Fully-automated production of [68Ga]Ga-PentixaFor on the module Modular Lab-PharmTracer

BACKGROUND: PentixaFor is a promising radiopharmaceutical for positron emission tomography in the detection of different tumor entities and other diseases. Until now, the synthesis of [68Ga]Ga-PentixaFor was reported for the automated synthesis module from Scintomics® only. Our aim was to evaluate the automated synthesis of this radiopharmaceutical on a different module in order to make it available for a broader community. RESULTS: The synthesis of [68Ga]Ga-PentixaFor with different amounts of PentixaFor (50 μg, 30 μg and 20 μg) on the Modular Lab PharmTracer (MLPT) from Eckert & Ziegler with the already established synthesis template for [68Ga]Ga-DOTATOC yielded best results with 50 μg PentixaFor for clinical multi-dose application. All different quality control parameters tested (e.g. sterility, stability and radiochemical purity) were in accordance with the European Pharmacopoeia. CONCLUSIONS: [68Ga]Ga-PentixaFor was successfully synthesized fully-automated on the synthesis module Modular Lab PharmTracer and can be used for multi-dose application in clinical settings

Mitoparans: mitochondriotoxic cell penetrating peptides and novel inducers of apoptosis.

Acknowledgments The authors would like to thank Keith Holding at the University of Wolverhampton for his outstanding technical support. This work was supported in part by Samantha Dickson Brain Tumour Trust.Introduction: The amphipathic helical peptide mastoparan (MP; H-INLKALAALAKKIL-NH2) inserts into biological membranes to modulate the activity of heterotrimeric G proteins and other targets. Moreover, whilst cell free models of apoptosis demonstrate MP to facilitate mitochondrial permeability transition and release of apoptogenic cytochrome c, MP-induced death of intact cells has been attributed to its non-specific membrane destabilising properties (necrotic mechanisms). However, MP and related peptides are known to activate other signalling systems, including p42/p44 MAP kinases and could therefore, also modulate cell fate and specific apoptotic events. The ability of MP to facilitate mitochondrial permeability in cell free systems has lead to proposals that MP could be of utility in tumour therapeutics provided that it conferred features of cellular penetration and mitochondrial localization. We have recently reported that our highly potent amphipathic MP analogue mitoparan (mitP; [Lys5,8Aib10]MP; Aib = -aminoisobutyric acid) specifically promotes apoptosis of human cancer cells, as was confirmed by in situ TUNEL staining and activation of caspase-3. Moreover, we have also demonstrated that mitP penetrates plasma membranes and redistributes to co-localize with mitochondria. Complementary studies, using isolated mitochondria, further demonstrated that mitP, through co-operation with a protein of the permeability transition pore complex voltage-dependent anion channel (VDAC), induced swelling and permeabilization of mitochondria, leading to the release of the apoptogenic factor cytochrome c. An expanding field of peptide and cell penetrating peptide (CPP) research has focussed on the selective targeting of tumours by engineering constructs that incorporate cell-specific or tissue–specific address motifs. Peptidyl address motifs could enhance the selectivity of drug delivery whilst the improved cellular uptake offered by CPP enhances bioavailability. Thus and as a potential therapeutic strategy, we extended our findings to design target-specific mitP analogues. The integrin-specific address motif RGD and a Fas ligand mimetic WEWT were incorporated by N-terminal acylation of mitP to produce novel tandem-linked chimeric peptides

College Readiness Initiative: AVID and Navigation 101

The purpose of this report is to provide summative feedback to personnel at the Office of Superintendent of Public Instruction (OSPI) and at the College Spark Washington regarding evidence of implementation and impact of the Advancement via Individual Determination (AVID) and Navigation 101 programs in schools funded by the College Readiness Initiative (CRI) in Washington State. The report, while addressing the effects of both programs, is also designed to provide formative feedback to assist in ongoing program development

Principals\u27 Perceptions about Alternate Route Programs in Rural Areas

Alternate route programs are increasingly serving schools in rural areas that may struggle to recruit new teachers. In this study, ten principals of middle schools from rural areas of Mississippi were interviewed regarding their perceptions of alternate route programs’ recruitment, selection, preparation, mentorship, support, and retention practices. Qualitative analysis of semi-structured interviews suggests that principals of rural schools had limited experience with alternatively certified teachers and, overall, their views were generally positive. They believed that these programs would help meet the high need for teachers in the state, and alternate route candidates may provide benefits to middle school students due to their greater content knowledge, experience, and maturity. However, they also held concerns regarding the absence of student teaching, alternatively certified teachers’ readiness for the classroom, and the amount and quality of support and mentoring in the first year of teaching

In Vitro Release of Interferon-Gamma from Peripheral Blood Lymphocytes in Cutaneous Adverse Drug Reactions

Background. Cutaneous drug reactions are common but diagnostically challenging due to phenotypic heterogeneity and simultaneous exposure to multiple drugs. These limitations prompted the development of diagnostic tests. Aims. To evaluate the performance of an in vitro assay measuring interferon-gamma release from patients' lymphocytes in the presence of causative drugs for the diagnosis of drug reactions. Methods. Mononuclear cells derived from patients were incubated with and without suspected drugs, and increment of interferon-gamma levels was measured by ELISA. We performed a telephonic survey to evaluate the effect of stopping the drugs incriminated by the assay on cutaneous manifestations. Results. We assessed 272 patients who used 1035 medications. When assessed against the questionnaire data collected at least 6 months after stopping the causative drug, sensitivity was found to be 83.61% and specificity 92.67%. Likelihood ratio for a positive test is 11.40 and for a negative test 0.18. Positive predictive value is 75.37% and negative predictive value is 95.47%. The test was found to perform significantly better in females and in older patients. Conclusions. Interferon-gamma release test is a useful adjunct tool in the diagnosis of cutaneous drug reactions

Digital Feedback for Digital Work? Affordances and Constraints of a Feedback App at InsurCorp

Little is known about how digital work shapes the exchange of performance feedback, even though today’s digital and global world demands for more continuous feedback than annual reviews. This research investigates a feedback app in a naturalistic context within a globally leading financial service corporation (InsurCorp). Drawing on malleability and voluntary participation, the app offers possibilities to send and request feedback between employees. Rich contextual insights from a multinational pilot study with 568 users are gained by triangulating qualitative data from 21 semi-structured interviews and69 feedback app user reviews with usage data. Anchored in the theory of affordances, we provide insights on use practices and find that the app affords operational-level feedback exchange on specific subjects, while general feedback on sensitive topics is preferably exchanged in person. To understand actualization facilitators and barriers, we take a social-technical systems perspective to elaborate contextual factors that influence the individual’s actualization decision

Myanmar’s Top-Down Transition: Challenges for Civil Society

This article historicises the nature of political transition in Myanmar to better appreciate the challenges faced by civil society. After Myanmar’s political reforms in 2011, Western donors rushed into the country in support of what they misunderstood as a remarkable instance of democratisation. In 2019, escalating civil war, ethnic cleansing, and contracting civil liberties urge a rethink. This article argues that viewing transition in Myanmar through the lens of democratisation has always been misleading and problematic. Partial liberalisation was orchestrated by the military to safeguard its own power. Reforms have not only benefited civil society but also enabled the growth of uncivil society, fuelling sectarian violence and bolstering military rule. Operating on the assumption of democratisation, Western donors shifted funds from grass-roots networks to militarised state bureaucracies that seek to co-opt peace-building and development projects for the purposes of ethnocratic state-building and counterinsurgency. Rethinking the nature of transition is pivotal for preventing inadvertently aiding authoritarianism and conflict

Girding the loins? Direct evidence of the use of a medieval English parchment birthing girdle from biomolecular analysis

In this paper, we describe palaeoproteomic evidence obtained from a stained medieval birth girdle using a previously developed dry non-invasive sampling technique. The parchment birth girdle studied (Wellcome Collection Western MS. 632) was made in England in the late fifteenth century and was thought to be used by pregnant women while giving birth. We were able to extract both human and non-human peptides from the manuscript, including evidence for the use of honey, cereals, ovicaprine milk and legumes. In addition, a large number of human peptides were detected on the birth roll, many of which are found in cervico-vaginal fluid. This suggests that the birth roll was actively used during childbirth. This study is, to our knowledge, the first to extract and analyse non-collagenous peptides from a birth girdle using this sampling method and demonstrates the potential of this type of analysis for stained manuscripts, providing direct biomolecular evidence for active use

RIC-3 expression and splicing regulate nAChR functional expression

Effects of FL human RIC-3 vs. mouse FL on α7 nAChR functional expression in X. leavis oocytes. Results were normalized to currents recorded in oocytes expressing the respective receptors in the absence of RIC-3 in the same experiment. Each bar represents 10–20 oocytes from 2 to 3 independent X. laevis. The y-axis ordinates are on a log scale. * indicates a p value of less than 0.05; ** indicates a p value of less than 0.01. (PDF 714 kb

Impact of a Formal Patient Safety and Quality Improvement Curriculum: A Prospective, Controlled Trial

Objective To assess the impact of implementing a dedicated Patient Safety and Quality Improvement (PSQI) curriculum for otolaryngology residents. Methods Residents in two otolaryngology residency programs were recruited to participate in the study. Residents at institution A (intervention group) participated in a formal, newly developed, year-long PSQI curriculum. Residents at institution B (control group) participated in traditional, morbidity, and mortality conference-based PSQI education, with no formal curriculum in place. Curriculum participants completed anonymous surveys to assess learner satisfaction. Validated instruments were administered to assess for changes in resident confidence in the ability to develop PSQI projects, their attitudes toward patient safety, and PSQI-related knowledge. The number and quality of PSQI-related resident projects were also assessed. Results Survey responses demonstrated excellent learner satisfaction with the curriculum. Based on validated instrument-based responses, both programs demonstrated similar confidence scores (P = 0.05), safety attitudes (P = 0.82), and PSQI knowledge (P = 0.29) at the beginning of the year. The residents of institution A demonstrated significant improvement in confidence (P = 0.00009) and knowledge (P = 0.0006) after completing the curriculum, with no improvement noted for residents at institution B in either confidence (P = 0.06) or knowledge (P = 0.79). Neither program demonstrated improvement in attitudes toward patient safety at the end of the year-long curriculum. Conclusion Implementing a formal curriculum dedicated to PSQI led to an improvement in PSQI-related project development confidence and PSQI knowledge. Attitudes toward safety did not improve over the course of a year. Longer-term studies involving multiple institutions and other interventions are needed to evaluate the impact and duration of changes that occur. Level of Evidence 1b Laryngoscope, 129:1100–1106, 201