bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure-mutagenicity relationships on quinoline and indole analogues in the Ames test
Authors: Kurakami Masaki , Hakura Atsushi , Sato Rika , Kawade Akihiro , Yamagata Takeshi , Koyama Naoki , Kakiuchi Dai , Asakura Shoji
Published: November 2024

Background

Although the in silico predictive ability of the Ames test results has recently made remarkable progress, there are still some chemical classes for which the predictive ability is not yet sufficient due to a lack of Ames test data. These classes include simple heterocyclic compounds. This study aimed to investigate the mutagenicity and structure-mutagenicity relationships for some heterocycles in the Ames test. In the present study, we selected 12 quinoline analogues containing one or two nitrogen atoms in the naphthalene ring and 12 indole analogues containing one to three nitrogen atoms in the indole ring, without any side moiety.

Results

The Ames test was performed with five standard bacterial strains (TA100, TA1535, TA98, TA1537, and WP2uvrA) using the pre-incubation method with and without rat liver S9. Five quinoline and two indole analogues were mutagenic. Among the five quinoline analogues, four were mutagenic in the presence of S9 mix with TA100, whereas cinnoline was mutagenic in the absence of S9 mix with TA1537. Among the two indole analogues, indazole was mutagenic in the presence and absence of S9 mix with WP2uvrA and 4-azaindole was mutagenic in the absence of S9 mix with TA1537. The mechanisms underlying the induction of mutagenesis appear to differ between quinoline and indole analogues. In addition, we performed in silico analysis of the mutagenicity of all these analogues using DEREK Nexus 6.1.1 (Lhasa Limited) and GT_EXPERT from CASE Ultra 1.8.0.5 (MultiCASE Inc.) as knowledge-based models and GT1_BMUT from CASE Ultra 1.8.0.5 (MultiCASE Inc.) as a statistical-based model. The knowledge-based model showed low sensitivity for both the quinoline and indole analogues (DEREK Nexus and GT_EXPERT: 20% for quinolines and 0% for indoles). Conversely, the statistical model showed high sensitivity (100% for both quinolines and indoles) and low specificity (43% for quinolines and 10% for indoles).

Conclusion

Based on the Ames test results, we proposed structural alerts noting that quinoline analogues were mutagenic when they had nitrogens in any of the positions 2, 5, 7, or 8 in addition to 1, and indole analogues were mutagenic when they had nitrogens at positions 2 or 4 in addition to 1.
DNA hypomethylation of INHBA promotes tumor progression and predicts prognosis and immune status of gastric cancer
Authors: Li Xueying , Jiang Haizhong , Fu Yangbo , Hu Qiying , Cai Xianlei , Xu Guoqiang
Published: November 2024

Objective

Gastric cancer (GC) is characterized by its high malignancy and poor prognosis. However, the role of Inhibin subunit beta A (INHBA) in GC remains insufficiently understood. This study aims to comprehensively evaluate the clinical significance, biological roles, and possible mechanisms of INHBA in GC.

Methods

Expression levels and survival analyses of the Inhibin beta family were assessed using online databases. A prediction model based on INHBA was developed. In addition, the associations between INHBA expression and immune status, and chemotherapy sensitivity were explored. In vitro experiments were conducted to investigate the biological impact of INHBA on GC cells. Pyrosequencing and the DNA methylation inhibitor, 5-AZA-2’-deoxycytidine (5-AZA-dC) were employed to elucidate the mechanisms underlying INHBA function.

Results

Our findings revealed that INHBA exhibited high expression in GC patients, and elevated INHBA expression correlated with worse outcomes. We developed a novel nomogram incorporating INHBA, age, and tumor node metastasis (TNM) stage to predict the prognosis of GC patients. Additionally, INHBA was found to be associated with suppressed infiltration of immune cells and chemosensitivity. Functionally, INHBA promoted the proliferation and invasiveness of GC cells. Mechanistically, pyrosequencing revealed DNA Hypomethylation of INHBA in the first exon region, and the effects of INHBA silencing were rescued by 5-AZA-dC treatment.

Conclusion

Our study suggests that DNA hypomethylation of INHBA contributes to the progression of GC. Furthermore, INHBA holds promise as a valuable biomarker for prognostic evaluation and immune status prediction in GC patients.
Erectile Dysfunction Therapy of Bariatric Patients: Tadalafil Biopharmaceutics and Pharmacokinetics Before vs. After Gastric Sleeve/Bypass
Authors: Porat Daniel , Dukhno Oleg , Cvijić Sandra , Dahan Arik
Published: November 2024

Bariatric surgery introduces significant changes in the gastrointestinal tract, which may affect oral drug absorption/bioavailability. Here we investigate the phosphodiesterase-5 inhibitor (PDE5i) tadalafil for potentially impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in vitro in different pHs, and ex vivo in gastric content aspirated from patients pre/post-surgery. Dissolution was studied in conditions mimicking pre/post-surgery stomach. Finally, the experimental data were used in physiologically-based pharmacokinetic (PBPK) model (GastroPlus®) to simulate pre- vs. post-surgery tadalafil PK. Tadalafil demonstrated low and pH-independent solubility, both in vitro and ex vivo. Tadalafil release from all drug products and under all gastric conditions was incomplete, with particularly poor dissolution (2%) of the highest dose under post-bariatric conditions. PBPK simulations revealed altered tadalafil PK after gastric bypass—but not after sleeve gastrectomy—compared to unoperated individuals, with 44–48% decreased Cmax, 35–56% decreased AUC and 44% shorter Tmax. This mechanistic analysis suggests that tadalafil may be as effective after sleeve gastrectomy as before the procedure; meanwhile, results after gastric bypass raise concerns regarding the bioperformance of the drug. In addition, the drug's duration of action may be much shorter after gastric bypass. Thus, the effectiveness of tadalafil, widely regarded as the ‘weekend pill’, may be shorter than expected among gastric bypass patients.

Graphical Abstract
There are clear challenges and is a clear need for action
Authors: Meyer-Hamme Johannes
Published: November 2024

The interview with Johannes Meyer-Hamme from University of Paderborn, Germany, addresses key questions about transcultural dialogue, the role of historical thinking, and the challenges of teaching history. The starting point is the question of how transcultural dialogue and historical thinking have changed in recent years from the perspective of the interviewee. The interview also discusses how transcultural academic exchange can be promoted, taking into account different educational contexts and social values. It further considers how to ensure that the academic debate is not dominated only by socially or economically privileged groups. Other topics include the role of digitalisation and online communities in history education, and the benefits of cross-disciplinary approaches. The extent to which current global challenges such as pandemics, wars and climate change underline the need for increased transcultural exchange in history education will also be addressed.
Świat z perspektywy sztuki, sztuka w perspektywie świata. #Interdyscyplinarność. Tom 6
Authors: Cieślikowska Joanna , Jaworski Marcin
Published: November 2024

The main theme of the sixth volume of the publishing series Świat w perspektywie sztuki, sztuka w perspektywie świata #Interdyscyplinarność (The World in the Perspective of Art, Art in the Perspective of the World #Interdisciplinarity) of the Faculty of Fine Arts of the Nicolaus Copernicus University in Toruń is interdisciplinarity.
The texts collected in the volume present various approaches to the interdisciplinary nature of art. They concern both creative participation, theoretical reflection and relations with other scientific disciplines. The thematic scope covers a wide spectrum of considerations and analyses – from scientific studies of contemporary concepts and ideas, through the presentation of research results and their methods, to the analysis of contemporary trends in art and the work of selected artists. The authors of the presented studies are representatives of various environments: artists, art theoreticians, educators and teachers. In their texts they refer to art, popular culture and art, media and music. What united them all was a genuine need to speak out on issues that remain extremely important to them. It concerns art, culture and artistic education.
Żywe dziedzictwo kopernikańskie. Współczesne inspiracje artystyczne i naukowe
Authors: Geron Małgorzata , Olszewska-Świetlik Justyna , Pręgowski Nikodem
Published: November 2024

Publication titled The Living Heritage of Copernicus: Contemporary Artistic and Scientific Inspirations was created on the occasion of the 550th anniversary of the birth of Nicolaus Copernicus. It consists of nine articles containing significant findings of Toruń researchers – art historians and conservators working at the Faculty of Fine Arts of the Nicolaus Copernicus University, and (as a separate part) a set of approximately forty artistic works made by academic teachers associated with the Faculty of Fine Arts, who – taking into account the wide spectrum of activities of Nicolaus Copernicus – undertook an artistic interpretation of his scientific achievements. The prepared publication is diverse, multi-threaded, and it combines a humanistic view with a technological approach and artistic sensitivity, whereas the direct inspiration for such a broad approach was the activity of the great resident of Toruń – Nicolaus Copernicus. This text refers to all articles included in this publication, but begins with a reminder of the material remains of previous anniversary celebrations, with particular emphasis on the celebrations of 1973, the most impressive material testimony of which is the campus of the Nicolaus Copernicus University. Joanna Kucharzewska, excerpt from the Introduction to the publication
Polsko-ukraińskie spotkania językowe
Authors: Butko Sophia , Gębka-Wolak Małgorzata
Published: November 2024

The monograph titled Polsko-ukraińskie spotkania językowe (Polish-Ukrainian language meetings) is the result of the 2022 project "Polskie cztery pory roku w Charkowie. Spotkania z polską kulturą, językiem i historią” ("Polish four seasons in Kharkiv. Encounters with Polish culture, language and history”) (financed by the NAWA programme “Promotion of the Polish language”, BJP/PJP/2021/1/00011/U). It was prepared by researchers from universities in Lviv, Lutsk, Kharkiv, Kraków, Łódź, Poznań, Toruń and Szczecin. The ten studies included in it, seven written in Polish and three in Ukrainian, provide a lot of previously unknown information about the Polish and Ukrainian languages and their mutual influence, the traces of which are confirmed in the lexicon and grammar. Looking at the Polish language through the prism of the structurally close Ukrainian language, and vice versa – at the Ukrainian language through the prism of the Polish language, allows us to notice new linguistic phenomena and better understand the knowledge about society, its history, culture and contacts preserved in the language. The authors of the publication hope that it will also contribute to strengthening the bonds and solidarity of two nations – Polish and Ukrainian.
Aktywność inwestycyjna polskich przedsiębiorstw w Kazachstanie (mechanizmy wsparcia). Raport
Authors: Jaworek Małgorzata , Karaszewski Włodzimierz , Kuczmarska Magdalena , Kuzel Marcin
Published: November 2024

The report from the 2022 study carried out by the team of the Nicolaus Copernicus University in Toruń as part of the project "Investment activity of Polish enterprises abroad – conditions, effects and prospects". The authors of the report, employees of the Department of Investment and Real Estate of the Faculty of Economic Sciences and Management at the Nicolaus Copernicus University in Toruń, have been conducting research on international capital flows in the form of foreign direct investment (FDI) for many years. Their first research work in this area covered FDI in Poland – the intensity, structure, determinants and effects of these investments. The research is continued in the national and regional scope, although the authors' current work is focused on the problem of investment activity of Polish enterprises abroad. In addition, the subject of the authors' scientific interest is the internationalisation of enterprises through capital, especially the activities of the world's largest direct investors, as well as multinational enterprises from developing countries. The results of their research have been published in numerous scientific studies – books and articles published at home and abroad. It is widely acknowledged that the FDI research centre in Toruń, which they co-found, is one of the leading in Poland. More about the research team: https://skolar.umk.pl.
Filozofia i psychologia egzystencjalna
Authors: Żelazny Mirosław
Published: November 2024

U zarania swego istnienia, to znaczy na początku drugiego dziesięciolecia dwudziestego wieku, egzystencjalizm był psychologią.Pomiędzy psychologią i filozofią nie było wówczas tak radykalnej różnicy jak wczasach współczesnych, w których wielu psychologów dokłada wielkich starań, by uprawianą przez siebie dyscyplinę prezentować jako naukę „poważną", wyraźnie oddzieloną od „bujającej w obłokach" filozofii. Zapominają oni o podstawowym kiedyś dla psychologii postulacie Wilhelma Diltheya: że językiem ścisłych pojęć można co prawda zjawiska precyzyjnie wyjaśniać, ale wyjaśnienie (sobie i komuś) i zrozumienie (przez siebie i kogoś) to dwa różne fenomeny ludzkiej świadomości. Dilthey był rzecznikiem psychologii rozumiejącej. Tradycję jego myśli kontynuują dziś przedstawiciele psychologii humanistycznej, przez którą rozumie się wiedzę o duchowym życiu człowieka, alternatywną, a czasem nawet opozycyjną wobec kierunków o orientacji scjentystycznej. Oczywiste jest przy tym, że użyte w tak ogólnym zakresie określenie „psychologia humanistyczna"może mieć sens tylko umowny. Każdy psycholog uważa przecież, że uprawiana przez niego dziedzina jest humanistyczna, bo inna być nie może. Łacińskie słowo „humanus" znaczy tyle, co „człowiek". I jeśli nawet współczesna psychologia zajmuje się również takimi zjawiskami, jak życie psychiczne zwierząt, to trudno byłoby znaleźć jej adepta, który zaprzeczyłby, że ostatecznym celem uprawianej przez niego dyscypliny jest poszukiwanie prawdy dotyczącej duszy człowieka. W dawnych czasach, gdy wszelka działalność określana dziś mianem naukowej wchodziła w zakres filozofii, nie było podziału na dyscypliny humanistyczne i niehumanistyczne. Nie dostrzegał go Newton, Leibniz, a nawet jeszcze Kant, dla których głównym przesłaniem wszelkiej wiedzy, nawet ścisłej matematyki, było zdobycie przez ludzką istotę prawdy o samej sobie i o swym przeznaczeniu.
Złoty kciuk. Młyn i młynarz w kulturze zachodu
Authors: Rzepkowski Krzysztof
Published: November 2024

Jak Europa długa i szeroka młynarze przez wieki cieszyli się złą reputacją zarówno w opinii ludzi pióra, jak i w oczach ludu. Cyceron uważał ich profesję za plugawe zajęcie, którym para się tylko motłoch, Boccaccio zrównywał ich status społeczny z ówczesnym statusem czarnoskórych Afrykanów, Chaucer odmalował jako nalanych opojów i bezwzględnych oszustów, a Rabelais widział w nich kutych złodziei. W przysłowiach, porzekadłach, ludowych podaniach, przyśpiewkach i balladach aż do XVII wieku niemal zawsze występowali jako pazerni bogacze i oszuści, którzy dla zysku są gotowi paktować nawet z diabłem, oraz wyzuci z zasad łajdacy, którzy dybią nie tylko na cudze ziarno, ale także na cudze żony. Uchodzili za synonim oszusta i prostaka, wcielenia zła, alegorię złodziejstwa, symbol nieuczciwości, rozwiązłości i hipokryzji. W czasach nowożytnych doczekali się zupełnie odmiennego wizerunku: jowialnych i poczciwych wieśniaków, żyjących beztrosko z dala od ludzi i spraw tego świata. Ich nalana, rumiana twarz, będąca dotąd jedynie oznaką pazerności, teraz zaczęła wyrażać także pełnię i radość życia, w którym nie stroni się od hedonistycznych przyjemności – kobiet, wina, śpiewu i tańca. Od tego momentu aż do końca tradycyjnego młynarstwa rozśpiewany i roztańczony młynarz będzie szedł w parze ze swym poprzednikiem – zachłannym i lubieżnym łajdakiem. Prezentowana książka jest zapisem ich kulturowej wędrówki przez wieki.
Świadkowie świadectw. Postpamięć zagłady w polskiej literaturze najnowszej
Authors: Mach Anna
Published: November 2024

Literatura postmemorialna omawiana przez badaczkę podejmuje wysiłek dawania świadectwa świadkom oraz bycia świadkiem świadectwa – zapewne nigdy do końca udany. Niełatwy proces włączania opowieści o Zagładzie dla wspólnotowej pamięci, który obserwujemy od lat80. XX wieku, jest tutaj poddawany wnikliwej i krytycznej analizie. Autorka rozważa, na ile melancholijny podmiot literatury lat 90. ubiegłego stulecia przełamuje narcystyczną dominantę wcześniejszej dekady, i pokazuje, w jaki sposób w twórczości epoki „powrotu Realnego” może zaistnieć etyczny aspekt postpamięci. W autobiograficznej twórczości przedstawicieli drugiego pokolenia ocalałych dostrzega zaś dramat milczenia i uwięzienie w potraumatycznym symptomie, na które powojenna Europa skazała ofiary Zagłady. Badania tu poczynione, dotyczące między innymi wczesnej recepcji tekstów sprzed transformacji, w której – kosztem podtrzymywania mitów polskiej tożsamości – pomija się lub marginalizuje żydowskie i zakładowe wątki, wykazują konieczność rewizji dotychczasowych rozpoznań i redefinicji kanonu polskiej literatury Szoa.
W poszukiwaniu pewności prawa. Precedens a przewidywalność orzeczeń sądowych w tradycji prawa anglosaskiego
Authors: Zych Tymoteusz
Published: November 2024

W tradycji prawa anglosaskiego instytucja wiążącego precedensu sądowego jest traktowana jako czynnik zwiększający poziom przewidywalności orzeczeń sądowych. Stanowisko to może prima facie wydawać się zaskakujące z perspektywy prawnika wykształconego w Europie kontynentalnej. W klasycznym pozytywistycznym paradygmacie prawniczym przyjętym w kontynentalnej kulturze prawnej instytucja wiążącego precedensu sądowego była traktowana z rezerwą, której znamiennym przykładem jest określenie superstition du cas, wykorzystywane w literaturze francuskiej do nazwania anglosaskiej zasady stare decisis. W prawie Europy kontynentalnej nowoczesna idea ius certum była utożsamiana z projektem kodyfikacji i założeniem, że prawo powinno być tworzone przez działającego racjonalnie legislatora, który miał zapewnić jego jednolity, spójny, zupełny i wewnętrznie niesprzeczny charakter. Normy zawarte w aktach legislacyjnych miały stanowić przesłankę niezawodnych wnioskowań sylogistycznych. O ile w jurysprudencji Europy kontynentalnej jest raczej akcentowany problem prawotwórczego charakteru rozstrzygnięcia sądowego w sprawie, dla której brak precedensu – czyli w przypadku, który w prawie anglosaskim jest określany mianem case of first impression – o tyle w prawie anglosaskim dużo większy nacisk kładziony jest na to, że w kolejnych rozpatrywanych sprawach reguły precedensowe stanowią ograniczenie arbitralności sędziowskiej. Autor książki podejmuje próbę określenia zależności między rozwojem sposobu pojmowania pewności prawa na przestrzeni dziejów prawa anglosaskiego a procesem kształtowania się w tym systemie wiążącej zasady stare decisis.
Revisión de casos clínicos mediante sesión virtual sincrónica en un servicio de neurología pediátrica
Authors: Henao Méndez Claudia Ximena
Published: November 2024

Con la llegada de la pandemia de covid-19 y las medidas de aislamiento físico, nació una comunidad de aprendizaje virtual en la que se realiza una exposición de un caso clínico real mediante una sesión sincrónica, moderada por un residente y orientada por el docente en un servicio de neuropediatría. En el presente capítulo se realiza una descripción de dicha actividad y se desarrolla un análisis para determinar sus fortalezas y oportunidades de mejora con base en la comparación con estrategias similares reportadas en la literatura, así como en la observación directa de una sesión y la aplicación de una encuesta a los residentes participantes; finalmente, se expone una propuesta de mejora para la estrategia en mención.
Exploring the role of the vestibular system in visuospatial memory in developmental dyslexia: Narrative review
Authors:   YMT College of Physiotherapy, Navi Mumbai, Maharashtra, India., Natrayan Ramesh , Kumar Chauhan Arvind ,   Swarnim start-up & innovation University, Gandhi Nagar, Gujarat, India.
Published: November 2024

Individuals with dyslexia face significant challenges when it comes to writing and reading, even though they can receive an education. Various theories suggest that difficulties in processing auditory and visual cues, crucial for reading, are the underlying cause of developmental dyslexia. The vestibular system intricately processes the visuospatial memory, essential to reading comprehension. This review aims to provide a detailed explanation of the crucial role of the vestibular system in visuospatial memory, cognition, and motor planning.
USE OF THE TROCHANTERIC FIXATION NAIL ADVANCED (TFNA) MAY INCREASE THE RISK FOR NAIL BREAKAGE AND EARLY BREAKAGE TIME COMPARED TO OTHER FREQUENTLY USED IMPLANTS
Authors: Karjalainen L.i , Lähdesmäki M. , Ylitalo A. , Eskelinen A. , Mattila V. M. , Repo J.
Published: November 2024

Background

Cephalomedullary nails are widely used for fixation of unstable pertrochanteric fractures. In 2018, the Depuy Synthes Trochanteric Fixation Nail - Advanced (TFNA) implant was introduced at a level I academic trauma center. Thereafter, the TFNA swiftly replaced the older implant models used at the time. Subsequently, clinical concerns were raised about the use of the TFNA due to reports of nail breakage. The purpose of this study was to investigate whether the concerns raised about the performance of the TFNA were valid and to assess long-term outcomes.

Methods

The data consisted of 2397 patients who had undergone a proximal femoral hip fracture procedure between 2014 and 2020. Data were handpicked from patient records. TFNA was compared with TFN, PFNA, Gamma3, and Intertan regarding nail breakage, breakage time and long-term outcomes.

Results

After exclusion a total of 23/1667 (1.4%) nails broke during the follow-up period. The TFNA broke the most often with 15 cases (2.0%), followed by the Gamma3 with five cases (1.1 %) and the PFNA with three cases (1.3%). Overall, the mean (SD) nail breakage time was 233 (147.8) days. However, for the TFNA, PFNA, and Gamma3, the mean breakage times were 176.8 days (109.9), 419 days (108.6), and 291.8 (153.4), respectively. In cox regression analysis we observed significant reduction in nail breakage when using PFNA with adjusted hazard risk of 0.081 [95% Ci, 0.011-0.576, p=0.011].

Conclusions

In our data, the TFNA had a slightly higher risk for nail breakage when compared to the PFNA and the Gamma3, with a risk difference of 0.7% and 0.9%, respectively. On average, the TFNA broke nearly four months earlier than the Gamma3 and more than eight months earlier than the PFNA. It should be noted, however, that implant breakage is a relatively infrequent complication.
STUDY TO EVALUATE NONOPERATIVE MANAGEMENT OF STABLE ANKLE FRACTURES AT A UNIVERSITY HOSPITAL
Authors: Bhat S. S. , Mathai N. J. , Raghavendra R. , Hodgson P.
Published: November 2024

Introduction

As per national guidelines for Ankle fractures in the United Kingdom, fractures considered stable can be treated with analgesia, splinting and allowed to weight bear as tolerated. The guidelines also suggest further follow-up not mandatory. This study was aimed at evaluating the current clinical practice of managing stable ankle fractures at a university hospital against national guidelines.

Method

The study was undertaken using retrospectively collected data, the inclusion criteria being all adults with stable ankle fracture pattern treated non-operatively between December 2022 and April 2023. Collected data included age of patient, date of injury, type of immobilization, number of clinical visits and any complications.

Results

41 cases were identified and analyzed. The mean age of the cohort was 49.8 years (Standard deviation 20.01). Twelve percent (n = 5) were reviewed in clinic, treated and discharged as stable Weber B type fracture pattern as per national guidelines after the first visit. About 52% (n = 21) were seen in clinic twice before discharge, first visit between 1-2 weeks and the last clinic visit between 5-7 weeks. About a third of patients (30%, n = 12) were seen in clinic on more than two occasions. At the first clinic visit 87% (n = 36) were given a boot and allowed to weight bear as tolerated. Two patients were diagnosed with deep vein thrombosis/pulmonary embolism during the treatment duration. Three patients had extended duration of follow up for ongoing symptoms. None discharged after first or second visit needed surgery for displaced or malunited fracture.

Conclusion

Patients discharged from clinic after first or second visit did not need any further surgery. As per national guidelines, patients deemed stable weber B lateral malleolus fracture pattern after weight bearing radiograph can be treated safely with a weight bearing walking boot with no further follow up.
3D SPHEROID CULTURE OF CHONDROCYTES TO STUDY THE INTERACTION OF CELLS AT THE CHONDRO-OSSEOUS BORDER OF ENCHONDRAL OSSIFICATION
Authors: Enderami E. , Timmen M. , Stange R.
Published: November 2024

Introduction

Cartilage comprises chondrocytes and extracellular matrix. The matrix contains different collagens, proteoglycans, and growth factors produced by chondroprogenitor cells that differentiate from proliferating to hypertrophic chondrocytes. In vitro chondrocyte growth is challenging due to differences in behaviour between 2D and 3D cultures. Our aim is to establish a murine 3D spheroid culture method using chondrocytes to study the complex interaction of cells on the chondro-osseous border during enchondral ossification.

Method

Primary chondrocytes were isolated from the knee of WT new-born mice and used to form 10,000 cell number spheroids. We used the ATDC5-chondrocyte cell line as an alternative cell type. Spheroids were observed for 7, 14, and 21 days before embedding in paraffin for slicing. Alcian blue staining was performed to identify proteoglycan positive areas to prove the formation of extracellular matrix in spheroids. Collagen type 2, and Collagen type X expression were analyzed via quantitative real-time PCR and immunohistochemistry.

Result

Alcian blue staining showed increasing matrix formation from day 7 to day 14 and proliferative chondrocytes at early time points. Both cell types showed increasing mRNA expression of Collagen type 2 from day 7 to day 21. Collagen type X positive staining starting from day 14 on confirmed the development of hypertrophic stage of chondrocytes. ATDC5 cells exhibited a slower progression in chondrogenic differentiation compared to primary chondrocytes.

Conclusion

In chondrocyte spheroids, we observed proceeding differentiation of chondrocytes reaching hypertrophic phase. Primary chondrocytes showed faster development than ATDC5 cell line. Overall, spheroid culture of chondrocytes could be a good basis to study the interaction of different cells types of the chondro-osseous border by combination of chondrocytes with e.g., endothelial cells and osteoblasts within the spheroid. Those organoid cultures might also help to reduce animal experiments in the future, by mimicking complex regeneration procedures like bone growth or fracture healing.

DFG(German Research Foundation)
BONE-TO-CARTILAGE INTERFACES: ADVANCING 3D-PRINTED NANOCOMPOSITES FROM NATURALLY DERIVED LOW-VISCOUS BIOMATERIALS
Authors: Maia J. , Bilo M. , Silva A. S. , Sobreiro-Almeida R. , Mano J.
Published: November 2024

Introduction

Ink engineering can advance 3D-printability for better therapeutics, with optimized proprieties. Herein, we describe a methodology for yielding 3D-printable nanocomposite inks (NC) using low-viscous matrices, via the interaction between the organic and inorganic phases by chemical coupling.

Method

Natural photocurable matrices were synthesized: a protein – bovine serum albumin methacrylate (BSAMA), and a polysaccharide – hyaluronic acid methacrylate (HAMA). Bioglass nanoparticles (BGNP) were synthesized and functionalized via aminosilane chemistry. The functionalization of BSAMA, HAMA, and BGNP were quantified via NMR. To arise extrudable inks, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) chemistry was used to link innate carboxylic groups of BSAMA/HAMA and amine-functionalized BGNP. Different crosslinker and BGNP amounts were tested. Visible light photopolymerization is performed, using lithium phenyl-2,4,6-trimethylbenzoylphosphinate. The NC's rheological, mechanical, and biological behavior was evaluated before 3D extrusion printability.

Result

All composite formulations effectively immobilized and homogeneously dispersed the BGNP, turning low-viscous materials (< 1 Pa) into shear-thinning formulations with tunable increased elastic/viscous moduli (50-500 Pa). More pronounced increments were found with increasing EDC/NHS and BGNP concentrations. The resulting inks produce robust and stable scaffolds successfully retrieved after post-print photocrosslinking (1-5 kPa). Bioactivity in simulated body fluid and in vitro assays using adipose-derive stem cells revealed a similar calcium/phosphate ratio to that of hydroxyapatite, and increased viability and metabolic activity. BSAMA and HAMA demonstrated distinct natures not only in printability but also in overall cellular performance and mechanical properties, making these ideal for interfacial tissue engineering.

Conclusion

This strategy demonstrated being effective and reproducible to advance nanocomposites for 3D printing using different types of biomaterials. Further, we envision using both inks to produce hierarchical constructs via extrusion printing, better mimicking bone-to-cartilage interfaces.

Acknowledgements

FCT grants (DOI:10.54499/2022.04605.CEECIND/CP1720/CT0021), (BI/UI89/10303/2022), (PRT/BD/154735/2023); EU's Horizon 2020 research and innovation programs InterLynk (Nº953169) and SUPRALIFE (Nº101079482) projects; CICECO-Aveiro Institute of Materials projects (DOI:10.54499/UIDB/50011/2020), (DOI:10.54499/UIDP/50011/2020), and (DOI:10.54499/LA/P/0006/2020), financed by FCT/MCTES(PIDDAC).
ACCURATE PREDICTION OF PEDICLE SCREW LOOSENING USING HOMOGENIZED NON-LINEAR FINITE ELEMENT MODELS
Authors: Mischler D. , Kessler F. , Zysset P. , Varga P.
Published: November 2024

Introduction

Pedicle screw loosening in posterior instrumentation of thoracolumbar spine occurs up to 60% in osteoporotic patients. These complications may be alleviated using more flexible implant materials and novel designs that could be optimized with reliable computational modeling. This study aimed to develop and validate non-linear homogenized finite element (hFE) simulations to predict pedicle screw toggling.

Method

Ten cadaveric vertebral bodies (L1-L5) from two female and three male elderly donors were scanned with high-resolution peripheral quantitative computed tomography (HR-pQCT, Scanco Medical) and instrumented with pedicle screws made of carbon fiber-reinforced polyether-etherketone (CF/PEEK). Sample-specific 3D-printed guides ensured standardized instrumentation, embedding, and loading procedures. The samples were biomechanically tested to failure in a toggling setup using an electrodynamic testing machine (Acumen, MTS) applying a quasi-static cyclic testing protocol of three ramps with exponentially increasing peak (1, 2 and 4 mm) and constant valley displacements. Implant-bone kinematics were assessed with a stereographic 3D motion tracking camera system (Aramis SRX, GOM). hFE models with non-linear, homogenized bone material properties including a strain-based damage criterion were developed based on intact HR-pQCT and instrumented 3D C-arm scans. The experimental loading conditions were imposed, the maximum load per cycle was calculated and compared to the experimental results. HR-pQCT-based bone volume fraction (BV/TV) around the screws was correlated with the experimental peak forces at each displacement level.

Result

The nonlinear hFE models accurately (slope = 1.07, intercept = 0.2 N) and precisely (R2 = 0.84) predicted the experimental peak forces at each displacement level. BV/TV alone was a weak predictor (R2<0.31).

Conclusion

The hFE models enable fast design iterations aiming to reduce the risk of screw loosening in low-density vertebrae. Improved flexible implant designs are expected to contribute to reduced complication rates in osteoporotic patients.
CHONDROGENESIS IN 3D-PRINTED HYDROGEL SCAFFOLDS SUPPLEMENTED WITH BIOACTIVE GLASS SPHERES
Authors: Gögele C. L. , Fleischmann N. , Müller S. , Liesenberg T. , Pizzadili G. , Wiltzsch S. , Gerdes T. , Schaefer-Eckart K. , Lenhart A. , Schulze-Tanzil G.
Published: November 2024

Introduction

Articular cartilage has a low self-regeneration capacity. Cartilage defects have to be treated to minimize the risk of the onset of osteoarthritis. Bioactive glass (BG) is a promising source for cartilage tissue engineering. Until now, conventional BGs (like BG1393) have been used, mostly for bone regeneration, as they are able to form a hydroxyapatite layer and are therefore, less suited for cartilage reconstruction. The aim of this study is to study the effect of 3D printed hydrogel scaffolds supplemented with spheres of the BG CAR12N to improve the chondrogenesis of mesenchymal stem cells (MSCs).

Method

Based on our new glass composition (CAR12N), small BG spheres (25-40 µm) were produced and mixed with hydrogel and primary human (h) MSCs. Grid printed scaffolds were cultivated up to 21 days in expansion or chondrogenic differentiation medium. Macroscopical images of the scaffolds were taken to observe surface changes. Vitality, DNA and sulfated glycosaminoglycan (GAG) content was semiquantitatively measured as well as extracellular matrix gene transcription.

Result

It was possible to print grid shaped hydrogel scaffolds with BG spheres and hMSCs. No significant changes in scaffold shape, surface or pore size were detected after 21 days in culture. The BG spheres were homogeneously distributed inside the grids. Vitality was significantly higher in grids with CAR12N spheres in comparison to those without. The DNA content remained constant over three weeks, but was higher in the sphere containing scaffolds than in those without BG spheres. GAG content in the grids increased not only with additional cultivation time but especially in grids with BG spheres in chondrogenic medium. Aggrecan and type II collagen gene expression was significantly higher grids cultured in the chondrogenic differentiation medium.

Conclusion

This developed 3D model, is very interesting to study the effect of BG on hMSCs and to understand the influence of leaking ions on chondrogenesis.
BIOMECHANICAL ASSESSMENT OF A NOVEL PEDICLE SCREW SYSTEM USING FINITE ELEMENT ANALYSIS
Authors: Einafshar M. M. , Massaad E. , Kiapour A.
Published: November 2024

Introduction

The biomechanical behavior of lumbar spine instrumentation is critical in understanding its efficacy and durability in clinical practice. In this study, we aim to compare the biomechanics of the lumbar spine instrumented with single-level posterior rod and screw systems employing two distinct screw designs: paddle screw versus conventional screw system.

Method

A fully cadaveric-validated 3D ligamentous model of the lumbopelvic spine served as the foundation for our comparative biomechanical analysis1. To simulate instrumentation, the intact spine was modified at the L4L5 level, employing either paddle screws or standard pedicle screws (SPS). The implants were composed of Ti-6AL-4V. Fixation at the S1 ensured consistency across loading scenarios. Loading conditions included a 400-N compressive load combined with a 10 N.m pure bending moment at the level of L1, replicating physiological motions of flexion-extension, lateral bending and axial rotation. We extracted data across various scenarios, focusing on the segmental range of motion at both implanted and adjacent levels.

Result

In the flexion of L4L5, the applied force ranged from -29.2 to 29.3 N in the paddle screw, while it ranged from -25 to 25 N in the PS system. Similarly, the extension of L4L5 ranged from -3.1 to 2.6 N in the paddle and ranged from -4.5 to 3.9 N in the SPS system. In terms of stress distributions on the screw, stress concentrations decreased in several cases in the paddle design compared to the SPS systems. Top of Form

Conclusion

The paddle screw enhanced the range of motion overall in both the upper adjacent segment (L3L4) and the lower adjacent segment (L5S1) compared to the conventional SPS system. The stability of the aimed segment was increased by 33% on average with the paddle screw compared to conventional PS. Increasing the stability of the host segment decreases the possibility of non-union and the rate of fusion failure 2.
MATRIX MAYHEM: INVESTIGATING THE EFFECTS OF PERICELLULAR PROTEOLYSIS ON BIOMECHANICAL PROPERTIES AND CALCIUM SIGNALLING IN ARTICULAR CARTILAGE
Authors: Nieuwstraten J. , Guilak F. , Danalache M.
Published: November 2024

Introduction

Within articular cartilage, chondrocytes reside within the pericellular matrix (PCM), collectively constituting the microanatomical entity known as a chondron. The PCM functions as a pivotal protective shield and mediator of biomechanical and biochemical cues. In the context of Osteoarthritis (OA), enzymatic degradation of the PCM is facilitated by matrix metalloproteinases (MMPs). This study delves into the functional implications of PCM structural integrity decline on the biomechanical properties of chondrons and impact on Ca2+ signaling dynamics.

Method

Chondrons isolated from human cartilage explants were incubated with activated MMP-2, -3, or -7. Structural degradation of the pericellular matrix (PCM) was assessed by immunolabelling (collagen type VI and perlecan, n=5). Biomechanical properties of chondrons (i.e. elastic modulus (EM)) were analyzed using atomic force microscopy (AFM). A fluorescent calcium indicator (Fluo-4-AM) was used to record and quantify the intracellular Ca2+ influx of chondrons subjected to single cell mechanical loading (500nN) with AFM (n=7).

Result

Each of the three MMPs disrupted the structural integrity of the PCM, leading to attenuated fluorescence intensity for both perlecan and collagen VI. A significant decrease of EM was observed for all MMP groups (p<0.005) with the most notable decrease observed for MMP-2 and MMP-7 (p<0.001). In alignment with the AFM results, there was a significant alteration in Ca2+ influx observed for all MMP groups (p<0.05), in particular for MMP-2 and MMP-7 (p<0.001).

Conclusion

Proteolysis of the PCM by MMP-2, -3, and -7 not only significantly alters the biomechanical properties of articular chondrons but also affects their mechanotransduction profile and response to mechanical loading, indicating a close interconnection between these processes. These findings underscore the influence of an intact pericellular matrix (PCM) in protecting cells from high stress profiles and carry implications for the transmission of mechanical signaling during OA onset and progression.
TIE2-ENHANCED NUCLEUS PULPOSUS CELL-DERIVED EXTRACELLULAR VESICLES ENHANCE DEGENERATIVE DISC CELL VIABILITY IN VITRO
Authors: Ambrosio L. , Schol J. , Fernández C. R. , Papalia R. , Vadalà G. , Denaro V. , Sakai D.
Published: November 2024

Introduction

Intervertebral disc degeneration (IDD) is a progressive process affecting all disc tissues, namely the nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplates (CEPs). Several cell-based therapies have been proposed to replenish the disc cell population and promote tissue regeneration. However, cell-free therapeutics have been increasingly explored due to potentially higher advantages and cost-effectiveness compared to cell transplantation. Recently, extracellular vesicles (EVs) isolated from healthy Tie2+-NP cells (NPCs) have shown promising regenerative outcomes on degenerative NPCs (dNPCs). The aim of this study was to assess the effect of such EVs on all disc cell types, including AF cells (AFCs) and CEP cells (CEPCs), compared to EVs isolated from bone-marrow derived mesenchymal stromal cells (BM-MSCs).

Method

NPCs harvested from young donors underwent an optimized culture protocol to maximize Tie2 expression (NPCsTie2+). BM-MSCs were retrieved from a commercial cell line or harvested during spine surgery procedures. EV characterization was performed via particle size analysis (qNano), expression of EV markers (Western blot), and transmission electron microscopy. dNPCs, AFCs, and CEPCs were isolated from surgical specimens of patients affected by IDD, culture-expanded, and treated with NPCsTie2+-EVs or BM-MSC-EVs ± 10 ng/mL IL-1b. EV uptake was assessed with PKH26 staining of EVs under confocal microscopy. Cell proliferation and viability were assessed with the CCK-8 assay.

Result

Upon characterization, isolated EVs exhibited the typical exosomal characteristics. NPCsTie2+-EVs and BM-MSC-EVs uptake was successfully observed in all dNPCs, AFCs, and CEPCs. Both EV products significantly increased dNPC, AFC, and CEPC viability, especially in samples treated with NPCsTie2+-EVs.

Conclusion

NPCsTie2+-EVs demonstrated to significantly stimulate the proliferation and viability of degenerative cells isolated from all disc tissues. Rather than the sole NP, EVs isolated by committed progenitors physiologically residing within the disc may exert their regenerative effects on the whole organ, thus possibly constituting the basis for a new therapy for IDD.
THE POTENTIAL OF STRAIN SENSORS ON A POSTERIOR INSTRUMENTATION TO ASSESS HEALING OF TRANSOSSEOUS FRACTURES IN A LUMBAR VERTEBRA: A CADAVERIC STUDY
Authors: Heumann M. , Jacob A. , Gueorguiev B. , Richards G. , Benneker L.
Published: November 2024

Introduction

Transosseous flexion-distraction injuries of the spine typically require surgical intervention by stabilizing the fractured vertebra during healing with a pedicle-screw-rod constructs. As healing is taking place the load shifts from the implant back to the spine. Monitoring the load-induced deflection of the rods over time would allow quantifiable postoperative assessment of healing progress without the need for radiation exposure or frequent hospital visits. This approach, previously demonstrated to be effective in assessing fracture healing in long bones and monitoring posterolateral spinal fusion in sheep, is now being investigated for its potential in evaluating lumbar vertebra transosseous fracture healing.

Method

Six human cadaveric spines were instrumented with pedicle-screws and rods spanning L3 vertebra. The spine was loaded in Flexion-Extension (FE), Lateral-Bending (LB) and Axial-Rotation (AR) with an intact L3 vertebra (representing a healed vertebra) and after transosseous disruption, creating an AO type B1 fracture. The implant load on the rod was measured using an implantable strain sensor (Monitor) on one rod and on the contralateral rod by a strain gauge to validate the Monitor's measurements. In parallel the range of motion (ROM) was assessed.

Result

The ROM increased significantly in all directions in the fractured model (p≤0.049). The Monitor measured a significant increase in implant load in FE (p=0.002) and LB (p=0.045), however, not in AR. The strain gauge detected an increased implant load not only in FE (p=0.001) and LB (p=0.016), but also in AR (p=0.047). The highest strain signal was found during LB for both, the Monitor, and the strain gauge.

Conclusion

After a complete transosseous disruption of L3 vertebra the load on the implants was significantly higher than in the intact respectively healed state. Innovative implantable sensors could be used to monitor those changes allowing the assessment of healing progression based on quantifiable data rather than CT-imaging.
EFFECTS OF LOW DOSE BMP-2 AND IMMUNOMODULATION TARGETING IL-1ß ON FRACTURE HEALING IN A FEMUR DEFECT MODEL IN RATS
Authors: Schröder M. , Gens L. , Arens D. , Giger N. , Gehweiler D. , Nehrbass D. , Zderic I. , Zeiter S. , Stoddart M. , Wehrle E.
Published: November 2024

Introduction

Immunomodulation represents a novel strategy to improve bone healing in combination with low doses of bone morphogenetic growth factors like BMP-2. This study aims to investigate the effect and timing of monoclonal anti-IL-1ß antibody administration with 1μg BMP-2 on bone healing over 14 weeks in a rat femur segmental defect model.

Method

2 mm femoral defects were created in 22-27 weeks-old female Fischer F344 rats, internally fixed with a plate (animal license: GR/19/2022) using established protocols for analgesia and anesthesia. Animals (n=4/group) received either a collagen sponge, a collagen sponge+1μg BMP-2 (InductOs, Medtronic) or a collagen sponge+1μg BMP-2 with a monoclonal anti-IL-1ß antibody (BioXCell, 10 mg/ml), administered intravenously under anesthesia every third day until day 15, from day 0 or 3. In vivo micro-CT was performed after surgery and at 2, 3, 4, 6, 8, 10 and 14-weeks post-OP. Mechanical properties of the operated femurs were assessed by 4-point bending (Instron5866) and compared to contralateral femurs (one-way ANOVA, GraphPad Prism8). Histopathological analysis was performed semi-quantitatively on Giemsa-Eosin-stained sections (Olympus BX63) using a six-grade severity grading scale.

Result

Operated femurs with BMP-2 reached an average stiffness of 91±37% of contralateral femurs, femurs in IL-1ß groups 105±11% (day 0) and 111±12% (day 3). Administration of anti-IL-1ß+1μg BMP-2 led to faster cortical bridging (3/4 femurs bridged by week 4 for day 0, 4/4 for day 3) than 1μg BMP-2 alone (0/4 by week 4). Micro-CT results confirmed histopathological evaluation, as collagen sponge alone led to non-union, complete bicortical bridging was observed for 3/4 femurs in the BMP-2 group and for 4/4 femurs in the IL-1β groups after 14 weeks.

Conclusion

Anti-IL-1ß had a beneficial effect on late fracture healing with faster cortical bridging and new bone formation than 1μg BMP-2 alone.

Acknowledgments

AO foundation. We thank Andrea Furter, Alisa Hangartner and Thomas Krüger for technical support.
NOVEL APPLICATION OF THE OXFORD KNEE SCORE TO ASSESS KNEE PAIN, FUNCTION, AND QUALITY OF LIFE AFTER WEIGHT LOSS SURGERY
Authors: Federer S. , Dunne M. , Pring C. , Smith N. , Hudson P.
Published: November 2024

Introduction

Many patients with obesity experience knee pain. Excess body weight is a modifiable risk factor for osteoarthritis (OA) and weight loss is encouraged in patients with OA. Bariatric surgery could improve or limit the progression of these conditions through significant weight loss. The Oxford Knee Score (OKS) is a validated tool in the assessment of knee replacement surgery for OA. We present a novel application of the OKS to assess knee pain & function after weight loss surgery. The primary aim of this study was to assess whether there was a significant difference in mean OKS before and 24 months after weight loss surgery.

Method

Eighteen female participants were included in this study. They underwent sleeve gastrectomy or Roux-en-Y gastric bypass. Patient demographics, body mass index (BMI) and OKS were collected pre- and 24 months post operatively.

Result

There was an increase in the mean OKS from 31.8 (SD 11.8) pre surgery to 36.6 (SD 12.3) at 24 months. This was statistically significant (95% CI 0.99-10.5, p=0.02). Mean BMI reduced from 46.6 kg/m2 (SD 5.8) to 33.0 kg/m2 (SD 3.5).

Conclusion

A significant improvement in mean OKS was seen after weight loss surgery. These findings demonstrate an improvement in knee pain & function with weight loss. This study contributes to a larger project evaluating the kinetic and kinematic changes to walking gait from weight loss.