A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575)

PURPOSE: To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. METHODS: Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. Gemcitabine was administered at 1,000 mg/m(2) on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). RESULTS: A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). CONCLUSIONS: RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0-24 h (AUC(0-24)) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified

Current views on the role of Notch signaling and the pathogenesis of human leukemia

The Notch signaling pathway is highly conserved from Drosophila to humans and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis

Health crisis and the EU’s HERA:amplifying partial organizing with resourcing for stability, agility, and evolvability

What design recommendations can be made for European Union (EU) organizing its health crisis preparedness and emergency response? The EU has recently established the Health Emergency Response and Health Authority (HERA) for coping with crises. However, as an international organization that lacks a legal means of extending its mandate over EU member states, HERA can potentially fail in its mission. To help prevent this potential failure, we make design recommendations that draw on resourcing theory to complement the limited—or partial—organizing capabilities of HERA. The design recommendations are tailored to three schemas that the analysis of the stakeholder feedback suggests: stability, agility, and evolvability. We outline HERA’s current actions and deliverables as mandated in its founding and suggest additional examples of ways to amplify crisis preparedness and emergency response. These recommendations stem from the proposed resourcing perspective within the constraints of an international, partial organization. We conclude with implications for future research and practice, focusing on how stability, agility and evolvability can amplify the HERA’s ability to meet its expectations.</p

Detection of the presence of gram-negative bacteria in salmon sashimi dishes served in local Japanese restaurants in the Mall of Asia, Pasay City, Philippines

The number of Japanese restaurants in the world increased exponentially from the year 2006 to 2017. As a result, sashimi, a raw Japanese delicacy, is made more accessible to a higher number of people. Since sashimi does not undergo the process of cooking, bacterial infections for the consumers are at a high level especially for those who may eat sashimi regularly. This study aimed to determine the presence of Gram-negative bacteria in salmon sashimi dishes served in five local Japanese restaurants in the Mall of Asia located in Pasay City, Philippines. Moreover, if Gram-negative bacteria are present, vaguely describe the amount of gram-negative bacteria through the specific metrics namely: thin, average, and thick. The results of this research were yielded through experimentation within the ‘laboratory of Angelo King building in De La Salle Medical and Health Sciences Institute. Seven replicates for each of the salmon sashimi samples were created. Laboratory examinations performed included autoclaving, weighing, homogenization, streaking, and incubation. Results gathered showed presence of Gram-negative bacteria in all replicates for all of the salmon sashimi samples. Moreover, three of the five samples expressed few Gram-negative bacterial growth while the remaining two samples expressed average to many. Following the data results, the researchers concluded that Gram-negative bacteria is present in all five salmon sashimi samples. However, samples from two restaurants were detected to have a higher concentration of Gram-negative bacteria