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RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

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Bone Research 2024年第1期12卷 165-179页

作者： Luis F.de Castro Jarred M.Whitlock Zachary Michel Kristen Pan Jocelyn Taylor Vivian Szymczuk Brendan Boyce Daniel Martin Vardit kram Rebeca Galisteo Kamran Melikov Leonid V.Chernomordik Michael T.Collins Alison M.Boyce Skeletal Disorders and Mineral Homeostasis Section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Section on Membrane Biology Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA Metabolic Bone Disorders Unit National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Department of Plastic and Reconstructive Surgery The Johns Hopkins Medical InstitutionsBaltimoreMDUSA Department of Pathology and Laboratory Medicine University of Rochester Medical CenterRochesterNYUSA NIDCR Genomics and Computational Biology Core National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA

Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established *** evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment *** this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical *** analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL *** sequencing of human and mouse tissue supported these *** interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on *** results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within *** findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

关键词： dysplasia treatment finding

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Galectin-3 inhibition as a potential therapeutic target in nonalcoholic steatohepatitis liver fibrosis

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World Journal of Hepatology 2023年第2期15卷 201-207页

作者： Michael kram Department of Gastroenterology Bon Secours Health System IncMonseyNY 10952United States

Nonalcoholic fatty liver disease continues to be one of the major health challenges facing the world,with estimates of non-alcoholic steatohepatitis(NASH)prevalence in over 25 percent of the world’s *** represents a spectrum of disease that may lead to hepatic fibrosis and eventual cirrhosis,with the risk of cirrhosis decompensation,and hepatocellular *** therapies are desperately needed for NASH,especially for later stages of fibrosis and ***-3 inhibition is being explored as a new liver antifibrotic *** concise review will outline the state of the art of this new therapeutic target.

关键词： Galectin-3 inhibition Non-alcoholic fatty liver disease Fibrosis Macrophage

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Metabolic cost of level,uphill,and downhill running in highly cushioned shoes with carbon-fiber plates

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Journal of Sport and Health Science 2022年第3期11卷 303-308页

作者： Clarissa S.Whiting Wouter Hoogkamer Rodger kram Locomotion Laboratory Department of Integrative PhysiologyUniversity of ColoradoBoulderCO 80309USA Integrative Locomotion Lab Department of KinesiologyUniversity of MassachusettsAmherstMA 01003USA

Background:Compared to conventional racing shoes,Nike Vaporfly 4% running shoes reduce the metabolic cost of level treadmill running by4%.The reduction is attributed to their lightweight,highly compliant,and resilient midsole foam and a midsole-embedded curved carbon-fiber *** investigated whether these shoes also could reduce the metabolic cost of moderate uphill(+3°) and downhill(-3°) *** tested the null hypothesis that,compared to conventional racing shoes,highly cushioned shoes with carbon-fiber plates would impart the same ~4%metabolic power(W/kg) savings during uphill and downhill running as they do during level ***:After familiarization,16 competitive male runners performed six 5-min trials(2 shoes × 3 grades) in 2 Nike marathon racing-shoe models(Streak 6 and Vaporfly 4%) on a level,uphill(+3°),and downhill(-3°) treadmill at 13 km/h(3.61 m/s).We measured submaximal oxygen uptake and carbon dioxide production during Minutes 4-5 and calculated metabolic power(W/kg) for each shoe model and grade ***:Compared to the conventional shoes(Streak 6),the metabolic power in the Vaporfly 4% shoes was 3.83%(level),2.82%(uphill),and2.70%(downhill)less(all p <0.001).The percent of change in metabolic power for uphill running was less compared to level running(p=0.04;effect size(ES)=0.561) but was not statistically different between downhill and level running(p=0.17;ES=0.356).Conclusion:On a running course with uphill and downhill sections,the metabolic savings and hence performance enhancement provided by Vaporfly 4% shoes would likely be slightly less overall,compared to the savings on a perfectly level race course.

关键词： Energetics Incline Locomotion Oxygen consumption Running economy

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A Space for Tears

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Sociology Study 2020年第2期10卷 53-60页

作者： Lucia kramárová ArtEZ University of the Arts Arnhemthe Netherlands

“A space for tears”explores the relations of the phenomenon of absence and performance and their implications for both art and life *** connections are uncovered through the exploration of the forms and modalities of absence,the positionality of absence as a constitutive element of performance,the affinity of absence and the questions of embodiment and the interconnection death and mourning ritual with *** driving force of this research is the need for(re)establishing a healthy relationship with absence,which would not be confined exclusively to the artistic *** paper is conceived as a hermeneutic study in a polemic tone,utilizing theoretical and literary works of poetry and prose as well as folk literature as equal *** plurality of sources and especially their form and origin ties in with the expansion beyond art practices,which bids to consider alternative repositories of *** and keeping the fluidity and ambivalence of the researched topics is a key feature of the research,which remains thoroughly *** study keeps the weave of conclusions open,ready to be correlated with practice.

关键词： absence performance ruin mortuary ritual touch

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Stop Laughing, I’m Dead!

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Sociology Study 2020年第3期10卷 149-152页

作者： Lucia kramárová ArtEZ University of the Arts Arnhemthe Netherlands

“Stop laughing,I’m dead”explores the implications and potentialities of the mode of address in the novel Suicide byÉdouard Levéin the valences of identification and potential overidentification of the subject of the novel with the author or the reader *** mode of address in question is the consistent and highly suggestive use of the personal pronoun“you”as a route of invocation of the novel’s main *** essay is conceived as an overlaying dialogue between two polarities of writing-academic writing and automatic journaling,which serves as a reflection and exploration of the fissure created by Levéhimself through his writing strategies and life events coinciding with the content of the *** essay thus attempts to speak from and speak to both the cognitive and affective tensions that arise from the reading and interpretation of Levé’s opus and continually renegotiate the positions of the reader,the writer,and the corpse.

关键词： author reader death ruin anecdote

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Neck Motion Restriction Negatively Affects Turning Stability in Community-Dwelling Older Adults with and without a History of Falls

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Advances in Aging Research 2022年第2期11卷 35-49页

作者： Luzit Hadad Herman Avner Cohen Netta kram Zvi Kozol Physical Therapy Department School for Community Health Professions Faculty of Health Sciences Ariel University Ariel Israel Rotschild Physiotherapy Department Clalit Health Services Petach-Tikva Israel Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel Pediatric Ambulatory Center General Health Services Petach Tikva Israel

Background: Many older adults fall while turning. During the turning maneuver, rotation of the head precedes the rest of the body, creating a spatial frame of reference. Limitations of the neck rotation, may interfere with the turning mechanism, affect stability, and lead to recurrent falls. However, the association between the range of the neck rotation and turning stability was not explored yet. Purpose: To compare the impact of restricting the neck rotation by a brace, on the turning stability of adults with and without a history of falls. Methods: An observational, cross-sectional study consisting of 59 adults (average age 76 ± 6.9). A group (N = 29) with at least 2 falls (FL) in the last year and a group (N = 30) without a history of falls in the last year (NFL). All participants performed three tests: Timed up and Go (TUG), 180° Turn Test (180 TT) and 360° Turn Test (360 TT) with and without a neck brace. Results: All the scores of the FL were lower than those of the NFL (p Application of the brace worsened the performance of the 180 TT and the 360 TT of both groups (p < 0.05) but there was no interaction between group and bracing. The TUG score of only the NFL was affected by the brace (p < 0.004). Interestingly, only the range of the right neck rotation was correlated with balance tests and number of falls (r = 0.272;p Conclusions: Restricting of the neck mobility worsened the turning stability of both groups but without interaction. The study reinforces the need of considering the neck range of motion when addressing adult stability. A decrease in the range of right neck rotation was identified as a risk factor for loss of balance.

关键词： Balance Turning Neck-Brace Neck-Rotation Fall

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