MSH2-MSH3 promotes DNA end resection during homologous recombination and blocks polymerase theta-mediated end-joining through interaction with SMARCAD1 and EXO1.

DNA double-strand break (DSB) repair via homologous recombination is initiated by end resection. The extent of DNA end resection determines the choice of the DSB repair pathway. Nucleases for end resection have been extensively studied. However, it is still unclear how the potential DNA structures generated by the initial short resection by MRE11-RAD50-NBS1 are recognized and recruit proteins, such as EXO1, to DSB sites to facilitate long-range resection. We found that the MSH2-MSH3 mismatch repair complex is recruited to DSB sites through interaction with the chromatin remodeling protein SMARCAD1. MSH2-MSH3 facilitates the recruitment of EXO1 for long-range resection and enhances its enzymatic activity. MSH2-MSH3 also inhibits access of POLθ, which promotes polymerase theta-mediated end-joining (TMEJ). Collectively, we present a direct role of MSH2-MSH3 in the initial stages of DSB repair by promoting end resection and influencing the DSB repair pathway by favoring homologous recombination over TMEJ.

EC-18 prevents autoimmune arthritis by suppressing inflammatory cytokines and osteoclastogenesis.

BACKGROUND: EC-18, a synthetic monoacetyldiaglyceride, exhibits protective effects against lung inflammation, allergic asthma, and abdominal sepsis. However, there have been no investigations to determine whether EC-18 has preventive potential in autoimmune diseases, especially rheumatoid arthritis (RA). METHODS: To investigate the efficacy of EC-18 on the development of RA, EC-18 was administered in a collagen-induced arthritis (CIA) murine model and disease severity and the level of inflammatory cytokines in the joint were investigated. The effect of EC-18 on the inflammation-related factors was investigated by flow cytometry, ELISA, western blot, and real-time PCR in splenocytes from mice and in peripheral blood mononuclear cells from healthy and patients with RA. The effect of EC-18 on osteoclastogenesis was investigated. RESULTS: EC-18 effectively reduced the clinical and histological severity of arthritis, similar to Janus kinase inhibitors include tofacitinib and baricitinib, in CIA. Furthermore, EC-18 exhibited a synergistic effect with methotrexate in preventing CIA. Treatment with EC-18 effectively reduced the production of inflammatory cytokines in immune cells and osteoclast differentiation in mice and patients with RA. CONCLUSION: These results suggest that EC-18 may be an effective strategy for RA.

Effect of socioeconomic disparities on the risk of COVID-19 in 8 metropolitan cities in the Korea: a community-based study.

OBJECTIVES: Socioeconomic disparities have been reported as major risk factors contributing to the spread of coronavirus disease 2019 (COVID-19) at the community level. We conducted an epidemiological study on COVID-19 incidence risk using area-based deprivation indices (DIs) reflecting the characteristics of the susceptible population. METHODS: A database of the confirmed COVID-19 cases in 8 metropolitan cities in Korea from January 20, 2020 to December 31, 2021 was combined with area-based DI scores and standardized prevalence rates of diabetes and hypertension from the Korean Community Health Survey. Relative risk (RR) levels were estimated using a generalized linear model with a Poisson distribution by age group. RESULTS: The risk of COVID-19 incidence generally increased with increasing age, especially in patients aged ≥75 years. The RR of COVID-19 incidence per interquartile range increment of the composite deprivation index (composite DI) was 1.54 (95% confidence interval [CI], 1.34 to 1.70). Notably, in the first wave, the risk of COVID-19 incidence was approximately 3 times higher in the region with the lowest socioeconomic status than in the region with the highest status (RR, 3.08; 95% CI, 2.42 to 3.78 based on the the composite DI and RR, 3.13; 95% CI, 2.53 to 3.83 based on the social deprivation index). CONCLUSIONS: This study provides scientific evidence that socioeconomic deprivation is an important risk factor for the spread of COVID-19. This finding suggests that a mid-term to long-term strategy is needed to protect susceptible populations and reduce the burden of COVID-19 in the community.

Preparation of high-quality YAG:Ce3+ ceramic phosphor by high-frequency induction heated press sintering methods.

This study investigates the characteristics of a ceramic phosphor (CP) for the converter of a high-power laser diode-based automobile headlamp synthesized by high-frequency induction heated press (HFP) sintering. The CP prepared by an HFP method exhibits remarkable optical properties that are comparable to spark plasma sintering. The effects of post-treatment process for controlling residual pores, as well as sintering temperature, sintering pressure and heating rate for optimization of the HFP sintering method, were studied. The HFP sintering process can be widely used in ceramics and lighting fields because it is designed relatively low cost compared to other techniques and exhibits excellent productivity.

A decrease in functional microbiomes represented as Faecalibacterium affects immune homeostasis in long-term stable liver transplant patients.

ABBREVIATIONS: LT, liver transplantation; HCC, hepatocellular carcinoma; IS, immunosuppressants; DC, dendritic cells; Treg, regulatory T; Th17, T helper 17; AST, aspartate transaminase; ALT, alanine transaminase; OUT, operational taxonomic unit; LEfSe, linear discriminant analysis effect size; LDA, linear discriminant analysis; IL, interleukin; TGF, transforming growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; TNF-α, tumor necrosis factor-α; MIP-1α, macrophage inflammatory protein-1α; IP-10, interferon γ-induced protein; MCP-1, monocyte chemoattractant protein-1; ACR, acute cellular rejection; NF-κB, nuclear factor κB; PT INR, prothrombin time; QC, quality check; PBMC, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay.

Early Intervention Reduces the Spread of COVID-19 in Long-Term Care Facilities in the Republic of Korea.

This study describes the epidemiological characteristics of coronavirus disease 2019 (COVID-19) based on reported cases from long-term care facilities. As of April 20th, 2020, 3 long-term care facilities in a metropolitan area of South Korea had reported cases of COVID-19. These facilities' employees were presumed to be the sources of infection. There were 2 nursing hospitals that did not report any additional cases. One nursing home had a total of 25 cases, with an attack rate of 51.4% (95% CI 35.6-67.0), and a fatality rate of 38.9% (95% CI 20.3-61.4) among residents. The results from this study suggest that early detection and maintenance of infection control minimizes the risk of rapid transmission.

Presenting characteristics and clinical outcome of patients with COVID-19 in South Korea: A nationwide retrospective observational study.

BACKGROUND: More than 13,000 cases were reported to be infected with COVID-19 by RT-PCR in South Korea. Most studies report clinical characteristics of hospitalized patients with COVID-19; the full spectrum of disease severity has thus not yet been well described. METHODS: Using retrospective observational methods, this study analyzed factors affecting early clinical symptoms, clinical progress, and severity of disease for COVID-19 positive patients released from quarantine to provide information on establishing optimized care for new patients. The medical data of 7803 laboratory-confirmed patients who had been discharged or died by April 30, 2020 were analyzed using multivariate logistic regression analysis. FINDINGS: On admission, 7383 (94•5%) patients were asymptomatic or showed mild illness, and 372 (4•8%) patients were severe illness. Also, 48 (0 0•6%) were hospitalized with critically ill when diagnosed. Most patients with asymptomatic or mild illness on admission remained mild until discharge, 253 (3•4%) progressed to severe illness, and 83 (1•1%) died in hospital. However, the case fatality were 29•8% and 62•5% in severe and critically ill patients, respectively. At admission, 73•0% of hospitalized patients had symptoms; most common were cough (42•5%), sputum (28•8%), and fever (20•1%). Only 35•2% of laboratory confirmed patients admitted to the temporary care facility complained of symptoms. Increasing odds of being critically ill was associated with older age (OR 28•93, 95% CI 13•34-62•75 for age >70y, vs. age <50 y; p<0•0001), being male (OR 2•15, 95% CI1•59-2•89; p<0•0001), fever (OR 2•52, 95% CI 1.84-3•45; p<0•0001), and shortness of breath (OR 7•40, 95% CI 5•37-10•19; p<0•0001). Comorbid illness significantly increased risk of critical illness or death. INTERPRETATION: Most cases were discharged as asymptomatic or recovered from mild illness, and only 9•7% developed severe disease requiring oxygen therapy or more. Case fatality rate was 2•9%, and markedly increased in those over age 50. Risk factors such as age, sex, fever, shortness of breath, and underlying disease can be useful in predicting future clinical severity. Additionally, the number of confirmed asymptomatic COVID-19 patients significantly contribute to continued spread. FUNDING: none.

Cottonseed Oil Protects Against Intestinal Inflammation in Dextran Sodium Sulfate-Induced Inflammatory Bowel Disease.

Dietary products may protect against inflammatory bowel disease (IBD) through mechanisms such as forming gut microbiota structures and providing substrates for microbial metabolism. Recently, many studies have been conducted on diets that potentially alleviate or suppress IBD development. To assess the efficacy of dietary oils in treating IBD, we examined the protective effects of olive oil, coconut oil, corn oil, and cottonseed oil in a dextran sodium sulfate (DSS)-induced colitis mouse model. Treatment with cottonseed oil or corn oil ameliorated the severity of DSS-induced colitis, alleviating weight loss and preventing the shortening of the intestine. Moreover, cottonseed oil or corn oil treatment significantly reduced the expression of inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-17, as well as the expression of oxidative stress markers, including 8-hydroxyguanosine and nitrotyrosine in colon sections, compared with vehicle treatment. Cottonseed oil treatment inhibited intestinal fibrosis by reducing the expression of α-smooth muscle actin and type I collagen, compared with vehicle treatment in mice with DSS-induced colitis. Cottonseed oil protects against intestinal inflammation and the development of intestinal fibrosis by reducing inflammatory cytokines and oxidative stress markers, and may therefore be useful as a dietary product with therapeutic benefits for IBD.

Effect of CT Reconstruction Algorithm on the Diagnostic Performance of Radiomics Models: A Task-Based Approach for Pulmonary Subsolid Nodules.

OBJECTIVE: We investigated whether the diagnostic performance of machine learning-based radiomics models for the discrimination of invasive pulmonary adenocarcinomas (IPAs) among subsolid nodules (SSNs) was affected by the proportion of images reconstructed with filtered back projection (FBP) and model-based iterative reconstruction (MBIR) in datasets used for feature extraction. MATERIALS AND METHODS: This retrospective study included 60 patients (23 men and 37 women; mean age, 61.4 years) with 69 SSNs (54 part-solid and 15 pure ground-glass nodules). Preoperative CT scans were reconstructed with both FBP and MBIR. A total of 860 radiomics features were obtained from the entire nodule volume, and 70 resampled nodule datasets with an increasing proportion of nodules with MBIR-derived features (from 0/69 to 69/69) were prepared. After feature selection using neighborhood component analysis, support vector machines (SVMs) and an ensemble model were used as classifiers for the differentiation of IPAs. The diagnostic performances of all blending proportions of reconstruction algorithms were calculated and analyzed. RESULTS: The ROC AUC and the diagnostic accuracy of the radiomics models decreased significantly as the number of nodules with MBIR-derived features increased, and this relationship followed cubic functions (R2 = 0.993 and 0.926 for SVM; R2 = 0.993 and 0.975 for the ensemble model; p < 0.001). The magnitude of variation in AUC due to the reconstruction algorithm heterogeneity was 0.39 for SVM and 0.39 for the ensemble model. CONCLUSION: Inclusion of CT scans reconstructed with MBIR for radiomics modeling can significantly decrease diagnostic performance for the identification of IPAs.

Convenience store visitors recall cigarette advertisements even if they do not purchase cigarettes.

BACKGROUND: This study examined the extent to which visitors to convenience stores remember the cigarette advertisements they encounter in these stores and investigated the relationships between how advertisements are recalled and attitudes toward them. METHODS: Exit surveys of 1007 visitors to three convenience stores located in Seoul, Korea, were conducted between 25 November 2015 and 7 December 2015. RESULTS: Of the respondents, 23.4% (n = 236) freely recalled the cigarette advertisement in the store just visited. However, the percentage of participants who correctly recalled the advertisement increased to 55.2% (n = 556) after we presented them with a card showing options for the advertisement (i.e. a cued recall task). Regardless of sex or purchasing cigarettes, free recall performance was significantly associated with age, number of weekly visits to the convenience store and current smoking status. In addition, free recall increased with having a positive attitude toward cigarette advertisements. CONCLUSIONS: Repeated visits to convenience stores may continue to expose individuals to cigarettes and their advertisements; such exposure may subconsciously affect recall of the advertisements and maintenance of a positive attitude toward cigarette advertisements. Therefore, to denormalize smoking in society, cigarette advertising and displays at points of sale including convenience stores, should be banned.

Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells.

Kaempferol, a flavonoid, found in traditional medicine, fruits, and vegetables, and an HDAC inhibitor, is a powerful anti-cancer reagent against various cancer cell lines. However, detailed mechanisms involved in the treatment of gastric cancer (GC) using kaempferol are not fully understood. In our study, we investigated the biological activity and molecular mechanism involved in kaempferol-mediated treatment of GC. Kaempferol promoted autophagy and cell death, and increased LC3-I to LC3-II conversion and the downregulation of p62 in GC. Furthermore, our results showed that kaempferol induces autophagic cell death via the activation of the IRE1-JNK-CHOP signaling, indicating ER stress response. Indeed, the inhibition of ER stress suppressed kaempferol-induced autophagy and conferred prolonged cell survival, indicating autophagic cell death. We further showed that kaempferol mediates epigenetic change via the inhibition of G9a (HDAC/G9a axis) and also activates autophagic cell death. Taken together, our findings indicate that kaempferol activates the IRE1-JNK-CHOP signaling from cytosol to nucleus, and G9a inhibition activates autophagic cell death in GC cells.

DSGOST regulates resistance via activation of autophagy in gastric cancer.

Danggui-Sayuk-Ga-Osuyu-Saenggang-Tang (DSGOST in Korean, Danggui-Sini-Jia-Wuzhuyu-Shengian-Tang in Chinese, and Tokishigyakukagoshuyushokyoto (TJ-38) in Japanese), a well-known traditional Korean/Chinese/Japanese medicine, has long been used to treat vascular diseases such as Raynaud's phenomenon (RP). However, anticancer effect of DSGOST remains elusive. In this study, we checked if DSGOST has an anticancer effect against gastric cancer cells, and investigated the mechanisms underlying DSGOST resistance. Moreover, DSGOST regulates chemoresistance in cisplatin-treated gastric cancer cells. Interestingly, DSGOST treatment induced the accumulation of GFP-LC3 puncta and increased the level of autophagy markers, such as LC3-II, ATG5, and Beclin-1, indicating activated autophagy. Furthermore, DSGOST could activate epithelial-to-mesenchymal transition (EMT) and exosomes via induction of autophagy. DSGOST in combination with TGFß also induced autophagy and EMT. However, autophagy inhibition induces DSGOST-mediated cell death in gastric cancer cells. In addition, autophagy inhibition blocks the activation of DSGOST-mediated EMT markers including N-cadherin, Snail, Slug, vimentin, ß-catenin, p-Smad2, and p-Smad3. Taken together, these findings indicated that prosurvival autophagy was one of the mechanisms involved in the resistance of gastric cancer to DSGOST. Targeting the inhibition of autophagy could be an effective therapeutic approach to overcome resistance to DSGOST in gastric cancer.

Preclinical pharmacokinetics, interspecies scaling, and pharmacokinetics of a Phase I clinical trial of TTAC-0001, a fully human monoclonal antibody against vascular endothelial growth factor 2.

BACKGROUND: VEGF is a highly selective mitogen that serves as the central regulator of tumor angiogenesis by mediating endothelial proliferation, permeability, and survival. Tanibirumab (TTAC-0001) is a fully human IgG1 monoclonal antibody derived from a fully human naïve single-chain variable fragment (ScFv) phage library that was developed to inhibit the effects of VEGF in the treatment of solid tumors, especially those of the brain. METHODS: In the present study, we conducted intravenous pharmacokinetic studies of TTAC-0001 in mice, rats, and cynomolgus monkeys. At the doses studied (3 mg/kg, 10 mg/kg, 30 mg/kg), TTAC-0001 exhibited dose proportionality in mice and monkeys. At a dose of ~10 mg/kg, the clearance of TTAC-0001 from serum was 0.017 mL/h in mice, 0.35 mL/h in rats, and 2.19 mL/h in cynomolgus monkeys, and the terminal half-life ranged from 20-30 h among the three species. Pharmacokinetic data in mice, rats, and cynomolgus monkeys were used to predict the pharmacokinetics of TTAC-0001 in humans using allometric scaling. The predicted serum clearance of TTAC-0001 in humans was 102.45 mL/h and the terminal half-life was 27.52 h. RESULTS: The maximum life span-corrected clearance value was 72.92 mL/h. The observed clearance in humans was more similar to the predicted scaled clearance. CONCLUSION: We investigated the pharmacokinetics of TTAC-0001 in mice, rats, and cynomolgus monkeys after intravenous administration. At the doses studied, TTAC-0001 exhibited dose proportionality in mice and monkeys. The scaled pharmacokinetics of TTAC-0001 reported here was useful for designing first-in-human studies. Allometric scaling in the therapeutic antibody is feasible.

A Combination with Probiotic Complex, Zinc, and Coenzyme Q10 Attenuates Autoimmune Arthritis by Regulation of Th17/Treg Balance.

Probiotic complex, zinc, and coenzyme Q10 (CoQ10) are recognized dietary supplements with an anti-inflammatory role. Although these supplementations are individually known to benefit rheumatoid arthritis (RA), there is no evidence suggesting any synergic effect. The primary goal of this study is to determine whether probiotic complex, zinc, and CoQ10 attenuate the development of collagen-induced arthritis (CIA). The combination of probiotic complex, zinc, and CoQ10 reduced CIA severity by downregulating the levels of IgG, IgG1, and IgG2a in serum. Joint inflammation, bone destruction, and cartilage damage were also improved by the complex. There was a decrease in the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-17, and vascular endothelial growth factor (VEGF) in the joint synovium. The balance between helper T 17 (Th17) cells and regulatory T (Treg) cells was shown to be controlled reciprocally by the complex. These findings suggest that the combination of probiotic complex, zinc, and CoQ10 can ameliorate the development of CIA by inhibiting the expression of proinflammatory cytokines, and is thus an important therapeutic candidate for RA treatment.

Metformin ameliorates experimental-obesity-associated autoimmune arthritis by inducing FGF21 expression and brown adipocyte differentiation.

Rheumatoid arthritis (RA) is a systemic autoimmune disease involving excessive inflammation. Recently, RA associated with a metabolic disorder was revealed to be non-responsive to RA medications. Metformin has been reported to have a therapeutic effect on RA and obesity. The aim of this investigation was to study the therapeutic effect and the underlying mechanism of metformin's action in an experimental model of collagen-induced arthritis (CIA) associated with obesity. Metformin was administered daily for 13 weeks to mice with CIA that had been fed a high-fat diet. Metformin ameliorated the development of CIA in obese mice by reducing autoantibody expression and joint inflammation. Furthermore, metformin decreased the expression levels of pSTAT3 and pmTOR and had a small normalizing effect on the metabolic profile of obese CIA mice. In addition, metformin increased the production of pAMPK and FGF21. Metformin also induced the differentiation of brown adipose tissue (BAT), which led to a reciprocal balance between T helper (Th) 17 and regulatory T (Treg) cells in vitro and in vivo. These results suggest that metformin can dampen the development of CIA in obese mice and reduce metabolic dysfunction by inducing BAT differentiation. Thus, metformin could be a therapeutic candidate for non-responsive RA.

Differences in visual fixation duration according to the position of graphic health warning labels: An eye-tracking approach.

INTRODUCTION: The Framework Convention on Tobacco Control (FCTC) recommends that graphic health warning labels (GHWLs) be positioned at the top of the principal area of cigarette packs, rather than at the bottom, to increase visibility. However, during the legislative process of introducing GHWLs in South Korea, the position of GHWLs has become a contested issue. The pro-tobacco industry group argued that the warnings should be placed at the bottom of cigarette packs because evidence for the effectiveness of the upper position was insufficient. Therefore, this study investigated whether the position of the GHWL affects eye movement. METHODS: Participants (30 daily smokers and 24 non-smokers) were shown six cigarette packs in random order with different position combinations (top, middle, bottom) and image concepts (skin aging, toxic constituents). Participants' eye movements were recorded using eye-tracking equipment to measure visual fixation duration in milliseconds (ms). RESULTS: Participants visually fixated longer on the health warning area than on the tobacco branding area (p<0.05). Mean fixation duration on the health warning area was significantly longer at the top or middle positions compared to the bottom, by 28% (mean difference=340 ms, p=0.006) and by 30% (mean difference=368 ms, p=0.002), respectively. By contrast, mean fixation duration on the branding area was longer with the warning at the bottom compared to top or middle positions by 25% and 33%, with mean differences of 157 ms (p=0.100) and 212 ms (p=0.026), respectively. No significant difference in fixation time was observed between the top and middle positions (p>0.05). CONCLUSIONS: The duration of visual fixation on GHWLs was longer when they were displayed at the top and middle, rather than at the bottom. Therefore, GHWLs should be positioned from the top to the middle of the tobacco package.

Tobacco company strategies for maintaining cigarette advertisements and displays in retail chain stores: In-depth interviews with Korean convenience store owners.

INTRODUCTION: This study gathered data from store owners regarding the advertising and display of, and the contractual arrangements and promotional activities related to, the sale of tobacco products in convenience stores. METHODS: In-depth interviews were conducted with three owners of convenience stores in South Korea: to examine the procedures for managing the sale of tobacco products; for allocating the advertising allowance for such products; and for coordinating the promotional activities of tobacco companies. RESULTS: All tobacco advertisements and displays in convenience stores are installed and managed in accordance with the contract between the tobacco companies and the convenience store headquarters. The headquarters receives an allowance from the tobacco company in return for maintaining and displaying their product and promotional materials. The headquarters then pays a monthly advertising allowance to each franchisee as an operating subsidy. However, the owners also stated that tobacco companies provide financial incentives directly to them to engage in illegal promotional activities. CONCLUSIONS: Because tobacco advertisements and displays at convenience stores are related to the profitability of these products, the participants in these relationships have become increasingly entangled. Illegal promotional activities must be monitored to limit tobacco sales and advertising. Furthermore, efforts to ban the advertising and display of tobacco products at the point of sale must be based on the development of policies emerging from an understanding of the roles of the major stakeholders.

Compliance of systematic reviews in ophthalmology with the PRISMA statement.

BACKGROUND: Systematic reviews and meta-analyses are becoming increasingly important methods to summarize published research. Studies of ophthalmology may present additional challenges because of their potentially complex study designs. The aim of this study was to evaluate the reporting quality of systematic reviews and meta-analyses on topics in ophthalmology to determine compliance with the PRISMA guidelines. We assessed articles published between 2010 and 2015 in the five major relevant journals with the highest impact factors. METHODS: The MEDLINE and EMBASE databases were searched to identify systematic reviews published between January 2010 and December 2015 in the following 5 major ophthalmology journals: Progress in Retinal and Eye Research, Ophthalmology, Archives of Ophthalmology, American Journal of Ophthalmology, and Survey of Ophthalmology. The screening, identification, and scoring of articles were independently performed by two teams, and the results were submitted to statistical analysis to determine medians, ranges, and 95% CIs. RESULTS: A total of 115 articles were included. The median compliance was 15 out of 27 items (56%), the range was 5-26 (26-96%), and the inter-quartile range was 10 (37%). Compliance was highest in items related to the 'description of rationale' (item 3, 100%) and sequentially lower in 'the general interpretation of results' (item 26, 96%) and 'the inclusion of a structured summary in the abstract' (item 2, 90%). Compliance was poorest in the items 'indication of review protocol and registration' (item 5, 9%), 'specification of risk of biases that may affect the cumulative evidence' (item 15, 24%), and 'description of clear objectives in the introduction' (item 4, 26%). CONCLUSION: The reporting quality of systematic reviews and meta-analyses in ophthalmology should be significantly improved. While we recommend the use of the PRISMA criteria as a guideline before journal submission, additional research aimed at identifying potential barriers to compliance may be required to improve compliance with PRISMA guidelines.

Phase I trial and pharmacokinetic study of tanibirumab, a fully human monoclonal antibody to vascular endothelial growth factor receptor 2, in patients with refractory solid tumors.

Background Tanibirumab is a fully human monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a first-in-human phase I study of tanibirumab in patients with solid tumors refractory to standard chemotherapy. Primary endpoints were evaluating safety, pharmacokinetics (PKs), estimating maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Methods We designed our study to escalate tanibirumab at 9 different dose levels with a 3 + 3 method and tanibirumab (1-28 mg/kg) was administered intravenously on D1, 8, 15 in 28-day courses. Dose limiting toxicities (DLTs) were only assessed during the first cycle of treatment and response evaluation was performed every 2 cycles. The effects of tanibirumab on several angiogenic factors were analyzed. Results From October 2011 to September 2013, a total of 26 patients with refractory solid tumors were enrolled. The median age was 58 years (range, 27-75) and 20 patients were male. The most common tumor type was colorectal cancer (N = 19) and seven patients had a history of previous bevacizumab treatment. As hemangioma continued to occur, the final dose level, 28 mg/kg, was not performed. DLTs were not found, and the MTD was confirmed to be 24 mg/kg. Hemangioma was observed in 16 patients (61.5%), but all were grade 1-2 and disappeared after discontinuation of the study drug. Among the 18 patients in the efficacy set, no objective response was observed, but 11 patients showed stable disease. PKs were characterized by dose-dependent linear exposure and the mean trough concentrations exceeded biologically relevant target levels at 12 mg/kg and above. Serum VEGF, soluble VEGFR-2, and PlGF increased at the 4 mg/kg dose level and above. Conclusions Treatment with tanibirumab showed a tolerable toxicity profile and modest clinical efficacy in patients with refractory solid tumors. A phase II trial of tanibirumab is ongoing now.

Identification of sennoside A as a novel inhibitor of the slingshot (SSH) family proteins related to cancer metastasis.

Phospho-cofilin (p-cofilin), which has a phosphate group on Ser-3, is involved in actin polymerization. Its dephosphorylated form promotes filopodia formation and cell migration by enhancing actin depolymerization. Protein phosphatase slingshot homologs (SSHs), known as dual-specificity phosphatases, catalyze hydrolytic removal of the Ser-3 phosphate group from phospho-cofilin. Aberrant SSH activity results in cancer metastasis, implicating SSHs as potential therapeutic targets for cancer metastasis. In this study, we screened 658 natural products purified from traditional oriental medicinal plants to identify three potent SSH inhibitors with submicromolar or single-digit micromolar Ki values: gossypol, hypericin, and sennoside A. The three compounds were purified from cottonseed, Saint John's wort, and rhubarb, respectively. Sennoside A markedly increased cofilin phosphorylation in pancreatic cancer cells, leading to impaired actin dynamics in pancreatic cancer cells with or without EGF stimulation and reduced motility and invasiveness in vitro and in vivo. Collaboratively, these results demonstrate that sennoside A is a novel inhibitor of SSHs and suggest that it may be valuable in the development of pharmaceutical drugs for treating cancer metastasis.