Phytochemical Profile, Antioxidant, Anti-Atopic, and Anti-Inflammatory Activities of Filipendula glaberrima Nakai at Different Growth Stages.

Since atopic dermatitis is an inflammatory skin disease, natural remedies, such as Filipendula glaberrima Nakai (FG), with anti-inflammatory properties are possible promising therapeutic options. This study aimed to investigate the therapeutic potential of FG extracts at different growth stages. Seven compounds were isolated from the FG leaf extracts using open-column chromatography, and they were analyzed using HPLC. The extracts were further evaluated for their total polyphenol and flavonoid content (TPC and TFC). The in vitro antioxidant properties of the FG extracts were evaluated using radical scavenging assays, whereas their anti-inflammatory activities were assessed by evaluating their ability to inhibit the production of inflammation-associated biomarkers using the Griess assay and ELISA, respectively. The MTT assay was used to evaluate the viability and cytotoxicity of the FG extracts in keratinocyte cell lines. The results showed that the full-flowering stage exhibited the highest TPC, TFC, and antioxidant activities, thus suggesting a positive correlation between these properties. All FG extracts showed significant anti-inflammatory activity by inhibiting the production of pro-inflammatory biomarkers in lipopolysaccharide-stimulated macrophages. Additionally, the FG extracts suppressed the production of cytokines and chemokines in keratinocytes, indicating their anti-atopic potential. HPLC analysis revealed that the full-flowering stage had the highest content of all the analyzed phytochemicals (gallic acid, (+)-catechin, hyperin, miquelianin, astragalin, afzelin, and quercetin). These results suggest that the full-flowering stage of FG is the most promising source for therapeutic applications owing to its superior phytochemical profile and biological activities. This study highlights the potential of FG extracts, particularly in its full-flowering stage, as a natural therapeutic agent for the management of inflammation-related diseases, and it can also serve as a reference for further research on FG.

3D-printed airway model as a platform for SARS-CoV-2 infection and antiviral drug testing.

We present a bioprinted three-layered airway model with a physiologically relevant microstructure for the study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection dynamics. This model exhibited clear cell-cell junctions and mucus secretion with an efficient expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Having infected air-exposed epithelial cells in the upper layer with a minimum multiplicity of infection of 0.01, the airway model showed a marked susceptibility to SARS-CoV-2 within one-day post-infection (dpi). Furthermore, the unique longevity allowed the observation of cytopathic effects and barrier degradation for 21 dpi. The in-depth transcriptomic analysis revealed dramatic changes in gene expression affecting the infection pathway, viral proliferation, and host immune response which are consistent with COVID-19 patient data. Finally, the treatment of antiviral agents, such as remdesivir and molnupiravir, through the culture medium underlying the endothelium resulted in a marked inhibition of viral replication within the epithelium. The bioprinted airway model can be used as a manufacturable physiological platform to study disease pathogeneses and drug efficacy.

Impact of IL-1ß on lung pathology caused by Mycobacterium abscessus infection and its association with IL-17 production.

Mycobacterium abscessus (MAB), a non-tuberculous mycobacterium (NTM), causes chronic pulmonary inflammation in humans. The NLRP3 inflammasome is a multi-protein complex that triggers IL-1ß maturation and pyroptosis through the cleavage of caspase-1. In this study, we investigated the roles of NLRP3 and IL-1ß in the host's defense against MAB. The IL-1ß production by MAB was completely abolished in NLRP3, but not NLRC4, deficient macrophages. The NLRP3 inflammasome components, which are ASC and caspase-1 were also found to be essential for IL-1ß production in response to MAB. NLRP3 and IL-1ß deficiency did not affect the intracellular growth of MAB in macrophages, and the bacterial burden in lungs of NLRP3- and IL-1ß-deficient mice was also comparable to the burden observed in WT mice. In contrast, IL-1ß deficiency ameliorated lung pathology in MAB-infected mice. Notably, the lung homogenates of IL-1ß-deficient mice had reduced levels of IL-17, but not IFN-γ and IL-4 when compared with WT counterparts. Furthermore, in vitro co-culture analysis showed that IL-1ß signaling was essential for IL-17 production in response to MAB. Finally, we observed that the anti-IL-17 antibody administration moderately mitigated MAB-induced lung pathology. These findings indicated that IL-1ß production contribute to MAB-induced lung pathology via the elevation of IL-17 production.

Is intensive chemotherapy and allogeneic stem cell transplantation mandatory for curing Philadelphia chromosome-positive acute lymphoblastic leukemia in young patients in the era of multitarget agents?

INTRODUCTION: The treatment outcomes for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) have improved with various tyrosine kinase inhibitors (TKIs) and bispecific T-cell engagers. Although allogeneic stem cell transplantation (allo-SCT) is the standard treatment for young patients with Ph+ALL, its role remains debatable in the era of TKIs and blinatumomab. AREAS COVERED: There are some issues regarding Ph+ALL. First, do young patients require intensive chemotherapy (IC) in the era of multitarget agents? Second, which TKI is preferred for frontline therapy? Third, should allo-SCT be performed in patients achieving complete remission with ponatinib and IC? Fourth, can chemo-free treatment lead to a cure without allo-SCT? We searched relevant literature from the last 30 years on PubMed; reviewed the role of chemo-free therapies and combinations of ponatinib and IC; and assessed the necessity of allo-SCT in young patients with Ph+ALL. EXPERT OPINION: Allo-SCT may not be needed, even in young patients with Ph+ALL treated with ponatinib-based IC or combined ponatinib and blinatumomab as frontline therapy. When adopting a ponatinib-based chemo-minimized regimen for induction, allo-SCT is needed with posttransplant ponatinib maintenance. Continuous exposure to ponatinib at pre- or post-transplant is regarded as one of the most important factor for the success of treatment.

Water Extract of Desalted Salicornia europaea Inhibits RANKL-Induced Osteoclast Differentiation and Prevents Bone Loss in Ovariectomized Mice.

Osteoporosis, which is often associated with increased osteoclast activity due to menopause or aging, was the main focus of this study. We investigated the inhibitory effects of water extract of desalted Salicornia europaea L. (WSE) on osteoclast differentiation and bone loss in ovariectomized mice. Our findings revealed that WSE effectively inhibited RANKL-induced osteoclast differentiation, as demonstrated by TRAP staining, and also suppressed bone resorption and F-actin ring formation in a dose-dependent manner. The expression levels of genes related to osteoclast differentiation, including NFATc1, ACP5, Ctsk, and DCSTAMP, were downregulated by WSE. Oral administration of WSE improved bone density and structural parameters in ovariectomized mice. Dicaffeoylquinic acids (DCQAs) and saponins were detected in WSE, with 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA being isolated and identified. All tested DCQAs, including the aforementioned types, inhibited osteoclast differentiation, bone resorption, and the expression of osteoclast-related genes. Furthermore, WSE and DCQAs reduced ROS production mediated by RANKL. These results indicate the potential of WSE and its components, DCQAs, as preventive or therapeutic agents against osteoporosis and related conditions.

Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy.

Background: Exploiting synthetic lethality (SL) relationships between protein pairs has emerged as an important avenue for the development of anti-cancer drugs. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of the NAD+ salvage pathway, having an SL relationship with nicotinic acid phosphoribosyltransferase (NAPRT), the key enzyme in the NAD+ Preiss-Handler pathway. NAMPT inhibitor holds clinical potential not only as a promising cancer treatment but also as a means of protection against chemotherapy-induced-peripheral-neuropathy (CIPN). However, as NAD+ is essential for normal cells, the clinical use of NAMPT inhibitors is challenging. This study aimed to identify a novel NAMPT inhibitor with enhanced selective cytotoxicity against NAPRT-deficient cancer cells as well as prominent efficacy in alleviating CIPN. Methods: We began by conducting drug derivatives screening in a panel of lung cancer cell lines to select an agent with the broadest therapeutic window between the NAPRT-negative and-positive cancer cell lines. Both in vitro and In vivo comparative analyses were conducted between A4276 and other NAMPT inhibitors to evaluate the NAPRT-negative cancer cell selectivity and the underlying distinct NAMPT inhibition mechanism of A4276. Patient-derived tumor transcriptomic data and protein levels in various cancer cell lines were analyzed to confirm the correlation between NAPRT depletion and epithelial-to-mesenchymal transition (EMT)-like features in various cancer types. Finally, the efficacy of A4276 for axonal protection and CIPN remedy was examined in vitro and in vivo. Results: The biomarker-driven phenotypic screening led to a discovery of A4276 with prominent selectivity against NAPRT-negative cancer cells compared with NAPRT-positive cancer cells and normal cells. The cytotoxic effect of A4276 on NAPRT-negative cells is achieved through its direct binding to NAMPT, inhibiting its enzymatic function at an optimal and balanced level allowing NAPRT-positive cells to survive through NAPRT-dependent NAD+ synthesis. NAPRT deficiency serves as a biomarker for the response to A4276 as well as an indicator of EMT-subtype cancer in various tumor types. Notably, A4276 protects axons from Wallerian degeneration more effectively than other NAMPT inhibitors by decreasing NMN-to-NAD+ ratio. Conclusion: This study demonstrates that A4276 selectively targets NAPRT-deficient EMT-subtype cancer cells and prevents chemotherapy-induced peripheral neuropathy, highlighting its potential as a promising anti-cancer agent for use in cancer monotherapy or combination therapy with conventional chemotherapeutics.

Environmental Determinants of Ferroptosis in Cancer.

Given the enormous suffering and death associated with human cancers, there is an urgent need for novel therapeutic approaches to target tumor growth and metastasis. While initial efforts have focused on the dysregulated oncogenic program of cancer cells, recent focus has been on the modulation and targeting of many "cancer-friendly," non-genetic tumor microenvironmental factors, which support and enable tumor progression and metastasis. Two prominent examples are anti-angiogenesis and immunotherapy that target tumor-supporting vascularization and the immune-suppressive tumor microenvironment (TME), respectively. Lately, there has been significant interest in the therapeutic potential of ferroptosis, a natural tumor suppression mechanism that normally occurs as a result of oxidative stress, iron imbalance, and accumulation of lipid peroxides. While numerous studies have identified various cell intrinsic mechanisms to protect or promote ferroptosis, the role of various TME stress factors are also recently recognized to modulate the tumor cells' susceptibility to ferroptosis. This review aims to compile and highlight evidence of these factors, how various TME stresses affect ferroptosis, and their implications in various stages of tumor development and expected response to ferroptosis-triggering therapeutics under development. Consequently, understanding ways to enhance ferroptosis sensitivity both intracellularly and in the TME may optimize therapeutic sensitivity to minimize or prevent tumor growth and metastasis.

Comparison of Sleep Disturbance, Physical Activity, and Health-Related Quality of Life According to Depressive Symptoms in Patients with Metabolic Syndrome: A Secondary Analysis from the Korea National Health and Nutrition Examination Survey Using a Propensity Score Matching Analysis.

Metabolic syndrome has become a global epidemic, and the age of its onset is decreasing. However, its prevalence can be reduced by lifestyle modifications. This study examined the differences in sleep disturbance, physical activity, and health-related quality of life associated with depressive symptoms in patients with metabolic syndrome aged ≥ 40 years. This cross-sectional secondary analysis of data from the 2016 and 2018 Korean National Health and Nutrition Examination Surveys. Of 1404 patients with metabolic syndrome aged ≥ 40 years, depressed and non-depressed patients (103 vs. 103) were matched 1:1 on demographic characteristics using propensity score matching. The outcome variables were then compared between the two groups. We investigated health status, including metabolic syndrome indices, health behaviors, such as sleep disturbances and physical activity, and health-related quality of life. After propensity score matching, health-related quality of life was the only variable that differed significantly between the groups; it was significantly lower in patients with depression (0.77) than in those without depression (0.88) (p = 0.001). Our results suggest that depression with metabolic syndrome is likely to cause a decrease in patients' quality of life; therefore, development of management systems and programs for early intervention to tackle at-risk groups is necessary.

Medical care costs at the end of life among older adults with cancer: a national health insurance data-based cohort study.

OBJECTIVE: Along with aging, the elderly population with cancers is increasing. The costs of end-of-life (EOL) care are particularly high among cancer patients. The purpose of this study was to investigate the trends in medical costs in the last year of life among older adults with cancer. DESIGN, SETTING, AND PARTICIPANTS: Using the Health Insurance Review and Assessment Services (HIRA) database for the period 2016-2019, we identified older adults aged ≥ 65 years who had a primary diagnosis of cancers and high-intensity treatment at least once in the intensive care unit (ICU) of tertiary hospitals. MAIN OUTCOMES AND MEASURES: High-intensity treatment was defined as receiving at least one of the following treatments: cardiopulmonary resuscitation, mechanical ventilation, extracorporeal membrane oxygenation, hemodialysis, and transfusion. The EOL medical treatment costs were calculated by dividing periods 1, 2, 3, 6, and 12 months from the time of death, respectively. RESULTS: The mean total EOL medical expense per older adult during the year before death was $33,712. The cost of EOL medical expenses for three months and one month before subjects' death accounted for 62.6% ($21,117) and 33.8% ($11,389) of total EOL costs, respectively. Among subjects who died while receiving high-intensity treatment in the ICU, the costs associated with medical treatments that occurred during the last month before death were 42.4% ($13,841) of the total EOL expenses during the year. CONCLUSION: The findings indicate that EOL care expenditures for the older population with cancer are highly concentrated until the last month. The intensity of medical care is an important and challenging issue in terms of care quality and cost suitability. Efforts are needed to properly use medical resources and provide optimal EOL care for older adults with cancer.

Oral Administration of Lactobacillus sakei CVL-001 Improves Recovery from Dextran Sulfate Sodium-Induced Colitis in Mice by Microbiota Modulation.

Inflammatory bowel disease (IBD) is an intestinal chronic inflammatory disease, and its incidence is steadily increasing. IBD is closely related to the intestinal microbiota, and probiotics are known to be a potential therapeutic agent for IBD. In our study, we evaluated the protective effect of Lactobacillus sakei CVL-001, isolated from Baechu kimchi, on dextran sulfated sodium (DSS)-induced colitis in mice. The oral administration of L. sakei CVL-001 according to the experimental schedule alleviated weight loss and disease activity in the mice with colitis. Furthermore, the length and histopathology of the colon improved. The expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß genes decreased in the colons of mice that were administered L. sakei CVL-001, whereas that of IL-10 increased. The expressions of genes coding for E-cadherin, claudin3, occludin, and mucin were also restored. In co-housed conditions, L. sakei CVL-001 administration did not improve disease activity, colon length, and histopathology. Microbiota analysis revealed that L. sakei CVL-001 administration increased the abundance of microbiota and altered Firmicutes/Bacteroidetes ratio, and decreased Proteobacteria. In conclusion, L. sakei CVL-001 administration protects mice from DSS-induced colitis by regulating immune response and intestinal integrity via gut microbiota modulation.

Extract of Aster koraiensis Nakai Leaf Ameliorates Memory Dysfunction via Anti-inflammatory Action.

Aster koraiensis Nakai (AK) leaf reportedly ameliorates health problems, such as diabetes. However, the effects of AK on cognitive dysfunction or memory impairment remain unclear. This study investigated whether AK leaf extract could attenuate cognitive impairment. We found that AK extract reduced the production of nitric oxide (NO), tumour necrosis factor (TNF)-α, phosphorylated-tau (p-tau), and the expression of inflammatory proteins in lipopolysaccharide- or amyloid-ß-treated cells. AK extract exhibited inhibitory activity of control specific binding on N-methyl-D-aspartate (NMDA) receptors. Scopolamine-induced AD models were used chronically in rats and acutely in mice. Relative to negative controls (NC), hippocampal choline acetyltransferase (ChAT) and B-cell lymphoma 2 (Bcl2) activity was increased in rats chronically treated with scopolamine and fed an AK extract-containing diet. In the Y-maze test, spontaneous alterations were increased in the AK extract-fed groups compared to NC. Rats administered AK extract showed increased escape latency in the passive avoidance test. In the hippocampus of rats fed a high-AK extract diet (AKH), the expression of neuroactive ligand-receptor interaction-related genes, including Npy2r, Htr2c, and Rxfp1, was significantly altered. In the Morris water maze assay of mice acutely treated with scopolamine, the swimming times in the target quadrant of AK extract-treated groups increased significantly to the levels of the Donepezil and normal groups. We used Tg6799 Aß-overexpressing 5XFAD transgenic mice to investigate Aß accumulation in animals. In the AD model using 5XFAD, the administration of AK extract decreased amyloid-ß (Aß) accumulation and increased the number of NeuN antibody-reactive cells in the subiculum relative to the control group. In conclusion, AK extract ameliorated memory dysfunction by modulating ChAT activity and Bcl2-related anti-apoptotic pathways, affecting the expression of neuroactive ligand-receptor interaction-related genes and inhibiting Aß accumulation. Therefore, AK extract could be a functional material improving cognition and memory.

WNK3 inhibition elicits antitumor immunity by suppressing PD-L1 expression on tumor cells and activating T-cell function.

Immune checkpoint therapies, such as programmed cell death ligand 1 (PD-L1) blockade, have shown remarkable clinical benefit in many cancers by restoring the function of exhausted T cells. Hence, the identification of novel PD-L1 regulators and the development of their inhibition strategies have significant therapeutic advantages. Here, we conducted pooled shRNA screening to identify regulators of membrane PD-L1 levels in lung cancer cells targeting druggable genes and cancer drivers. We identified WNK lysine deficient protein kinase 3 (WNK3) as a novel positive regulator of PD-L1 expression. The kinase-dead WNK3 mutant failed to elevate PD-L1 levels, indicating the involvement of its kinase domain in this function. WNK3 perturbation increased cancer cell death in cancer cell-immune cell coculture conditions and boosted the secretion of cytokines and cytolytic enzymes, promoting antitumor activities in CD4+ and CD8+ T cells. WNK463, a pan-WNK inhibitor, enhanced CD8+ T-cell-mediated antitumor activity and suppressed tumor growth as a monotherapy as well as in combination with a low-dose anti-PD-1 antibody in the MC38 syngeneic mouse model. Furthermore, we demonstrated that the c-JUN N-terminal kinase (JNK)/c-JUN pathway underlies WNK3-mediated transcriptional regulation of PD-L1. Our findings highlight that WNK3 inhibition might serve as a potential therapeutic strategy for cancer immunotherapy through its concurrent impact on cancer cells and immune cells.

Selective cytotoxicity of a novel mitochondrial complex I inhibitor, YK-135, against EMT-subtype gastric cancer cell lines due to impaired glycolytic capacity.

Epithelial-to-mesenchymal transition (EMT)-subtype gastric cancers have the worst prognosis due to their higher recurrence rate, higher probability of developing metastases and higher chemoresistance compared to those of other molecular subtypes. Pharmacologically actionable somatic mutations are rarely found in EMT-subtype gastric cancers, limiting the utility of targeted therapies. Here, we conducted a high-throughput chemical screen using 37 gastric cancer cell lines and 48,467 synthetic smallmolecule compounds. We identified YK-135, a small-molecule compound that showed higher cytotoxicity toward EMT-subtype gastric cancer cell lines than toward non-EMT-subtype gastric cancer cell lines. YK-135 exerts its cytotoxic effects by inhibiting mitochondrial complex I activity and inducing AMP-activated protein kinase (AMPK)-mediated apoptosis. We found that the lower glycolytic capacity of the EMT-subtype gastric cancer cells confers synthetic lethality to the inhibition of mitochondrial complex I, possibly by failing to maintain energy homeostasis. Other well-known mitochondrial complex I inhibitors (e.g., rotenone and phenformin) mimic the efficacy of YK-135, supporting our results. These findings highlight mitochondrial complex I inhibitors as promising therapeutic agents for EMT-subtype gastric cancers and YK-135 as a novel chemical scaffold for further drug development. [BMB Reports 2022; 55(12): 645-650].

Targeting extracellular matrix glycation to attenuate fibroblast activation.

The extracellular matrix (ECM) of the tumor microenvironment undergoes constant remodeling that alters its biochemical and mechano-physical properties. Non-enzymatic glycation can induce the formation of advanced glycation end-products (AGEs), which may cause abnormal ECM turnover with excessively cross-linked collagen fibers. However, the subsequent effects of AGE-mediated matrix remodeling on the characteristics of stromal cells in tumor microenvironments remain unclear. Here, we demonstrate that AGEs accumulated in the ECM alter the fibroblast phenotype within a three-dimensional collagen matrix. Both the AGE interaction with its receptor (RAGE) and integrin-mediated mechanotransduction signaling were up-regulated in glycated collagen matrix, leading to fibroblast activation to acquire a cancer-associated fibroblast (CAF)-like phenotype. These effects were blocked with neutralizing antibodies against RAGE or the inhibition of focal adhesion (FA) signaling. An AGE cross-link breaker, phenyl-4,5-dimethylthiazolium bromide (ALT 711), also reduced the transformation of fibroblasts into the CAF-like phenotype because of its dual inhibitory role in the AGE-modified matrix. Apart from targeting the AGE-RAGE interaction directly, the decreased matrix stiffness attenuated fibroblast activation by inhibiting the downstream cellular response to matrix stiffness. Our results suggest that indirect/direct targeting of accumulated AGEs in the ECM has potential for targeting the tumor stroma to improve cancer therapy. STATEMENT OF SIGNIFICANCE: Advanced glycated end-products (AGEs)-modified extracellular matrix (ECM) is closely associated with pathological states and is recognized as a critical factor that precedes tumorigenesis. While increased matrix stiffness is known to induce fibroblast activation, less is known about how both biochemical and mechano-physical changes in AGE-mediated matrix-remodeling cooperate to produce a myofibroblastic cancer-associated fibroblast (CAF)-like phenotype. For the first time, we found that both the AGE interaction with its receptor (RAGE) and integrin-mediated mechanotransduction were up-regulated in glycated collagen matrix, leading to fibroblast activation. We further demonstrated that an AGE cross-link breaker, ALT-711, reduced the CAF-like transformation because of its dual inhibitory role in the AGE-modified matrix. Our findings offer promising extracellular-reversion strategies targeting the non-enzymatic ECM glycation, to regulate fibroblast activation.

Receptor-interacting protein kinase 2 contributes to host innate immune responses against Fusobacterium nucleatum in macrophages and decidual stromal cells.

PROBLEM: Chorioamnionitis is caused by a bacterial infection that ascends from the vagina and can cause adverse pregnancy outcomes (APOs). Fusobacterium nucleatum (F. nucleatum) is a periodontal pathogen associated with the occurrence of APOs. In this study, we evaluated whether receptor-interacting protein kinase 2 (Ripk2), an adaptor protein of the cytosolic receptors nucleotide-binding oligomerization domain (NOD)1 and NOD2, in macrophages and human decidual stromal cells (hDSCs) contributes to immune responses against F. nucleatum. METHOD OF STUDY: Bone marrow-derived macrophages (BMDMs) isolated from wild-type (WT) and Ripk2-deficient mice and hDSCs were cultured with F. nucleatum (MOI 1, 10, 100). BMDMs and hDSCs were assessed using enzyme-linked immunosorbent assay, Western blot analysis, real-time PCR, and nitrite assay. RESULTS: Fusobacterium nucleatum-induced production of IL-6, but not of TNF-α and IL-10, was lower in Ripk2-deficient BMDMs than in WT cells. Western blotting revealed a decrease in F. nucleatum-induced p65 phosphorylation in Ripk2-deficient macrophages, whereas mitogen-activated protein kinases activation was comparable between WT and Ripk2-deficient cells. The production of nitric oxide (NO) in response to F. nucleatum and the gene and protein expression of inducible NO synthase was impaired in Ripk2-deficient BMDMs. In hDSCs, F. nucleatum upregulated the gene and protein expression of NOD1, NOD2, and Ripk2 in a time-dependent manner. F. nucleatum also increased the production of IL-6, CXCL8, and CCL2, whereas this production was decreased by the Ripk2 inhibitors SB203580 and PP2. CONCLUSIONS: In conclusion, Ripk2 signaling appears to contribute to the F. nucleatum-induced immune response and can be a preventive and therapeutic target against APOs.

Pharmacogenomic Analysis Reveals CCNA2 as a Predictive Biomarker of Sensitivity to Polo-Like Kinase I Inhibitor in Gastric Cancer.

Despite recent innovations and advances in early diagnosis, the prognosis of advanced gastric cancer remains poor due to a limited number of available therapeutics. Here, we employed pharmacogenomic analysis of 37 gastric cancer cell lines and 1345 small-molecule pharmacological compounds to investigate biomarkers predictive of cytotoxicity among gastric cancer cells to the tested drugs. We discovered that expression of CCNA2, encoding cyclin A2, was commonly associated with responses to polo-like kinase 1 (PLK1) inhibitors (BI-2536 and volasertib). We also found that elevated CCNA2 expression is required to confer sensitivity to PLK1 inhibitors through increased mitotic catastrophe and apoptosis. Further, we demonstrated that CCNA2 expression is elevated in KRAS mutant gastric cancer cell lines and primary tumors, resulting in an increased sensitivity to PLK1 inhibitors. Our study suggests that CCNA2 is a novel biomarker predictive of sensitivity to PLK1 inhibitors for the treatment of advanced gastric cancer, particularly cases carrying KRAS mutation.

A Genome-wide Functional Signature Ontology Map and Applications to Natural Product Mechanism of Action Discovery.

Gene expression signature-based inference of functional connectivity within and between genetic perturbations, chemical perturbations, and disease status can lead to the development of actionable hypotheses for gene function, chemical modes of action, and disease treatment strategies. Here, we report a FuSiOn-based genome-wide integration of hypomorphic cellular phenotypes that enables functional annotation of gene network topology, assignment of mechanistic hypotheses to genes of unknown function, and detection of cooperativity among cell regulatory systems. Dovetailing genetic perturbation data with chemical perturbation phenotypes allowed simultaneous generation of mechanism of action hypotheses for thousands of uncharacterized natural products fractions (NPFs). The predicted mechanism of actions span a broad spectrum of cellular mechanisms, many of which are not currently recognized as "druggable." To enable use of FuSiOn as a hypothesis generation resource, all associations and analyses are available within an open source web-based GUI (http://fusion.yuhs.ac).

Infectious diseases in international adoptees from South Korea.

The purpose of this literature review is to discuss infectious diseases found in children adopted from South Korea but not commonly seen in pediatric primary care settings in the United States, as well as summarize screening tests and guidelines for early management of these medical conditions. The diseases were selected based on statistics from the Korea Center for Disease Control and Prevention and discussed in terms of pathophysiology, clinical manifestations, screening tests, management regimens, and implications on pre and post-adoptions. Additionally, current recommendations for the immunization of internationally adopted children and the immunization schedule in South Korea were reviewed. Pediatric primary care providers play a critical role in assessing newly arrived children from South Korea, providing age-appropriate immunizations, and educating the adoptive families about screening tests and management regimens when there are positive screening or diagnostic results and clinical symptoms.