MEK inhibitors cobimetinib and trametinib, regressed a gemcitabine-resistant pancreatic-cancer patient-derived orthotopic xenograft (PDOX).

A pancreatic ductal adenocarcinoma (PDAC), obtained from a patient, was grown orthotopically in the pancreatic tail of nude mice to establish a patient-derived orthotopic (PDOX) model. Seven weeks after implantation, PDOX nude mice were divided into the following groups: untreated control (n = 7); gemcitabine (100 mg/kg, i.p., once a week for 2 weeks, n = 7); cobimetinib (5 mg/kg, p.o., 14 consecutive days, n = 7); trametinib (0.3 mg/kg, p.o., 14 consecutive days, n = 7); trabectedin (0.15 mg/kg, i.v., once a week for 2 weeks, n = 7); temozolomide (25 mg/kg, p.o., 14 consecutive days, n = 7); carfilzomib (2 mg/kg, i.v., twice a week for 2 weeks, n = 7); bortezomib (1 mg/kg, i.v., twice a week for 2 weeks, n = 7); MK-1775 (20 mg/kg, p.o., 14 consecutive days, n = 7); BEZ-235 (45 mg/kg, p.o., 14 consecutive days, n = 7); vorinostat (50 mg/kg, i.p., 14 consecutive days, n = 7). Only the MEK inhibitors, cobimetinib and trametinib, regressed tumor growth, and they were more significantly effective than other therapies (p < 0.0001, respectively), thereby demonstrating the precision of the PDOX models of PDAC and its potential for individualizing pancreatic-cancer therapy

Plasmodium vivax resistance to chloroquine in Dawei, southern Myanmar.

OBJECTIVE: To assess the efficacy of chloroquine in the treatment of Plasmodium vivax malaria in in Dawei District, southern Myanmar. METHODS: Enrolled patients at Sonsinphya clinic >6 months of age were assessed clinically and parasitologically every week for 28 days. To differentiate new infections from recrudescence, we genotyped pre- and post-treatment parasitaemia. Blood chloroquine was measured to confirm resistant strains. RESULTS: Between December 2002 and April 2003, 2661 patients were screened, of whom 252 were included and 235 analysed. Thirty-four per cent (95% CI: 28.1-40.6) of patients had recurrent parasitaemia and were considered treatment failures. 59.4% of these recurrences were with a different parasite strain. Two (0.8%) patients with recurrences on day 14 had chloroquine concentrations above the threshold of 100 ng/ml and were considered infected with chloroquine resistant parasites. 21% of failures occurred during the first 3 weeks of follow-up: early recurrence and median levels of blood chloroquine comparable to those of controls suggested P. vivax resistance. CONCLUSIONS: Plasmodium vivax resistance to chloroquine seems to be emerging in Dawei, near the Thai-Burmese border. While chloroquine remains the first-line drug for P. vivax infections in this area of Myanmar, regular monitoring is needed to detect further development of parasite resistance

Advances in crowd analysis for urban applications through urban event detection

The recent expansion of pervasive computing technology has contributed with novel means to pursue human activities in urban space. The urban dynamics unveiled by these means generate an enormous amount of data. These data are mainly endowed by portable and radio-frequency devices, transportation systems, video surveillance, satellites, unmanned aerial vehicles, and social networking services. This has opened a new avenue of opportunities, to understand and predict urban dynamics in detail, and plan various real-time services and applications in response to that. Over the last decade, certain aspects of the crowd, e.g., mobility, sentimental, size estimation and behavioral, have been analyzed in detail and the outcomes have been reported. This paper mainly conducted an extensive survey on various data sources used for different urban applications, the state-of-the-art on urban data generation techniques and associated processing methods in order to demonstrate their merits and capabilities. Then, available open-access crowd data sets for urban event detection are provided along with relevant application programming interfaces. In addition, an outlook on a support system for urban application is provided which fuses data from all the available pervasive technology sources and finally, some open challenges and promising research directions are outlined

Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14

Pityriasis rubra pilaris (PRP) represents a group of rare chronic inflammatory skin disorders in which ~1 in 20 affected individuals show autosomal dominant inheritance. In such cases, there may be gain-of-function mutations in CARD14, encoding caspase recruitment domain-containing protein 14 (CARD14) that activates the non-canonical nuclear factor-kappa B (NF-κB) pathway, thereby promoting cutaneous inflammation. Here, we report a mother and son with PRP due to a new missense mutation in CARD14 and describe the beneficial clinical effects of ustekinumab, a monoclonal antibody against interleukins-12 and -23, in both subjects. A 49 year-old female and her 20 year-old son had lifelong, generalised, patchy erythematous scale with a few islands of sparing, as well as minor nail ridging and mild palmoplantar keratoderma, features consistent with generalised PRP. Topical steroids, phototherapy and oral retinoids proved ineffective therapies. Following informed consent, Sanger sequencing of CARD14 in both individuals revealed a new heterozygous single nucleotide transversion in exon 16, c.356T>G, resulting in the missense mutation, p.Met119Arg. Ustekinumab, at a dose of 45mg every 12 weeks, brought about a significant physical and emotional improvement in both the mother and son within a few days of the initial dose, which was sustained on maintenance dosing. This report highlights the therapeutic potential of biologics that downregulate NF-kB signalling in familial PRP with mutations in CARD14. This article is protected by copyright. All rights reserved

Fluorescent humanized anti-CEA antibody specifically labels metastatic pancreatic cancer in a patient-derived orthotopic xenograft (PDOX) mouse model.

Pancreatic cancer is a highly lethal disease in part due to incomplete tumor resection. Targeting by tumor-specific antibodies conjugated with a fluorescent label can result in selective labeling of cancer in vivo for surgical navigation. In the present study, we describe a patient-derived orthotopic xenograft model of pancreatic cancer that recapitulated the disease on a gross and microscopic level, along with physiologic clinical manifestations. We additionally show that the use of an anti-CEA antibody conjugated to the near-infrared (NIR) fluorescent dye, IRDye800CW, can selectively highlight the pancreatic cancer and its metastases in this model with a tumor-to-background ratio of 3.5 (SEM 0.9). The present results demonstrate the clinical potential of this labeling technique for fluorescence-guided surgery of pancreatic cancer

Utility of Parental Mediation Model on Youth’s Problematic Online Gaming

The Parental Mediation Model PMM) was initially designed to regulate children’s attitudes towards the traditional media. In the present era, because of prevalent online media there is a need for similar regulative measures. Spending long hours on social media and playing online games increase the risks of exposure to the negative outcomes of online gaming. This paper initially applied the PMM developed by European Kids Online to (i) test the reliability and validity of this model and (ii) identify the effectiveness of this model in controlling problematic online gaming (POG). The data were collected from 592 participants comprising 296 parents and 296 students of four foreign universities, aged 16 to 22 years in Kuala Lumpur (Malaysia). The study found that the modified model of the five-factor PMM (Technical mediation, Monitoring mediation, Restrictive mediation, Active Mediation of Internet Safety, and Active mediation of Internet Use) functions as a predictor for mitigating POG. The findings suggest the existence of a positive relation between ‘monitoring’ and ‘restrictive’ mediation strategies and exposure to POG while Active Mediation of Internet Safety and Active mediation of Internet use were insignificant predictors. Results showed a higher utility of ‘technical’ strategies by the parents led to less POG. The findings of this study do not support the literature suggesting active mediation is more effective for reducing youth’s risky behaviour. Instead, parents need to apply more technical mediations with their children and adolescents’ Internet use to minimize the negative effects of online gaming

Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.

Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing's sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients'outcome. Here we report efficacy of rMETase against Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing's sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing's sarcoma

Artemisinin resistance in Plasmodium falciparum malaria.

BACKGROUND: Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance. METHODS: In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance. RESULTS: We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. CONCLUSIONS: P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.