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Toxic erythema of chemotherapy is an umbrella term for several non-allergic cutaneous reactions to chemotherapeutic agents. Given the heterogenous range of presentations, we will review the differential diagnoses and treatment approaches, particularly for hospitalized patients. Early recognition, holding chemotherapy, or dose reduction and monitoring fluid balance for severely ill patients is the mainstay of treatment. Supportive care with topical steroids, emollients, and wound care have shown benefit. Toxic erythema of chemotherapy can mimic several common eruptions seen in oncologic patients. The recognition of both clinical and pathological features by inpatient dermatologists allows for appropriate management, and dose reduction if necessary, in order for patients to continue oncologic treatment.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Bacillus cereus is a foodborne pathogen and cause a frequent problem due to the biofilms forming in equipment of food production plants. Autoinducer-2 (AI-2) involved in interspecies communication, plays a role in the biofilm formation of B. cereus. In this study, biofilm formation by thirty-nine B. cereus strains isolated from foods produced in Korea was determined. To investigate the effect of AI-2 on biofilm formation by B. cereus SBC27, which had the highest biofilm-forming ability, biofilm densities formed after addition of the AI-2 from Staphylococcus aureus and Escherichia coli were analysed. As a result, it was found that the quorum sensing molecule AI-2 could induce biofilm formation by B. cereus within 24 h, but it may also inhibit biofilm formation when more AI-2 is added after 24 h. Thus, these results improve our understanding of biofilm formation by food-derived B. cereus and provide clues that could help to reduce the impact of biofilms, the biggest problem in food processing environments, which has an impact on public health as well as the economy.

Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However, the correlation between plasma VPA concentrations and CYP2C9 and CYP2A6 gene variations is uncertain. This meta-analysis aimed to investigate the relationship between CYP2C9 and CYP2A6 variants and plasma concentrations of VPA. The PubMed, Web of Science, and EMBASE databases were searched for qualifying studies published until July 2019. Cohort studies that included standardized plasma VPA concentrations and CYP2C9 and CYP2A6 genotypes were reviewed. The mean difference and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. Data analysis was performed using Review Manager (version 5.3) and RStudio (version 3.6). In total, we analyzed data from six studies involving 807 patients. We found that CYP2C9*3 was associated with standardized plasma VPA concentration; *3 allele carriers had a 0.70-μg/mL higher concentration per mg/kg than non-carriers (95% CI 0.25, 1.15; P = 0.002). We also found a significant association between the CYP2A6*4 and standardized trough VPA concentration; patients with the *4 allele had a 0.48-μg/mL higher concentration per mg/kg than patients without the *4 allele (95% CI 0.10, 0.86; P = 0.01). This meta-analysis demonstrated that CYP2C9*3 and CYP2A6*4 genetic variants affect plasma VPA concentrations. For epilepsy patients with these genotypes, dose adjustment may be necessary to ensure VPA’s therapeutic effect.

WHAT IS KNOWN AND OBJECTIVE With increased opioid use, drug-drug interactions (DDIs) and associated adverse events are growing among geriatric patients. However, the clinical significance of potential metabolic DDIs associated with opioid use has not been fully evaluated among geriatric patients. Particularly, cytochrome (CYP) P450 enzymes are important in drug metabolism of oxycodone and a black box warning for oxycodone reveals serious risks associated with drug-oxycodone interactions. This study focused on the use of oxycodone in geriatric patients to evaluate its adverse drug reactions (ADRs) and DDIs associated with CYP P450 enzymes. METHODS A retrospective cohort study using patients treated at Korea Veterans Hospital was performed. Data from male patients aged 65 years and older who received oxycodone were analysed. Binomial variables describing patient-related characteristics, drug-related characteristics and CYP-mediating drugs were constructed. Associations between these variables and the frequency of ADRs were determined. The odds ratio (OR) and adjusted odds ratio (AOR) were calculated from univariable and multivariable analyses, respectively. RESULTS AND DISCUSSION Among 111 patients, 32.4% experienced at least one ADR. The most common ADR was gastrointestinal-related (n = 21), followed by dizziness and drowsiness (n = 8). Use of either CYP2D6 inhibitors or CYP3A4 inhibitors increased the rate of ADRs by 20.4 and 25.4 times, respectively. In the case of patients taking both inhibitors, the adjusted OR was 48.6, and the attributable risk was 97.9%. WHAT IS NEW AND CONCLUSION This study suggests that inappropriate combinations of oxycodone with CYP2D6 inhibitors and/or CYP3A4 inhibitors may warrant treatment modification to avoid ADRs in geriatric patients. Clinicians should monitor any signs of ADRs that may reflect DDIs while a geriatric patient is taking oxycodone.

In this study, the risk factors associated with sodium overcorrection were investigated with an optimal cutoff for baseline serum sodium for use in daily clinical practice. Electronic medical records of patients who received tolvaptan for non-hypovolemic hyponatremia were reviewed. Demographic and clinical data including age, sex, weight, height, comorbidity, cause of hyponatremia, hypertonic saline use, and comedication were collected. Baseline laboratory parameters measured included serum sodium, serum potassium, serum creatinine, blood urea nitrogen, serum tonicity, ALT, AST, and urine osmolality. The primary outcome was the overcorrection of serum sodium, which was defined as an increase in serum sodium by more than 10 mmol/L in 24 h. From a total of 77 patients included in the analysis, 24 (31.2%) showed sodium overcorrection (> 10 mmol/L/24 h); 2 (2.6%) in heart failure cohort, 17 (22.1%) in SIADH cohort, and 5 (6.5%) in unknown cause cohort. More than half of patients (51.9%) were administered hypertonic saline prior to tolvaptan. Hypertension, cancer, diuretics, baseline serum sodium, and SIADH were associated with the risk of overcorrection in the univariable analysis. Significant factors for the overcorrection from multivariable analysis were lower body mass index, presence of cancer (adjusted odds ratio, 10.87; 95% CI, 1.23–96.44), and lower serum sodium at baseline (adjusted odds ratio, 0.76 for every 1 mEq/L increase; 95% CI, 0.61–0.94). The overcorrection of hyponatremia in non-hypovolemic patients treated with tolvaptan was significantly associated with lower body mass index, presence of cancer, and lower serum sodium at baseline. In subgroup analysis using SIADH patients, baseline sodium and cancer were found to be significant factors of overcorrection.

The purpose of this study was to investigate the genetic effects of ADCY9 on ritodrine responses in patients with preterm labor. Five single nucleotide polymorphisms (SNPs) of the ADYC9 gene in 163 patients in preterm labor were genotyped: rs879619, rs2601796, rs2531988, rs2531995, and rs2230739. Additionally, rs598961 of the PDE4B gene and rs1042719 of the ADRB2 gene were included for analysis. Patients with CC genotype of ADCY9 rs879619 had a 2.0-fold (95% confidence interval [CI]: 1.3, 3.2) higher hazard of time to delivery than T allele carriers. Patients with combined genotypes of CC in ADCY9 rs879619, AA in PDE4B rs598961, and GC, CC in ADRB2 rs1042719 showed a greater hazard of time to delivery than patients with other combinations (adjusted hazard ratio [AHR] 3.2, 95% CI: 1.7, 6.3), whereas patients carrying the C allele of ADCY9 rs2531995, G allele of PDE4B rs598961, and GG genotype of ADRB2 rs1042719 had a lower hazard of time to delivery than patients carrying other genotypes (AHR 0.4, 95% CI: 0.2, 0.7). Regarding ritodrine-induced adverse drug events (ADEs), height less than 160 cm and CC genotype of ADCY9 rs2531995 showed a greater risk of ADEs. The results of our study suggest that ADCY9 polymorphisms could affect the efficacy and safety of β2-adrenergic agonists.

Personalised medicine is a new and developing field that carries a great potential for future healthcare applications, for prediction, diagnostic and treatment. Personalised medicine allows targeted treatment of different subgroups of patients, making it possible to tailor the treatment to the best-responding patients, while avoiding non-responders or patients that are likely to suffer adverse effects. Data is crucial in the research for personalised medicine as the interesting potential for the clinical use of personalised medicine may become hampered by absence of reliable large data sets. Conclusive evidence on relevant information of molecular mechanisms is not readily available, as most data often comes from inconclusive and relatively small studies of insufficient quality. Once collected, it is claimed that biomedical data becomes often fragmented, as there are numerous IP claims including both patents and trade secret, as well as the reluctance among the researchers in sharing data. Fragmentation in biomedical data is further exasperated by complex legal, moral and ethical questions surrounding biomedical data. While the need to share personal and private genetic information to advance research and industrial development is acknowledged, there are fundamental moral and ethical questions stemming from the general discomfort against exclusive control of an individual rights’ holder over genetic information. As rights overlap, restriction in one right affects access in other right in personalised medicine. Arguably, the recent move by the US courts to strictly regulate the patentability of diagnostic tools in biomedicine to address the problem of the individual rights holder pushed the shift in protection as trade secrets. Moral and ethical questions become even more controversial where machine learning algorithm (AI artificial intelligence) is used in the personalised medicine. AIs and machine learning algorithms are used to discover genes and variants related to specific decisions, to handle next generation sequencing so that they can be analysed in the full context of other genomics and clinical information to drive personalised medicine research. Not only the data sets, the selection of the correct machine algorithms is crucial in their use in personalised medicines. When AIs routinely processes private medical data, to make sure such algorithm based decision making is morally unbiased and ethically correct, the disclosure of the algorithm may be necessary. However, restricting patenting of algorithms for fear of depriving basic research tools from the public, simultaneously creates incentive to protect these algorithms as trade secret. This chapter explores this conundrum of patent and trade secret trade off in the context of AIs used in personalised medicine. Among others, the chapter discusses how these questions are addressed in the current EU law at the interface of GDPR, trade secret directive and biotechnology Directive. The combination of development in the technological sectors – use of AIs in biomedicines and legal changes – restrictive patent eligibility, genetic privacy and expansive trade secret protection could lead to an under-use of valuable biomedical data, which may result in a new type of tragedy of anti-commons. The paper concludes by revisiting the function of patent right and suggests that it may be necessary to introduce additional regulatory measures to mandate ethical disclosure of algorithm for public policy.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus and cutaneous dry skin. Here, we investigated whether topical application of NI-01 composed of six herbal medicines has a therapeutic effect on AD in vivo. Twelve marker compounds of NI-01 were analyzed by high-performance liquid chromatography with a photodiode array detector for quality control. To induce AD, house dust mite extract was applied to the shaved dorsal skin and ear surfaces of NC/Nga mice twice a week for 6 weeks. NI-01 (1, 2, or 4 mg/mouse) was applied daily to the site for experiment periods. The coefficient of determination of each compound showed good linearity (&ge, 0.9999). The recovery rate of the 12 marker components was 96.77%&ndash, 105.17%, intra and interday precision and repeatability were &le, 1.40%. Topical application of NI-01 reduced house dust mite induced AD symptoms. The increased expressions of interleukin-4 and intercellular adhesion molecule-1 caused by house dust mites were markedly suppressed in NI-01-treated mice. Corticosterone levels significantly decreased, whereas serotonin levels increased with NI-01 application. These results suggest that NI-01 alleviates AD symptoms by inhibiting infiltration of inflammatory cells, thereby decreasing AD-related stress. NI-01 could be beneficial for the treatment of AD-like skin diseases.

N-acetyltransferase 2 (NAT2) acetylator status can be classified into three groups depending on the number of rapid alleles (e.g., NAT2*4): rapid, intermediate, and slow acetylators. Such acetylator status may influence the occurrence of adverse drug reactions (ADRs) during sulfasalazine treatment. This systematic review and meta-analysis aimed to evaluate the association between NAT2 acetylator status and ADRs of sulfasalazine. We searched for qualified studies in PubMed, Web of Science, Embase, and the Cochrane Library. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between NAT2 acetylator status and ADRs of sulfasalazine. Nine cohort studies involving 1,077 patients were included in the meta-analysis. NAT2 slow acetylators were associated with an increase in overall ADRs (OR 3.37, 95% CI: 1.43 to 7.93; p = 0.005), discontinuation due to overall ADRs (OR 2.89, 95% CI: 1.72 to 4.86; p p NAT2 slow acetylators are at risk of ADRs during sulfasalazine treatment. Based on our findings, NAT2 genotyping may be useful to predict the occurrence of ADRs during sulfasalazine treatment.

Although many earlier studies revealed an effect of glutathione-S-transferase (GST) gene polymorphisms on tyrosine kinase inhibitor (TKI) treatment responses in chronic myeloid leukemia (CML) patients, the significance of this relationship remains controversial. This study aimed to review and meta-analyze treatment responses to TKIs in patients with CML and GST gene polymorphisms, including GSTT1, GSTM1, and GSTP1. We searched four medical databases, PubMed, Web of Science, the Cochrane Library, and Embase, by using keywords related to GST gene polymorphisms and clinical responses in CML patients receiving TKI treatment. The meta-analysis was performed using RevMan version 5.3 and Comprehensive Meta-Analysis software version 3.0. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine the association between GSTT1, GSTM1, and GSTP1 polymorphisms and TKI treatment responses in patients with CML. The null polymorphisms of GSTT1 and GSTM1 did not affect TKI treatment responses, while the GSTP1 Ile105Val polymorphism had a significant impact on responses to TKI. Patients who were GSTP1 variant allele carriers (AG + GG) had poor responses to TKI treatment compared to patients who were wild-type homozygote carriers (AA) (OR 1.85, 95% CI 1.31–2.62; p

Aim We performed a systematic review and meta-analysis to compare the efficacy and safety of ticagrelor and prasugrel with those of clopidogrel in CYP2C19 reduced-metabolizers. Methods PubMed, Cochrane and Web of Science were systematically searched for randomized controlled trials or cohort studies up to January 2020. The primary endpoint was major adverse cardiovascular events (MACE), including cardiovascular (CV) death, all-cause death, myocardial infarction (MI), stent thrombosis and stroke. The secondary endpoint was bleeding. Pooled effects were measured by relative risk (RR) with 95% confidence intervals (CIs). Publication bias was evaluated with Egger's regression test and adjusted by trim and fill method. Results Twelve studies comprising 5829 CV patients with CYP2C19 loss-of-function alleles were included. Patients who received ticagrelor or prasugrel showed a lower risk of MACE than those who received clopidogrel (RR 0.524; 95% CI: 0.375, 0.731). The former also had lower risks of CV death (RR 0.409; 95% CI: 0.177, 0.946), all-cause death (RR 0.441; 95% CI: 0.263, 0.739), MI (RR 0.554; 95% CI: 0.414, 0.741) and stent thrombosis (RR 0.587; 95% CI: 0.348, 0.988) than the latter patient group. The risk of stroke was not significantly different between patients receiving the alternatives and those receiving clopidogrel (RR 0.605; 95% CI: 0.257, 1.425). Major and minor bleeding risk was not significantly different between patients treated with alternatives and clopidogrel (RR 1.019; 95% CI: 0.827, 1.260 and RR 1.235; 95% CI: 0.581, 2.628, respectively). Conclusion CYP2C19 reduced-metabolizers can expect better clinical outcome on using prasugrel or ticagrelor rather than clopidogrel.

This systematic review and meta-analysis aimed to evaluate the impact of COVID-19 on pregnant women. We searched for qualified studies in PubMed, Embase, and Web of Science. The clinical characteristics of pregnant women with COVID-19 and their infants were reported as means and proportions with 95% confidence interval (CI). Nine studies involving with 93 pregnant women with COVID-19 and 103 infants were included in the meta-analysis. Pregnant women with COVID-19 have relatively mild symptoms. However, abnormal proportions of laboratory parameters were similar or even increased, compared to general population. Around 30% of pregnant women with COVID-19 experienced preterm delivery, whereas the mean birth weight was 3214.7g. Fetal death, severe neonatal asphyxia, and detection of SARS-CoV-2 were observed in about 2%, whereas no neonatal death was found. In conclusion, the current review will serve as an ideal basis for future considerations in the treatment and management of COVID-19 in pregnant women.

Age is a well‐known influential factor in bone healing, with younger patients generally healing bone fractures more rapidly and suffering fewer complications compared with older patients. Yet the impact age has on the response to current bone healing treatments, such as delivery of bone morphogenetic protein 2 (BMP‐2), remains poorly characterized. It remains unclear how or if therapeutic dosing of BMP‐2 should be modified to account for age‐related differences in order to minimize potential adverse effects and consequently improve patient bone‐healing outcomes. For this study, we sought to address this issue by using a preclinical critically sized segmental bone defect model in rats to investigate age‐related differences in bone repair after delivery of BMP‐2 in a collagen sponge, the current clinical standard. Femoral defects were created in young (7‐week‐old) and adult (8‐month‐old) rats, and healing was assessed using gene expression analyses, longitudinal radiography, ex vivo micro‐computed tomography (µCT), as well as torsional testing. We found that young rats demonstrated elevated expression of genes related to osteogenesis, chondrogenesis, and matrix remodeling at the early 1‐week time point compared with adult rats. These early gene expression differences may have impacted long‐term healing as the regenerated bones of young rats exhibited higher bone mineral densities compared with those of adult rats after 12 weeks. Furthermore, the young rats demonstrated significantly more bone formation and increased mechanical strength when BMP‐2 dose was increased from 1 µg to 10 µg, a finding not observed in adult rats. Overall, these results indicate there are age‐related differences in BMP‐2‐mediated bone regeneration, including relative dose sensitivity, suggesting that age is an important consideration when implementing a BMP‐2 treatment strategy. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

The objectives of the study were to determine the diversity of organic acid resistance as well as the toxin gene profiles of Bacillus cereus isolated from red pepper powder and to analyze the inhibition kinetics of unstressed type culture and resistant food isolates against organic acids. Among 68 B. cereus isolated from red pepper and processing environmental samples (n = 180), 1.4–16.7% of the cells could survive at 0.5% of acetic, malic and tartaric acid. Parameter α of the Weibull model for type strain were up to threefold lower than for resistant food isolate at 0.2% or lower concentration of organic acid treatment. All the B. cereus isolates were positive for three genes in the nonhemolytic enterotoxin complex (nheA, nheB and nheC), entFM and bceT genes. The ces gene-encoding emetic toxin was detected in nine (13.2%) of the 68 isolates tested. Practical Applications Bacillus cereus is an etiological agent of foodborne illness in Korea. The food products under risk for B. cereus food poisoning are pasteurized (dairy foods or cooked chilled foods) and dry foods. When B. cereus has been exposed to sublethal acid treatment conditions, adapted or resistant strains have developed. Acid resistance of the strain cause a food safety problem because it may result in enhanced protection for cells which are subsequently exposed to lethal heat or hydrogen peroxide stress. The rate of acid resistance and the kinetic parameters of wild type food isolates against organic acid treatment can be used to develop intervention strategies and in risk assessment to assure food safety. A diversity of toxin gene profiles which include diarrheal and emetic toxins also provide useful information in risk assessment of food poisoning caused by B. cereus.

Sixty six corn samples freshly harvested in Korea were analyzed for the occurrence of aflatoxin and aflatoxigenic Aspergillus using chromatographic and multiplex polymerase chain reaction (PCR) methods. Aflatoxin and aflatoxigenic Aspergillus were detected in 13.6% (0.02 to 0.48 μg kg−1) and 3.0% of the corn samples, respectively. Aflatoxigenic Aspergillus isolates and A. flavus KCCM60330 showed high similarity (98–98.8%). These results suggest that occurrence of aflatoxin and aflatoxigenic Aspergillus in corn harvested from Korea is low.

Yongdamsagan-tang, a traditional herbal formula, is used widely for the treatment of inflammation and viral diseases. In this study, we investigated whether Yongdamsagan-tang water extract (YSTE) affects testosterone propionate- (TP-) induced benign prostatic hyperplasia (BPH) in a rat model. To induce BPH, rats were injected subcutaneously with 10 mg/kg of TP every day. YSTE was administrated daily by oral gavage at doses of 200 and 500 mg/kg along with the TP injection. After 4 weeks, prostates were collected, weighed, and analyzed. The relative prostrate weight was significantly lower in both YSTE groups (200 and 500 mg/kg/day) compared with the TP-induced BPH group. YSTE administration reduced the expression of proliferation markers PCNA, cyclin D1, and Ki-67 and the histological abnormalities observed in the prostate in TP-induced BPH rats. YSTE attenuated the increase in the TP-induced androgen concentration in the prostate. The YSTE groups also showed decreased lipid peroxidation and increased glutathione reductase activity in the prostate. These findings suggest that YSTE effectively prevented the development of TP-induced BPH in rats through antiproliferative and antioxidative activities and might be useful in the clinical treatment of BPH.

Contemporary patent laws based on the norms of the WTO-TRIPS Agreement seem to be driven toward technological neutrality and universal applicability. In most countries, a technologically neutral standard of patentability applies in a non-discriminating manner, regardless of the field of technology, and regardless of the identity of the inventor and the place of the invention. Neutrality in the substantive aspects of patent laws, among others, now extends to the subject matter neutrality—that the availability of patent protection is not tied to the technological field and neutrality in the enjoyment of the right. In contrast to this neutral outlook of contemporary patent law, subjective policy aspects of patent law have long been part of patent law making. For society, the need for an economic and innovation policy not to subject to a certain field of industry to patenting still exists. As a matter of practice, the need to differentiate various technological fields so as to determine exact parameters for substantive patent examination continues to exist. New emerging technologies such as cloud computing and 3D printing are good examples.

PurposeNew business models, such as life‐cycle contracting, challenge the narrow and static understanding of contracts with hard and precise terms. The aim of this paper is to examine how flexibility could be incorporated into contracting processes.Design/methodology/approachThe data of the paper have been gathered applying the triangular method; first, by interviewing key personnel participating in contracting at eight Finnish firms; second, examining contract and other documents of those companies; and third, studying earlier research on contracting practices. Theoretically, the paper is based on relational contract and proactive approaches to law on the one hand and on organizational studies based on new institutional economics on the other.FindingsFlexibility is often introduced to contracts with relational methods, relying on good personal relationships between business partners or negotiation power and negotiation skills. Contract documents often do not contain mechanisms for dealing with contingencies, or “soft” contract terms. The paper finds the following reasons that may explain this. First, firms heavily rely on model contracts to develop their own templates and the lack of contract models in new business areas hinders firms to develop their templates. Second, unfamiliarity with using soft elements makes it difficult to use them. Additionally, in some cases firms may prefer using relational capability.Research limitations/implicationsThe findings need verification from further multidisciplinary empirical research.Practical implicationsThe findings support firms in developing their contracting capabilities to meet the requirements of the changing business environment and gain competitive advantage from well‐organized contracting.Originality/valueThis paper is one of the first empirical studies comprising also the legal approach.

The purpose of the paper is to empirically study firms' practises of knowledge and intellectual property (IP) management in customer–supplier relationships. The work applies the qualitative methodology of multiple case studies, and the material was collected in semi-structured interviews with management personnel at 36 organisations in Finland and in the Netherlands. Almost every firm had innovation relationships with their customers and suppliers, but the forms these relationships took, and the kinds of practices they involved, varied greatly. As a result, the firms considered the management of knowledge and IP in these relationships very challenging. We argue that by distinguishing knowledge management in the exploration phase of new business from knowledge management in the exploitation phase of innovation outcome, the firms could manage the knowledge and IP better. Accordingly, the paper introduces three propositions to support the knowledge and IP management in customer–supplier relationships.

As the paradigm of innovation becomes more user oriented and collaborative, to benefit from this changing paradigm, firms need to adjust their intellectual property rights management strategy and devise tools to manage openness. Crucially, firms need to resolve is how to interface the “closed innovation” paradigm required to acquire intellectual property rights in law and to introduce openness in the process of innovation and decentralised innovation process. While the topic of open innovation has produced numerous works especially in the area of business administration and organizational studies, literature on interfacing open innovation with intellectual property law is rare or rather focused on specific subject matters of IP. For example, legal research on open innovation focus on computer, open source software or user generated contents types. This leaves out vast areas of technology uncovered and under researched. Based on literature review and qualitative case studies on a group of Finnish firms, this paper aims to identify tools that are required to manage openness, in response to legal context, and examine to what degree the protection of intellectual property, in particular patent, can be adapted or interfaced with open innovation paradigm. The paper finds that (1) open innovation is dynamic, (2) all commercial open innovation is always managed or controlled, and that (3) actors and modalities of exchanges are heterogeneous and dynamic. Multiple claim holders – as contributors, investors, co-inventors, collaborator call for a governance structure over how their claims can be prioritised. This paper argues that intellectual property law do regulate the question of co-inventor, co-creator, and co-owner but do not regulate how these rights may be coordinated or managed, in what hierarchy. Thus, we argue that to prevent disputes, proactive private ordering is necessary. Furthermore, while open innovation benefits from open exchange in communication, in the absence of clear and certain rules on how such exchange lead to loss of right, “open” communication may not occur. In other words, unless openness is managed implicitly or explicitly, communications that are crucial in open innovation will not occur. Thus we find that openness in innovation is always managed either formally (through formal governance means i.e. contract, explicit firm policy) or informally (through community norms, trust and implicit corporate culture).The paper argues that governance means are best provided by the firms either as a contracts, or general policy over information exchanges, in other words a broader form of contract (Private ordering). As a secondary option, a certain proposals to the patent law revision can also be made through introduction of limitation and exception to the right. This paper has two practical implications. First, in the absence of proper legal safeguard for own collaborative input, the paper advocates contract based governance approach. Reflecting this, open and collaborative innovation requires firms to more actively and strategically involve in the governance of intellectual property. Secondly, as a proposal for patent law reform, the paper may enlighten law and policy makers to explores for a creation of particular defence against the claims of infringement in patent law.

Complex questions seem to arise as validly granted computer program and Internet related patents are used and enforced. Enforcement of computer program and Internet patents raises several interesting points that shed lights on how the doctrines surrounding patent infringement is structured. As computer programs are highly accumulative, and incremental, even when used in a non-Internet context, computer program patents increases possibility of partial or incomplete infringement. In today's globalized economy, modular production of computer program products often involve cross border production, utilizing lower production costs. On the other hand, the concept of patent right, based on national patent law, is based on the idea that the effect of right is territorial, and its infringement often by a singular and complete action. In this context, this paper discusses how the computer program patent challenges this model of single infringer, within one territory with one complete action of infringement. In the context of globalised economy, this paper comparatively reviews some of the theories of infringements in the patent laws of Japan, the US and in Europe, that aim to bridge the patchwork patent infringement doctrines to regulate these fragmented activities.

Unlike X-ray systems, a terahertz imaging system can distinguish low-density materials in a food matrix. For applying this technique to food inspection, imaging resolution and acquisition speed ought to be simultaneously enhanced. Therefore, we have developed the first continuous-wave sub-terahertz transmission imaging system with a polygonal mirror. Using an f-theta lens and a polygonal mirror, beam scanning is performed over a range of 150 mm. For obtaining transmission images, the line-beam is incorporated with sample translation. The imaging system demonstrates that a pattern with 2.83 mm line-width at 210 GHz can be identified with a scanning speed of 80 mm/s. (C) 2015 Optical Society of America

Objective: Xanthii fructus (Compositae) is a traditional herbal medicine used for treating headache, toothache, pruritus, empyema, and rhinitis. In this study of the quality control of X. fructus, we performed simultaneous analysis of nine marker compounds: Protocatechuic acid (1), chlorogenic acid (2), caffeic acid (3), 4,5-dicaffeoylquinic acid (4), ferulic acid (5), 3,5-dicaffeoylquinic acid (6), 1,3-dicaffeoylquinic acid (7), 1,4-dicaffeoylquinic acid (8), and 4,5-dicaffeoylquinic acid (9). Materials and Methods: Nine components were separated using reversed-phase SunFire™ C18 analytical column and analyzed using high-performance liquid chromatography. We examined the biological effects of the nine marker compounds by determining their anti-inflammatory activities in the murine macrophage cell line RAW 264.7. Results: Among the nine marker compounds, eight significantly inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-α) production. 1, 3, 5 had significant inhibitory effects on LPS-induced prostaglandin E2 (PGE2) production in RAW 264.7 cells. None of the tested marker compounds had a significant effect on interleukin-6 production in LPS-treated RAW 264.7 cells. Our data demonstrated that each marker compound from X. fructus exerts anti-inflammatory activity by targeting different inflammation-related pathways such as the TNF-α or PGE2 pathway. Conclusion: Further experiments using in vitro and in vivo models are needed to identify the mechanisms responsible for the anti-inflammatory properties of each marker compound. SUMMARY Simultaneous analysis of nine phenylpropanoids in the Xanthii fructus was established using HPLC-PDA system.1,4-dicaffeoylquinic acid significantly inhibited LPS-stimulated TNF-a production.Protocatechuic acid, caffeic acid and ferulic acid had significant inhibitory effects on LPS-induced PGE2 production in RAW 264.7 cells.

Technical standards that facilitate interoperability are believed to be crucial in the growth and development of the network and computer industry. In a modular and globalized economy, it is believed that the development of compatibility standards benefit from being widely accessible. On the other hand, as intellectual property is based on the idea of exclusion and creates incentives for the right holder to arbitrarily discriminate the access to the protected information, it seems to be inherently incompatible with the efficient development of public, non-discriminatory and well-understood compatibility standards. Literature studying standardization invariably discuss this problem from various angles. However the relationship of standardization and intellectual property from the point of law has only been started to be of concern, as some of the more onerous business practices, such as hold-up or industry standard capture problem began to surface, in a anticipatory standardization. Most of these comments focus on the strategic use and abuse of intellectual property prior to, during and after the setting of the standards, either by an organisation or by a dominant firm, suggesting solutions mainly from contractual, or antitrust or competition law perspective. This paper argues that intellectual property law based solution should accompany these, with the example of patent law, and attempts to identify the aspects of patent law where the solutions to these problems could be based on. This is because often patent law includes specific tools of regulating uses beyond the grants of patents. As the problems are caused by some of expansionary shifts in the doctrines within patent law discipline, it is possible to devise the solution within the discipline of patent law. In sum, standards and standardization should be a concern for patent law.

Background: Rat mast cells were regarded as a good model for mast cell function in immune response. Methods: Rat bone marrow mast cells (BMMC) were prepared both by recombinant rat IL-3 (rrIL-3) and by recombinant mouse stem cell factor (rmSCF), and investigated for both proliferation and differentiation in time course. Rat BMMC was induced by culture of rat bone marrow cells (BMCs) in the presence of both rrIL-3 (5 ng/ml) and rmSCF (5 ng/ml). Culture media were changed 2 times per week with the cell number condition of 5×10 4 /ml in 6 well plate. Proliferation was analyzed by cell number and cell counting kit-8 (CCK-8) and differentiation was by rat mast cell protease (RMCP) II and histamine. Results: Cell proliferation rates reached a maximum at 8 or 11 days of culture and decreased thereafter. However, both RMCP II production and histamine synthesis peaked after 11 days of culture. By real time RT-PCR, the level of histidine decarboxylase mRNA was more than 500 times higher on culture day 11 than on culture day 5. By transmission electron microscopy, the cells were heterogeneous in size and contained cytoplasmic granules. Using gated flow cytometry, we showed that cultured BMCs expressed high levels of FceRI and the mast cell antigen, ganglioside, on culture day 11. Conclusion: These results indicate that rat BMMCs were generated by culturing BMCs in the presence of rrIL-3 and rmSCF and that the BMMCs have the characteristics of mucosal mast cells.

Intellectual property law has been criticised for over-arching scope of protection and at the same time, for insufficient protection. This seeming contradiction may stem from the discrepancies between the actual innovation practice and process and the models adopted in law. This paper illustrates this contradiction in the patent laws' treatment of collaborative innovators. Particularly, this study examines how the participation of multiple innovators at the initial stage of the innovation is regulated under the patent laws in the US, Japan and, to an extent, in Europe. A single entity perspective and a concurrent closed invention model implied in law create legal uncertainties for collaborative innovators. This brings forward the organisational capability that provides inter- and intra-firm governance structure over the innovative process and the uses of innovation in managing the uncertainties before, during and after collaboration. This capability is in a central role in addressing the seeming contradiction.

Purpose: Patients with multiple myelma (MM) are at increased risk for developing thromboembolism (TE) compared with the general population. Introduction of thalidomide into the treatment of MM has resulted in the surprising increase of TE. We planned to identify incidence of TE and risk factors for the development of TE in Korean MM patients. Patients and Methods: Retrospective medical records review of Korean MM registry from 25 centers in Korea between 1997 and 2007 was performed. We assessed the incidence of arterial and venous TE in MM patients during thalidomide treatment. Potential risk factors for TE included disease status at thalidomide administration, concomitant use of other chemotherapeutic agents or steroid, past medical history and TE prophylaxis. Kaplan-Meier method for time variable from the first date of thalidomide to development of TE was used. Results: A total number of 360 MM patients (median age 61, range 32–88) received thalidomide. 23, 62 and 265 patients had stage ±, II, and III disease according to Durie-Salmon Staging respectively at the diagnosis, which was equivalent to 79, 146 and 112 patients for stage ±, II and III by International Staging System. 156 patients received thalidomide as frontline therapy, while 153 and 48 patients received thalidomide for progressive disease and relapsed disease respectively. 243, 139, 172 and 60 patients experienced treatment with steroid, alkylating agents, anthracyclin and bortezomib prior to thalidomide respectively. 9 patients had previous history of TE before thalidomide administration. 135 patients received aspirin as prophylaxis for TE while 3 and 2 patients received warfarin and low molecular weight heparin as prophylaxis. Median follow up duration was 29.2 months and median duration of thalidomide use was 8.13 months. During thalidomide treatment, 249 (69%) patients stopped thalidomide due to unsatisfactory effect or intolerable toxicity. 14 patients (3.9%) developed TE, where 12 with the venous TE and 2 with the arterial TE. There was no TE-related mortality. Site of the venous TE included lung (7 patients), lower extremity (4 patients), upper extremity (1 patient) and neck (1 patient). One patient had pulmonary and lower extremity TE at the same time. Arterial embolism developed in the cerebral and peripheral artery respectively. No single clinical parameter such as MM status, past medical history and treatment regimen was predictive marker for development of TE. Incidence of TE in patients who received thalidomide as a frontline therapy (7/156) was not different from that in patients who received thalidomide for progressive or relapsed disease (7/201, p=0.296). Prophylactic treatment for TE did not influence the development of TE (p=0.942). Conclusion: Incidence of TE during thalidomide treatment in Korean MM patients was low. No single clinical parameter was proven as a risk factor for TE. The prophylactic anticoagulation in Korean MM patients who will be treated with thalidomide is not necessary.