Bone Therapeutics: Safety Considerations, Session Summary

This session was a series of presentations focused on safety considerations for late stage or currently marketed bone therapeutic agents. The first presentation was an overview of a major regulatory requirement in the nonclinical filing package for bone therapeutics, studies designed to assess the impact of an agent on bone quality. Two presentations focused on safety issues associated with drugs whose primary mechanism of action is inhibition of bone resorption. Typical findings associated with this class of agents in general and reproductive toxicology studies were reviewed, highlighting INHAND (International Harmonization of Nomenclature and Diagnostic Criteria) nomenclature. This was followed by an overview of safety issues that have been identified largely through clinical experience. Similar presentations followed emphasizing safety and regulatory issues associated with classes of drugs whose primary mechanism of action is stimulation of bone formation known broadly as bone anabolic agents. The major focus of these discussions was carcinogenicity risk assessment. The final presentation was an introduction to a rapidly evolving area in bone therapeutics, treatment of rare genetic bone diseases, and the developmental challenges associated with these indications and novel therapeutic modalities.

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Fluorescent potentiometric dyes for membrane-potential imaging

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100168566 ◽

1994 ◽

Vol 52 ◽

pp. 166-167

Author(s):

Leslie M. Loew

Keyword(s):

Membrane Potential ◽

Single Cells ◽

Quantitative Imaging ◽

Optical Recording ◽

Biological Processes ◽

Major Focus ◽

The Past ◽

Excitable Systems ◽

Major Application ◽

The Impact

A major application of potentiometric dyes has been the multisite optical recording of electrical activity in excitable systems. After being championed by L.B. Cohen and his colleagues for the past 20 years, the impact of this technology is rapidly being felt and is spreading to an increasing number of neuroscience laboratories. A second class of experiments involves using dyes to image membrane potential distributions in single cells by digital imaging microscopy - a major focus of this lab. These studies usually do not require the temporal resolution of multisite optical recording, being primarily focussed on slow cell biological processes, and therefore can achieve much higher spatial resolution. We have developed 2 methods for quantitative imaging of membrane potential. One method uses dual wavelength imaging of membrane-staining dyes and the other uses quantitative 3D imaging of a fluorescent lipophilic cation; the dyes used in each case were synthesized for this purpose in this laboratory.

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Influence of DAFS-25+polizon composition on blood and functional state of liver of steers at fattening

Veterinaria Kubani ◽

10.33861/2071-8020-2020-1-15-18 ◽

2020 ◽

pp. 15-18

Author(s):

Inna R. Kilmetova ◽

◽

Igor A. Rodin ◽

Nazira I. Khayrullina ◽

Nikolay G. Fenchenko ◽

...

Keyword(s):

Functional State ◽

White Blood Cells ◽

Live Weight ◽

The Body ◽

Farm Animals ◽

Control Group ◽

Standard Diet ◽

The Impact ◽

Experimental Group ◽

Stimulation Of

Summary. The disbalanced feeding and the uneven distribution of micro- and macroelements in the environment leads to a trace element, in particular hypomelanosis. To accelerate the growth and preservation of young farm animals include in the diet of various biological additives and drugs, which include selenium. For stimulation of weight gain in the livestock industry, as well as for the prevention and treatment of pathological processes in addition to micro - and macrouse amino acids, primarily methionine. The aim of this work was to study the influence of composition of DAFS-25+Polizon on morpho-biochemical parameters of blood and functional state of the liver in fattening bulls of black-motley breed in the conditions of the Republic of Bashkortostan. Experiments using were conducted on bull-calves of black-motley breed of the properties in the properties age from 6 to 15 months. The first experimental group during the experiment was additionally given the composition of DAFS-25+Polizon at a dose of 2 mg/kg, the animals of the control group received a standard diet. To assess the impact of the composition DAFS-25+Polizon on metabolism cattle studied morphological and biochemical indicators of blood and conducted histological examination of the liver. It is established that the use of the composition of DAFS-25+Polizon at a dose of 2 mg/kg increases the number of erythrocytes and hemoglobin in the experimental group and reduces the amount of white blood cells. The serum content of total protein, phosphorus and calcium increases in the group of experimental animals. Microscopic examination of the liver revealed no changes in the structure of the organ and hepatocytes in the experimental group, whereas in the control group hemodynamic disorders and dystrophic changes in liver cells were observed. Thus, the use of the composition DAFS-25+Polizon at a dose of 2 mg/kg of live weight in fattening bulls black-and-white breed contributes to the increase of redox processes in the body, stimulation of metabolism, prevent the development of liver disorders of cellular mechanisms of metabolism, optimizes the structure of the liver, which generally provides higher productivity.

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The Management of Post-Tonsillectomy Morbidity in Patients With Sleep Apnoea

Revista de Chimie ◽

10.37358/rc.19.10.3738 ◽

2019 ◽

Vol 70 (10) ◽

pp. 3738-3740

Keyword(s):

Day Surgery ◽

Sleep Apnoea ◽

Integrative Approach ◽

Multicenter Studies ◽

Therapeutic Modalities ◽

Advantages And Disadvantages ◽

Obstructive Sleep ◽

Wide Range ◽

The Impact ◽

Surgery Center

The Tonsillectomy in children or adults is an intervention commonly encountered in the ENT (Ear Nose and Throat) and Head and Neck surgeon practice. The current tendency is to perform this type of surgery in major ambulatory surgery centers. Two objectives are thus pursued: first of all, the increase of the patient quality of life through the reintegration into the family as quickly as possible and secondly, the expenses associated with continuous hospitalization are reduced. Any tertiary (multidisciplinary) sleep center must ensure the complete diagnosis and treatment (including surgery) of sleep respiratory disorders. Under these conditions the selection of patients and especially the implementation of the specific protocols in order to control the postoperative complications it becomes essential. The present paper describes our experience of tonsillectomy as treatment for selected patients with chronic rhonchopathy (snoring) and mild to moderate obstructive sleep apnoea. It was presented the impact of antibiotics protocols in reducing the main morbid outcomes following tonsillectomy, in our day surgery center. The obtained results can also be a prerequisite for the integrative approach of the patients with sleep apnoea who were recommended surgical treatment. Considering the wide range of therapeutic modalities used in sleep apnoea, each with its specific advantages and disadvantages, more extensive and multicenter studies are needed. Keywords: post-tonsillectomy morbidity, day surgery center, sleep disorders

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The Impact of Bushfire Smoke on Cattle—A Review

Animals ◽

10.3390/ani11030848 ◽

2021 ◽

Vol 11 (3) ◽

pp. 848

Author(s):

Benjamin Eid ◽

David Beggs ◽

Peter Mansell

Keyword(s):

Particulate Matter ◽

Prolonged Exposure ◽

Negative Impact ◽

Airborne Particulate Matter ◽

Mortality Rates ◽

Airborne Particulate ◽

Primary Mechanism ◽

Background Mortality ◽

Fire Front ◽

The Impact

In 2019–2020, a particularly bad bushfire season in Australia resulted in cattle being exposed to prolonged periods of smoke haze and reduced air quality. Bushfire smoke contains many harmful pollutants, and impacts on regions far from the fire front, with smoke haze persisting for weeks. Particulate matter (PM) is one of the major components of bushfire smoke known to have a negative impact on human health. However, little has been reported about the potential effects that bushfire smoke has on cattle exposed to smoke haze for extended periods. We explored the current literature to investigate evidence for likely effects on cattle from prolonged exposure to smoke generated from bushfires in Australia. We conducted a search for papers related to the impacts of smoke on cattle. Initial searching returned no relevant articles through either CAB Direct or PubMed databases, whilst Google Scholar provided a small number of results. The search was then expanded to look at two sub-questions: the type of pollution that is found in bushfire smoke, and the reported effects of both humans and cattle being exposed to these types of pollutants. The primary mechanism for damage due to bushfire smoke is due to small airborne particulate matter (PM). Although evidence demonstrates that PM from bushfire smoke has a measurable impact on both human mortality and cardiorespiratory morbidities, there is little evidence regarding the impact of chronic bushfire smoke exposure in cattle. We hypothesize that cattle are not severely affected by chronic exposure to smoke haze, as evidenced by the lack of reports. This may be because cattle do not tend to suffer from the co-morbidities that, in the human population, seem to be made worse by smoke and pollution. Further, small changes to background mortality rates or transient morbidity may also go unreported.

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The Role of BMP Signaling in Osteoclast Regulation

Journal of Developmental Biology ◽

10.3390/jdb9030024 ◽

2021 ◽

Vol 9 (3) ◽

pp. 24

Author(s):

Brian Heubel ◽

Anja Nohe

Keyword(s):

Bone Formation ◽

Bone Morphogenetic Proteins ◽

Bone Diseases ◽

Bmp Signaling ◽

Bone Homeostasis ◽

Direct Stimulation ◽

Federal Drug Administration ◽

Bmp Pathway ◽

Stimulation Of

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

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The Impact of Geography in Hepatocellular Carcinoma: A Retrospective Population Based Study

Current Oncology ◽

10.3390/curroncol28010042 ◽

2021 ◽

Vol 28 (1) ◽

pp. 396-404

Author(s):

Irene S. Yu ◽

Shiru L. Liu ◽

Valeriya Zaborska ◽

Tyler Raycraft ◽

Sharlene Gill ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Retrospective Chart Review ◽

Population Based ◽

Tumor Board ◽

Treatment Center ◽

Population Based Study ◽

Therapeutic Modalities ◽

Quaternary Center ◽

Statistics Canada ◽

The Impact

Background: The treatment of hepatocellular carcinoma (HCC) includes different therapeutic modalities and multidisciplinary tumor board reviews. The impact of geography and treatment center type (quaternary vs. non-quaternary) on access to care is unclear. Methods: A retrospective chart review was performed on HCC patients who received sorafenib in British Columbia from 2008 to 2016. Patients were grouped by Statistics Canada population center (PC) size criteria: large PC (LPC), medium PC (MPC), and small PC (SPC). Access to specialists, receipt of liver-directed therapies, and survival outcomes were compared between the groups. Results: Of 286 patients, the geographical distribution was: LPC: 75%; MPC: 16%; and SPC: 9%. A higher proportion of Asians (51% vs. 9% vs. 4%; p < 0.001), Child–Pugh A (94% vs. 83% vs. 80%; p = 0.022), and hepatitis B (37% vs. 15% vs. 4%; p < 0.001) was observed in LPC vs. MPC vs. SPC, respectively. LPC patients were more likely referred to a hepatologist (62% vs. 48% vs. 40%; p = 0.031) and undergo transarterial chemoembolization (TACE) (43% vs. 24% vs. 24%; p = 0.018). Sixty percent were treated at a quaternary center, and the median overall survival (OS) was higher for patients treated at a quaternary vs. non-quaternary center (28.0 vs. 14.6 months, respectively; p < 0.001) but similar when compared by PC size. Treatment at a quaternary center predicted an improved survival on multivariate analysis (hazard ratio (HR): 0.652; 95% confidence interval (CI): 0.503–0.844; p = 0.001). Conclusions: Geography did not appear to impact OS but patients from LPC were more likely to be referred to hepatology and undergo TACE. Treatment at a quaternary center was associated with an improved survival.

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Modulation of outer medullary NaCl transport and oxygenation by nitric oxide and superoxide

AJP Renal Physiology ◽

10.1152/ajprenal.00096.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. F979-F996 ◽

Cited By ~ 14

Author(s):

Aurélie Edwards ◽

Anita T. Layton

Keyword(s):

Nitric Oxide ◽

Active Transport ◽

Collecting Duct ◽

Thick Ascending Limb ◽

Outer Medulla ◽

Nacl Transport ◽

Complex Interactions ◽

Medullary Thick Ascending Limb ◽

The Impact ◽

Stimulation Of

We expanded our region-based model of water and solute exchanges in the rat outer medulla to incorporate the transport of nitric oxide (NO) and superoxide (O2−) and to examine the impact of NO-O2− interactions on medullary thick ascending limb (mTAL) NaCl reabsorption and oxygen (O2) consumption, under both physiological and pathological conditions. Our results suggest that NaCl transport and the concentrating capacity of the outer medulla are substantially modulated by basal levels of NO and O2−. Moreover, the effect of each solute on NaCl reabsorption cannot be considered in isolation, given the feedback loops resulting from three-way interactions between O2, NO, and O2−. Notwithstanding vasoactive effects, our model predicts that in the absence of O2−-mediated stimulation of NaCl active transport, the outer medullary concentrating capacity (evaluated as the collecting duct fluid osmolality at the outer-inner medullary junction) would be ∼40% lower. Conversely, without NO-induced inhibition of NaCl active transport, the outer medullary concentrating capacity would increase by ∼70%, but only if that anaerobic metabolism can provide up to half the maximal energy requirements of the outer medulla. The model suggests that in addition to scavenging NO, O2− modulates NO levels indirectly via its stimulation of mTAL metabolism, leading to reduction of O2 as a substrate for NO. When O2− levels are raised 10-fold, as in hypertensive animals, mTAL NaCl reabsorption is significantly enhanced, even as the inefficient use of O2 exacerbates hypoxia in the outer medulla. Conversely, an increase in tubular and vascular flows is predicted to substantially reduce mTAL NaCl reabsorption. In conclusion, our model suggests that the complex interactions between NO, O2−, and O2 significantly impact the O2 balance and NaCl reabsorption in the outer medulla.

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Modulation of Antigen Display on PapMV Nanoparticles Influences Its Immunogenicity

Vaccines ◽

10.3390/vaccines9010033 ◽

2021 ◽

Vol 9 (1) ◽

pp. 33

Author(s):

Marie-Eve Laliberté-Gagné ◽

Marilène Bolduc ◽

Caroline Garneau ◽

Santa-Mariela Olivera-Ugarte ◽

Pierre Savard ◽

...

Keyword(s):

Immune Response ◽

Influenza A ◽

Matrix Protein ◽

Cell Epitope ◽

Vaccine Antigen ◽

Vaccine Platform ◽

Peptide Antigens ◽

C Terminus ◽

The Impact ◽

Stimulation Of

Background: The papaya mosaic virus (PapMV) vaccine platform is a rod-shaped nanoparticle made of the recombinant PapMV coat protein (CP) self-assembled around a noncoding single-stranded RNA (ssRNA) template. The PapMV nanoparticle induces innate immunity through stimulation of the Toll-like receptors (TLR) 7 and 8. The display of the vaccine antigen at the surface of the nanoparticle, associated with the co-stimulation signal via TLR7/8, ensures a strong stimulation of the immune response, which is ideal for the development of candidate vaccines. In this study, we assess the impact of where the peptide antigen is fused, whether at the surface or at the extremities of the nanoparticles, on the immune response directed to that antigen. Methods: Two different peptides from influenza A virus were used as model antigens. The conserved M2e peptide, derived from the matrix protein 2 was chosen as the B-cell epitope, and a peptide derived from the nucleocapsid was chosen as the cytotoxic T lymphocytes (CTL) epitope. These peptides were coupled at two different positions on the PapMV CP, the N- (PapMV-N) or the C-terminus (PapMV-C), using the transpeptidase activity of Sortase A (SrtA). The immune responses, both humoral and CD8+ T-cell-mediated, directed to the peptide antigens in the two different fusion contexts were analyzed and compared. The impact of coupling density at the surface of the nanoparticle was also investigated. Conclusions: The results demonstrate that coupling of the peptide antigens at the N-terminus (PapMV-N) of the PapMV CP led to an enhanced immune response to the coupled peptide antigens as compared to coupling to the C-terminus. The difference between the two vaccine platforms is linked to the enhanced capacity of the PapMV-N vaccine platform to stimulate TLR7/8. We also demonstrated that the strength of the immune response increases with the density of coupling at the surface of the nanoparticles.

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Therapeutic Value of Single Nucleotide Polymorphisms on the Efficacy of New Therapies in Patients with Multiple Sclerosis

Journal of Personalized Medicine ◽

10.3390/jpm11050335 ◽

2021 ◽

Vol 11 (5) ◽

pp. 335

Author(s):

María José Zarzuelo Romero ◽

Cristina Pérez Ramírez ◽

María Isabel Carrasco Campos ◽

Almudena Sánchez Martín ◽

Miguel Ángel Calleja Hernández ◽

...

Keyword(s):

Multiple Sclerosis ◽

Mechanism Of Action ◽

Dimethyl Fumarate ◽

Response To Treatment ◽

Nucleotide Polymorphisms ◽

New Therapies ◽

Therapeutic Value ◽

The Impact

The introduction of new therapies for the treatment of multiple sclerosis (MS) is a very recent phenomenon and little is known of their mechanism of action. Moreover, the response is subject to interindividual variability and may be affected by genetic factors, such as polymorphisms in the genes implicated in the pathologic environment, pharmacodynamics, and metabolism of the disease or in the mechanism of action of the medications, influencing the effectiveness of these therapies. This review evaluates the impact of pharmacogenetics on the response to treatment with new therapies in patients diagnosed with MS. The results suggest that polymorphisms detected in the GSTP1, ITGA4, NQO1, AKT1, and GP6 genes, for treatment with natalizumab, ZMIZ1, for fingolimod and dimethyl fumarate, ADA, for cladribine, and NOX3, for dimethyl fumarate, may be used in the future as predictive markers of treatment response to new therapies in MS patients. However, there are few existing studies and their samples are small, making it difficult to generalize the role of these genes in treatment with new therapies. Studies with larger sample sizes and longer follow-up are therefore needed to confirm the results of these studies.

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The New Flow Control Devices Autonomously Controlling the Performance of Matrix Acid Stimulation Operations in Carbonate Reservoirs

10.2118/205975-ms ◽

2021 ◽

Author(s):

Mojtaba Moradi ◽

Michael R Konopczynski

Keyword(s):

Flow Control ◽

Dynamic Change ◽

Injection Rate ◽

Control Flow ◽

Carbonate Reservoir ◽

Operating Conditions ◽

Carbonate Reservoirs ◽

High Permeability ◽

The Impact ◽

Stimulation Of

Abstract Matrix acidizing is a common but complex stimulation treatment that could significantly improve production/injection rate, particularly in carbonate reservoirs. However, the desired improvement in all zones of the well by such operation may not be achieved due to existing and/or developing reservoir heterogeneity. This paper describes how a new flow control device (FCD) previously used to control water injection in long horizontal wells can also be used to improve the conformance of acid stimulation in carbonate reservoirs. Acid stimulation of a carbonate reservoir is a positive feedback process. Acid preferentially takes the least resistant path, an area with higher permeability or low skin. Once acid reacts with the formation, the injectivity in that zone increases, resulting in further preferential injection in the stimulated zone. Over-treating a high permeability zone results in poor distribution of acid to low permeability zones. Mechanical, chemical or foam diversions have been used to improve stimulation conformance along the wellbore, however, they may fail in carbonate reservoirs with natural fractures where fracture injectivity dominates the stimulation process. A new FCD has been developed to autonomously control flow and provide mechanical diversion during matrix stimulation. Once a predefined upper limit flowrate is reached at a zone, the valve autonomously closes. This eliminates the impact of thief zone on acid injection conformance and maintains a prescribed acid distribution. Like other FCDs, this device is installed in several compartments in the wells. The device has two operating conditions, one, as a passive outflow control valve, and two, as a barrier when the flow rate through the valve exceeds a designed limit, analogous to an electrical circuit breaker. Once a zone has been sufficiently stimulated by the acid and the injection rate in that zone exceeds the device trip point, the device in that zone closes and restricts further stimulation. Acid can then flow to and stimulate other zones This process can be repeated later in well life to re-stimulate zones. This performance enables the operators to minimise the impacts of high permeability zones on the acid conformance and to autonomously react to a dynamic change in reservoirs properties, specifically the growth of wormholes. The device can be installed as part of lower completions in both injection and production wells. It can be retrofitted in existing completions or be used in a retrievable completion. This technology allows repeat stimulation of carbonate reservoirs, providing mechanical diversion without the need for coiled tubing or other complex intervention. This paper will briefly present an overview of the device performance, flow loop testing and some results from numerical modelling. The paper also discusses the completion design workflow in carbonates reservoirs.

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