A High Throughput Protein Formulation Platform: Case Study of Salmon Calcitonin

Purpose: The feasibility of using high throughput spectroscopy for characterization and selection of physically stable protein formulations was studied. Materials and Methods: A hundred aqueous formulations of salmon calcitonin (sCT) were prepared using 20 buffer compositions. The solutions had pH values between 2.5 and 10.5. The stability of the sCT formulations was analyzed over 1week by the following assays: (1) protein concentration, (2) volume control by measuring pathlength, (3) turbidity (absorbance at 350nm), (4) intrinsic tyrosine fluorescence, (5) 1-anilino-naphthalene-8-sulfonate (ANS) fluorescence, (6) Nile Red fluorescence. Addition of the dyes (Nile Red and ANS) was used to study protein conformational changes. Results: After 1day, 27 out of the 100 formulations of salmon calcitonin were stable. After 7days, 12 stable sCT formulations remained. The best salmon calcitonin formulation was in 10mM sodium acetate buffer with pH values between 3.5 and 5.5. Conclusions: The findings are in accordance with the sCT formulations that were patented and used commercially. This can be considered as a proof of concept for the high throughput protein formulation platfor

The Native American postmodern-mimetic novel.

This dissertation examines a new literary phenomenon---the Native American Postmodern---Mimetic novel. This genre is heralded by N. Scott Momaday's House Made of Dawn, and it is exemplified by his subsequent novel, The Ancient Child. It consists of the real-world difficulties of Native Americans overlaid with postmodern literary techniques to create a unique dialogical narrative

Reconciling competing priorities in commissioning: the future of bone densitometry service for North Wales

BACKGROUND: Osteoporosis creates brittle bones susceptible to fracture, with resulting high levels of morbidity and mortality. Poor access to bone densitometry services for the residents of North Wales led to the Welsh Assembly Government offering capital to purchase a dual-energy X-ray absorptiometry (DXA) scanner, used to diagnose osteoporosis, for the region. The commissioning question for the six Local Health Boards across North Wales was where to site the new scanner. This decision needed to reflect current inequalities in access to services and concerns over inappropriate prescribing relative to Welsh norms. METHODS: Epidemiological, corporate and comparative healthcare needs assessments were performed. In addition, two cross-sectional surveys were conducted to determine the views of general practices and users of bone densitometry services resident in North Wales. An option appraisal and sensitivity analysis of 13 costed options for DXA scanning was conducted. RESULTS: We estimated that only 31% of the people in North Wales who met national guidelines were receiving DXA scans. There was definite inequity of access to the current service provided by area of residence. There was also evidence of inequity of access by age and sex. The most suitable option identified in the option appraisal was a bone densitometry service based in the central location of Llandudno. CONCLUSION: The assessment identified significant unmet need for DXA scanning. A recommendation was made to improve access through the introduction of a new bone densitometry service based at Llandudno. This would double scanning provision provided and reduce travel costs and time for many North Wales residents. This recommendation was adopted by a joint commissioning group established by the six Local Health Boards in North Wales at the end of 2004 – evidence based commissioning in practice

Evaluation of a locked nucleic acid form of antisense oligo targeting HIF-1α in advanced hepatocellular carcinoma

BACKGROUND: Hypoxia-inducible factor 1α (HIF-1α) is a gene that regulates tumor survival, neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma (HCC). RO7070179 is a HIF-1α inhibitor that decreases HIF-1α mRNA and its downstream targets, it could be a potential treatment in HCC. AIM: To evaluate safety and preliminary activity of RO7070179 in patients with previously treated HCC, with focus on a patient with prolonged response to RO7070179. METHODS: In the preclinical study of RO7070179 in a HCC xenograft model, the mice were separated into 4 groups with each group received doses of 0, 3, 10 and 30 mg/kg for total 10 doses. HCC patients who failed at least one line of systemic treatment, received RO7070179 as a weekly infusion, each cycle is 6 wk. We evaluated the safety and HIF-1α mRNA levels of RO7070179. RESULTS: Preclinical evaluation of RO7070179 in orthotopic HCC xenograft model showed no significant differences in HCC tumor weight between the 3 and 10 mg/kg groups. However, dose of 10 mg/kg of RO7070179, has shown 76% reduction of the amount of HIF-1α mRNA in HCC tissue. In the phase 1b study of RO7070179 in previously treated HCC patients, 8 out of 9 were evaluable: 1 achieved PR and 1 SD. The patient with PR responded after 2 cycles treatments, which has been maintained for 12 cycles. This patient also showed reduction in perfusion of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) after 1 cycle of treatment. After 1 cycle of treatment, both patients with PR and SD showed decrease in HIF-1α mRNA at the root of biopsies (each biopsy was divided into 2 specimens, the tip and the root). CONCLUSION: RO7070179 can reduce HIF-1α mRNA level in HCC patients with SD or PR. It is well tolerated at 10 mg/kg, with transaminitis as the dose of increased toxicity. This study indicates that RO7070179 might benefit HCC patients, and an early signal for clinical benefit can potentially be predicted through changes in either mRNA level or DCE-MRI within 1 cycle of therapy

Frequency of Injuries from Line Entanglements, Killer Whales, and Ship Strikes on Bering-Chukchi-Beaufort Seas Bowhead Whales

We analyzed scarring data for Bering-Chukchi-Beaufort (BCB) Seas bowhead whales (Balaena mysticetus) harvested by Alaska Native hunters to quantify the frequency of line entanglement, ship strikes, and killer whale-inflicted injuries. We had 904 records in our database for whales landed between 1990 and 2012, and after data quality screening, we found 521 records containing information on scarring. Logistic regression was used to evaluate different combinations of explanatory variables (i.e., body length, sex, year, year-group) to develop a prediction model for each scar type. We also list bowhead whales that were harvested, found dead, or observed alive entangled in commercial line/fishing gear. Our findings suggest that about 12% of harvested bowheads show entanglement scars. Their frequency is highly correlated with body length and sex: about 50% of very large bowheads (> 17 m) show such scars, while whales under 9 m rarely do, and males show a significantly higher rate than females. Scars associated with ship strikes are infrequent and occur on ~2% of all harvested whales; body length, sex, and year were not significant factors. Scarring from attempted killer whale predation was evident on ~8% of landed whales. As with entanglement injuries, the frequency of killer whale scars was much higher (> 40%) on whales more than 16 m in length and statistically more frequent in the second half of the study (2002 – 12). Increased killer whale injuries in the recent decade are consistent with studies conducted on bowheads of the Eastern Canada-West Greenland population. The findings presented here reflect the most thorough analysis of injury rates from entanglement, ships, and killer whales for the BCB bowheads conducted to date. They indicate that (1) entanglement rates primarily from pot fishing gear (crab or cod or both) are relatively high for very large and presumably older bowheads, (2) collisions with ships are infrequent at present, and (3) scarring from killer whales is frequent on very large adult whales (> 17 m). Considering that bowhead habitat is changing rapidly (e.g., sea ice reduction), industrial ship traffic in the Arctic is increasing, and commercial fishing operations are expanding to the north, we strongly recommend that monitoring of scarring and injuries on harvested bowheads continue into the future as a means of documenting change.Nous avons analysé les données sur les cicatrices que portent les baleines boréales (Balaena mysticetus) des mers de Béring, des Tchouktches et de Beaufort capturées par des chasseurs autochtones de l’Alaska afin de quantifier la fréquence d’emmêlements dans des filets de pêche, de collisions avec des navires et de blessures infligées par des épaulards. Notre base de données contenait 904 enregistrements portant sur des baleines prises entre 1990 et 2012 et, après une sélection des données selon leur qualité, nous avons trouvé 521 enregistrements comptant de l’information sur des cicatrices. Une méthode de régression logistique a été utilisée pour évaluer différentes combinaisons de variables explicatives (longueur corporelle, sexe, année et année-groupe, par exemple) afin de concevoir un modèle prédictif pour chaque type de cicatrice. Nous énumérons également les baleines boréales retrouvées emmêlées dans des engins ou des filets de pêche commerciale qui ont été capturées, trouvées mortes ou observées vivantes. Nos découvertes suggèrent qu’environ 12 % des baleines boréales capturées portent des cicatrices causées par l’emmêlement. La fréquence des cicatrices est étroitement liée à la longueur corporelle et au sexe : environ 50 % des baleines boréales de très grande taille (> 17 m) montrent de telles cicatrices, tandis que les baleines mesurant moins de 9 m portent rarement de telles cicatrices. Par ailleurs, les mâles affichent beaucoup plus de cicatrices que les femelles. Les cicatrices reliées à des collisions avec des navires sont rares et n’apparaissent que sur environ 2 % de toutes les baleines capturées; la longueur corporelle, le sexe et l’année n’étaient pas des facteurs importants. Les cicatrices causées par des tentatives de prédation par les épaulards étaient apparentes sur environ 8 % des baleines prises. Comme pour les blessures causées par l’emmêlement, la fréquence des cicatrices causées par des épaulards était beaucoup plus élevée(> 40 %) sur les baleines mesurant plus de 16 m de longueur et statistiquement plus fréquente dans la deuxième partie de l’étude (2002–2012). L’augmentation des blessures causées par des épaulards au cours de la dernière décennie concorde avec les études réalisées sur la population des baleines boréales de l’est du Canada et de l’ouest du Groenland. Les résultats présentés dans cette étude reflètent l’analyse la plus profonde du taux de blessures causées par l’emmêlement, les navires et les épaulards sur les baleines boréales des mers de Béring, des Tchouktches et de Beaufort à avoir été réalisée jusqu’à présent. Les observations indiquent que : 1) le taux d’emmêlement découlant principalement des engins ou casiers de pêche (crabe ou morue ou les deux) est relativement élevé chez les baleines boréales de très grande taille et probablement plus vieilles, 2) les collisions avec les navires sont rares en ce moment, et 3) les cicatrices causées par des épaulards sont fréquentes chez les baleines adultes de très grande taille (> 17 m). Étant donné le changement rapide de l’habitat de la baleine boréale (diminution des glaces marines, par exemple), l’augmentation de la circulation maritime industrielle dans l’Arctique et l’intensification des opérations de pêche commerciale au nord, nous recommandons fortement de continuer de surveiller les cicatrices et les blessures des baleines boréales capturées afin de documenter les changements

Quality Improvement of Self-Piercing Riveting of High Strength Aluminum Alloys

Described are metal products including metal alloy substrates joined by self-piercing rivets, and methods and apparatus for joining metal alloy substrates using self-piercing rivets. For high-strength metal alloy substrates, the disclosed joining techniques involve retrogressing portions of the metal alloy substrates, such as by heating using a laser heating source, a conductive heating source, or an inductive heating source, to produce crack-free joined metal products

A review of clinical practice guidelines found that they were often based on evidence of uncertain relevance to primary care patients

Objectives: Primary care patients typically have less severe illness than those in hospital and may be overtreated if clinical guideline evidence is inappropriately generalized. We aimed to assess whether guideline recommendations for primary care were based on relevant research. Study Design and Setting: Literature review of all publications cited in support of National Institute for Health and Care Excellence (NICE) recommendations for primary care. The relevance to primary care of all 45 NICE clinical guidelines published in 2010 and 2011, and their recommendations, was assessed by an expert panel. Results: Twenty-two of 45 NICE clinical guidelines published in 2010 and 2011 were relevant to primary care. These 22 guidelines contained 1,185 recommendations, of which 495 were relevant to primary care, and cited evidence from 1,573 research publications. Of these cited publications, 590 (38%, range by guideline 6–74%) were based on patients typical of primary care. Conclusion: Nearly two-third (62%) of publications cited to support primary care recommendations were of uncertain relevance to patients in primary care. Guideline development groups should more clearly identify which recommendations are intended for primary care and uncertainties about the relevance of the supporting evidence to primary care patients, to avoid potential overtreatment

Sensitivity of human pluripotent stem cells to insulin precipitation induced by peristaltic pump-based medium circulation: Considerations on process development

Controlled large-scale production of human pluripotent stem cells (hPSCs) is indispensable for their envisioned clinical translation. Aiming at advanced process development in suspension culture, the sensitivity of hPSC media to continuous peristaltic pump-based circulation, a well-established technology extensively used in hydraulically-driven bioreactors, was investigated. Unexpectedly, conditioning of low protein media (i.e. E8 and TeSR-E8) in a peristaltic pump circuit induced severe viability loss of hPSCs cultured as aggregates in suspension. Optical, biochemical, and cytological analyses of the media revealed that the applied circulation mode resulted in the reduction of the growth hormone insulin by precipitation of micro-sized particles. Notably, in contrast to insulin depletion, individual withdrawal of other medium protein components (i.e. bFGF, TGFβ1 or transferrin) provoked minor reduction of hPSC viability, if any. Supplementation of the surfactant glycerol or the use of the insulin analogue Aspart did not overcome the issue of insulin precipitation. In contrast, the presence of bovine or human serum albumin (BSA or HSA, respectively) stabilized insulin rescuing its content, possibly by acting as molecular chaperone-like protein, ultimately supporting hPSC maintenance. This study highlights the potential and the requirement of media optimization for automated hPSC processing and has broad implications on media development and bioreactor-based technologies. © 2017 The Author(s).Horizon 2020/Marie Skłodowska-Curie Individual Fellowship POSEIDONDFG/EXC/REBIRTHDFG/EXC62/3DFG/ZW64/4-1BMBF/13N12606BMBF/13N14086StemBANCCH2020/TECHNOBEATHannover Medical School internal program (HiLF)Joachim Herz Stiftun

Advancing Research Data Management in Universities of Science and Technology

The white paper ‘Advancing Research Data Management in Universities of Science and Technology’ shares insights on the state-of-the-art in research data management, and recommendations for advancement. A core part of the paper are the results of a survey, which was distributed to our member institutions in 2019 and addressed the following aspects of research data management (RDM): (i) the establishment of a RDM policy at the university; (ii) the provision of suitable RDM infrastructure and tools; and (iii) the establishment of RDM support services and trainings tailored to the requirements of science and technology disciplines. The paper reveals that while substantial progress has been made, there is still a long way to go when it comes to establishing “advanced-degree programmes at our major universities for the emerging field of data scientist”, as recommended in the seminal 2010 report ‘Riding the Wave’, and our white paper offers concrete recommendations and best practices for university leaders, researchers, operational staff, and policy makers. The topic of RDM has become a focal point in many scientific disciplines, in Europe and globally. The management and full utilisation of research data are now also at the top of the European agenda, as exemplified by Ursula von der Leyen addressat this year’s World Economic Forum.However, the implementation of RDM remains divergent across Europe. The white paper was written by a diverse team of RDM specialists, including data scientists and data stewards, with the work led by the RDM subgroup of our Task Force Open Science. The writing team included Angelina Kraft (Head of Lab Research Data Services at TIB, Leibniz University Hannover) who said: “The launch of RDM courses and teaching materials at universities of science and technology is a first important step to motivate people to manage their data. Furthermore, professors and PIs of all disciplines should actively support data management and motivate PhD students to publish their data in recognised digital repositories.” Another part of the writing team was Barbara Sanchez (Head of Centre for Research Data Management, TU Wien) and Malgorzata Goraczek (International Research Support / Data Management Support, TU Wien) who added:“A reliable research data infrastructure is a central component of any RDM service. In addition to the infrastructure, proper RDM is all about communication and cooperation. This includes bringing tools, infrastructures, staff and units together.” Alastair Dunning (Head of 4TU.ResearchData, Delft University of Technology), also one of the writers, added: “There is a popular misconception that better research data management only means faster and more efficient computers. In this white paper, we emphasise the role that training and a culture of good research data management must play.