300-mediated p53 acetylation and stabilization. Taken together, inhibition of Skp2 functions (either proteolytic function or non-proteolytic function) is emerging as a promising and novel anti-cancer strategy. In the present review, we highlight the development of Skp2 inhibitors with different mechanisms of action.

Analysis of expert consultation referrals for anesthesia-related issues (December 2008-July 2010): KSA legislation committee report.

BACKGROUND: Since 2009, database construction of anesthesia-related adverse events has been initiated through the legislation committee of the Korean Society of Anesthesiologists (KSA), based on expert consultation referrals provided by police departments, civil courts, and criminal courts. METHODS: This study was a retrospective descriptive analysis of expert consultation referrals on surgical anesthesia-related cases between December 2008 and July 2010. RESULTS: During the given period, 46 surgical anesthesia-related cases were referred to the KSA legislation committee for expert consultation. Because six cases were excluded due to insufficient data, 40 cases were included in the final analysis. Of 40 cases, 29 (72.5%) resulted in death. Respiratory events were most common in both surviving/disabled and dead patients (36.4 vs. 51.7%, respectively; P > 0.05). Overall, respiratory depression due to the drugs used for monitored anesthesia care (MAC) was the most common specific mechanism (25%), in which all but one case (profound brain damage) resulted in death. In all of these cases, surgeons or physicians provided MAC without the help of anesthesiologists. CONCLUSIONS: Overall, the most common damaging mechanism was related to respiratory depression due to sedatives or anesthetics used for MAC. Almost all MAC injury cases are believed to be preventable with the use of additional or better monitoring and an effective response to initial physiological derangement. Thus, it is essential to establish practical MAC guidelines and adhere to these guidelines strictly to reduce the occurrence of severe anesthesia-related adverse outcomes.

The effect of mechanical ventilation tidal volume during pneumoperitoneum on shoulder pain after a laparoscopic appendectomy.

BACKGROUND: Postlaparoscopic shoulder pain (PLSP) frequently occurs after various laparoscopic surgical procedures. Its mechanism is commonly assumed to be overstretching of the diaphragmatic muscle fibers due to the pressure of a pneumoperitoneum, which causes phrenic nerve-mediated referred pain to the shoulder. Based on this hypothesis, we speculated that during inspiration, the lung could squeeze out the phrenic nerve with carbon dioxide gas against the constantly pressurized abdominal cavity with increasing tidal volume (V(T)). Thus, we examined whether mechanical ventilation with a low V(T) (LTV, V(T) 7 ml/kg) during a pneumoperitoneum might reduce PLSP in patients undergoing laparoscopic appendectomy compared with ventilation with the traditional V(T) (TTV, V(T) 10 ml/kg). METHODS: In a prospective trial, 64 adult patients undergoing laparoscopic appendectomy were randomly assigned to two groups of 32 each (LTV and TTV groups). Intravenous ketorolac was used as a postoperative rescue analgesic. The 2-, 4-, 24-, and 48-h postoperative incidence and severity of PLSP, severity of surgical pain, and need for rescue analgesia was assessed. RESULTS: The overall incidence of PLSP was similar in both groups (57.1% in the LTV group vs. 65.5% in the TTV group). Compared with the TTV group, the incidence and PLSP verbal rating scale (VRS) did not decrease in the LTV group throughout the study period. No statistically significant differences were observed in the VRS surgical pain score, the cumulative ketorolac consumption at each time point, or the time to first rescue analgesia. CONCLUSIONS: Mechanical ventilation with a reduced 7 ml/kg V(T) during a pneumoperitoneum does not reduce the frequency and severity of PLSP after laparoscopic appendectomy compared with ventilation with the traditional V(T) (10 ml/kg).