bluuebunny/crossref_metadata_2025_split huggingface dataset:
De‐novo “germline second hit” loss‐of‐heterozygosity RBP3 deletion mutation causing recessive high myopia
Authors: Gombosh Maya , Yogev Yuval , Hadar Noam , Proskorovski‐Ohayon Regina , Aharoni Sarit , Gradstein Libe , Birk Ohad S. 
Published: June 2023

AbstractKnudson's “two hit” hypothesis, mostly associated with cancer, relates to a primary heterozygous germline mutation complemented by a somatic mutation in the second allele. When the somatic “second hit” is a deletion mutation, the heterozygosity due to the first hit is lost (“loss of heterozygosity”). As the rate of germline mutations is almost two orders of magnitude lower than that of somatic mutations, de‐novo germline mutations causing autosomal recessive diseases in carriers of inherited heterozygous mutations are not common. We delineate a case of high myopia presenting at infancy with mild diminution of retinal responses. Exome sequencing identified a paternally inherited apparently homozygous missense mutation in RBP3. Chromosomal microarrays delineated a de‐novo germline heterozygous deletion encompassing RBP3, verified through revision of WES data. Thus, we demonstrate an inherited RBP3 missense mutation complemented by a de‐novo germline RBP3 deletion, causing loss of heterozygosity of the inherited mutation. We describe a novel RBP3 missense mutation, report the first isolated RBP3 deletion, and demonstrate infantile high myopia as an initial presentation of RBP3 disease. Notably, we highlight de‐novo germline deletion mutations causing “loss of heterozygosity” of inherited heterozygous mutations, culminating in autosomal recessive diseases, and discuss the scarce literature.
Dimensional changes after horizontal and vertical guided bone regeneration without membrane fixation using the retentive flap technique: A 1‐year retrospective study
Authors: Park Jin‐Young , Chung Hye‐Min , Strauss Franz‐Josef , Lee Jung‐Seok 
Published: June 2023

AbstractAimTo evaluate the dimensional changes after horizontal and vertical guided bone regeneration (GBR) without membrane fixation using the retentive flap technique.MethodsThis study retrospectively examined two cohorts that received vertical or horizontal ridge augmentations (VA or HA groups). GBR was performed using particulate bone substitutes and resorbable collagen membranes. The augmented sites were stabilized using the retentive flap technique without any additional membrane fixation. The augmented tissue dimensions were assessed using cone‐beam computed tomography at preoperative, immediately postoperative (IP), 4 months (4M), and 1 year (1Y).ResultsPostoperative vertical bone gain in 11 participants of VA group amounted to 5.96 ± 1.88 mm at IP, which decreased to 5.53 ± 1.62 at 4M and to 5.26 ± 1.52 mm at 1Y (intragroup p < 0.05). The horizontal bone gain at IP in 12 participants amounted to 3.98 ± 2.06 mm, which decreased to 3.02 ± 2.06 at 4M and to 2.48 ± 2.09 mm at 1Y (intragroup p < 0.05). The mean implant dehiscence defect height after 1Y was 0.19 ± 0.50 mm in the VA group, and 0.57 ± 0.93 mm in the HA group.ConclusionGBR without membrane fixation using the retentive flap technique seems to preserve the radiographic bone dimensions of vertically augmented sites. This technique may be less effective at preserving the width of the augmented tissue.
Exosomal miR‐6733‐5p mediates cross‐talk between glioblastoma stem cells and macrophages and promotes glioblastoma multiform progression synergistically
Authors: Huang Shilu , Liu Liang , Xu Zhipeng , Liu Xinglei , Wu Anyi , Zhang Xiaopei , Li Zengyang , Li Suwen , Li Yongdong , Yuan Jiaqi , Cheng Shan , Li Haoran , Dong Jun 
Published: June 2023

AbstractAimExosomal miRNAs derived from glioblastoma stem cells (GSCs) are important mediators of immunosuppressive microenvironment formation in glioblastoma multiform (GBM), especially in M2‐like polarization of tumor‐associated macrophages (TAMs). However, the exact mechanisms by which GSCs‐derived exosomes (GSCs‐exo) facilitate the remodeling of the immunosuppressive microenvironment of GBM have not been elucidated.MethodsTransmission electron microscopy (TME) and nanoparticle tracking analysis (NTA) were applied to verify the existence of GSCs‐derived exosomes. Sphere formation assays, flow cytometry, and tumor xenograft transplantation assays were performed to identify the exact roles of exosomal miR‐6733‐5p. Then, the mechanisms of miR‐6733‐5p and its downstream target gene regulating crosstalk between GSCs cells and M2 macrophages were further investigated.ResultsGSCs‐derived exosomal miR‐6733‐5p induce macrophage M2 polarization of TAMs by positively targeting IGF2BP3 to activate the AKT signaling pathway, which further facilitates the self‐renewal and stemness of GSCs.ConclusionGSCs secrete miR‐6733‐5p‐rich exosomes to induce M2‐like polarization of macrophages, as well as enhance GSCs stemness and promote malignant behaviors of GBM through IGF2BP3 activated AKT pathway. Targeting GSCs exosomal miR‐6733‐5p may provide a potential new strategy against GBM.
Differences in survival prognosticators between children and adults with H3K27M‐mutant diffuse midline glioma
Authors: Gong Xuan , Kuang Shuwen , Deng Dongfeng , Wu Jun , Zhang Longbo , Liu Chao 
Published: June 2023

AbstractAimsH3K27M‐mutant diffuse midline glioma (DMG) is a rare and aggressive central nervous system tumor. The biological behavior, clinicopathological characteristics, and prognostic factors of DMG have not yet been completely uncovered, especially in adult patients. This study aims to investigate the clinicopathological characteristics and identify prognostic factors of H3K27M‐mutant DMG in pediatric and adult patients, respectively.MethodsA total of 171 patients with H3K27M‐mutant DMG were included in the study. The clinicopathological characteristics of the patients were analyzed and stratified based on age. The Cox proportional hazard model was used to determine the independent prognostic factors in pediatric and adult subgroups.ResultsThe median overall survival (OS) for the entire cohort was 9.0 months. Significant differences were found in some clinicopathological characteristics between children and adults. The median OS was also significantly different between the pediatric and adult subgroups, with 7.1 months for children and 12.3 months for adults (p < 0.001). In the overall population, the multivariate analysis identified adult patients, single lesion, concurrent chemoradiotherapy/radiotherapy, and intact ATRX expression as independent favorable prognostic factors. In the age‐stratified subgroups, the prognostic factors varied between children and adults, with intact ATRX expression and single lesion being independent favorable prognostic factors in adults, while infratentorial localization was significantly associated with worse prognosis in children.ConclusionsThe differences in clinicopathological features and prognostic factors between pediatric and adult patients with H3K27M‐mutant DMG suggest the need for further clinical and molecular stratification based on age.
A spatiotemporal gene expression and cell atlases of the developing rat ovary
Authors: Shi Yong , Guo Yanjie , Zhou Jiayi , Cui Guanshen , Cheng Jung‐Chien , Wu Ying , Zhao Yong‐Liang , Fang Lanlan , Han Xiao , Yang Yun‐Gui , Sun Yingpu 
Published: June 2023

AbstractNormal ovarian development is necessary for the production of healthy oocytes. However, the characteristics of oocytes development at different stages and the regulatory relationship between oocytes and somatic cells remain to be fully explained. Here, we combined scRNA‐seq and spatial transcriptomic sequencing to profile the transcriptomic atlas of developing ovarian of the rat. We identified four components from developing granulosa cells including cumulus, primitive, mural, and luteal cells, and constructed their differential transcriptional regulatory networks. Several novel growth signals from oocytes to cumulus cells were identified, such as JAG1‐NOTCH2 and FGF9‐FGFR2. Moreover, we observed three cumulus sequential phases during follicle development determined by the key transcriptional factors in each cumulus phase (Bckaf1, Gata6, Cebpb, etc.), as well as the potential pinpointed roles of macrophages in luteal regression. Altogether, the single‐cell spatial transcriptomic profile of the ovary provides not only a new research dimension for temporal and spatial analysis of ovary development, but also valuable data resources and a research basis for in‐depth excavation of the mechanisms of mammalian ovary development.
Endothelial Stat3 activation promotes osteoarthritis development
Authors: Li Jiadong , Zhang Wencai , Liu Xinru , Li Guangfeng , Gu Yuyuan , Zhang Kun , Shen Fuming , Wu Xiang , Jiang Yingying , Zhang Qin , Zhou Fengjin , Xu Ke , Su Jiacan 
Published: June 2023

AbstractThe mechanism of the balance between subchondral angiogenesis and articular damage within osteoarthritis (OA) progression remains a mystery. However, the lack of specific drugs leads to limited clinical treatment options for OA, frequently failing to prevent eventual joint destruction in patients. Increasing evidence suggests that subchondral bone angiogenesis precedes cartilage injury, while proliferating endothelial cells (ECs) induce abnormal bone formation. Signal transducer and activator of transcription 3 (Stat3) is triggered by multiple cytokines in the OA microenvironment. Here, we observed elevated Stat3 activation in subchondral bone H‐type vessels. Endothelial Stat3 activation will lead to stronger cell proliferation, migration and angiogenesis by simulating ECs in OA. In contrast, either Stat3 activation inhibition or knockdown of Stat3 expression could relieve such alterations. More interestingly, blocking Stat3 in ECs alleviated angiogenesis‐mediated osteogenic differentiation and chondrocyte lesions. Stat3 inhibitor reversed surgically induced subchondral bone H‐type vessel hyperplasia in vivo, significantly downregulating vessel volume and vessel number. Due to the reduced angiogenesis, subchondral bone deterioration and cartilage loss were alleviated. Overall, our data suggest that endothelial Stat3 activation is an essential trigger for OA development. Therefore, targeted Stat3 blockade is a novel promising therapeutic regimen for OA.
Small interference (RNAi) technique: Exploring its clinical applications, benefits and limitations
Authors: Redhwan Moqbel Ali Moqbel , M.G. Hariprasad , Samaddar Suman , Hard Sumaia Abdulbari Ahmed Ali , Yadav Vidyabhushan , Mukherjee Apurbo , Kumar Rahul 
Published: June 2023

AbstractBackgroundSmall interference RNA (siRNA) has emerged as the most desired method for researchers and clinicians who wish to silence a specific gene of interest and has been extensively developed as a therapeutic agent. This review points to collecting all clinical trials on siRNA and understanding its benefits, pharmacokinetics and safety by reading articles published in the last 5 years.Materials and MethodsSearching in the PubMed database using ‘siRNA’ and ‘in vivo’ with limits to articles published in the previous 5 years, article type ‘clinical trials’ and language ‘English’ to acquire papers on in vivo studies on siRNA approaches. Features of siRNA clinical trials registered at https://clinicaltrials.gov/ were analysed.ResultsSo far, 55 clinical studies have been published on siRNA. Many published clinical trials on siRNA showed tolerability, safety and effectiveness in treating cancers like breast, lung, colon, and other organs and other diseases like viral infections and hereditary diseases. Many different routes of administration can silence many genes at the same time. Limitations and uncertainties associated with siRNA treatment include the effectiveness of cellular uptake, precise targeting of the intended tissue or cell and prompt elimination from the body.ConclusionsThe siRNA or RNAi method will be one of the most critical and influential techniques to fight against many different diseases. Although the RNAi approach has certain advantages, it also has limitations concerning clinical applications. Overcoming these limitations remains a daunting challenge.
Central nervous system tumours among users of vaginal oestradiol tablets: A nationwide population‐based study
Authors: Pourhadi Nelsan , Meaidi Amani , Friis Søren , Torp‐Pedersen Christian , Mørch Lina S. 
Published: June 2023

AbstractBackground and purposeIt is currently unknown whether vaginal oestradiol is associated with development of meningioma and glioma. The aim of this study was to examine associations between cumulative use and treatment intensity of vaginally administered oestradiol tablets and incidence of meningioma and glioma in a nationwide, population‐based study.MethodsWe conducted a nested case–control study within a nationwide cohort of Danish women followed from 2000 to 2018. The cohort consisted of 590,676 women aged 50–60 years at study start, without prior cancer diagnosis or use of systemic hormone therapy. Information on cumulative dose, duration, and intensity of vaginal oestradiol tablet use was assessed from filled prescriptions. Conditional logistic regression provided adjusted hazard ratios (HRs) for the association between vaginal oestradiol use and diagnosis of meningioma or glioma.ResultsWe identified 1108 women with meningioma and 835 with glioma. Of these, 19.8% and 14.0% used vaginal oestradiol tablets, respectively. The HRs in those with ever‐use of vaginal oestradiol tablets was 1.14 (95% confidence interval [CI] 0.97–1.34) for meningioma and 0.90 (95% CI 0.73–1.11) for glioma. The corresponding HRs for new users exclusively were 1.18 (95% CI 0.99–1.40) for meningioma and 0.89 (95% CI 0.71–1.13) for glioma. Intensity of vaginal oestradiol tablet use according to duration and user status yielded slightly elevated HRs for meningioma without an apparent dose–response pattern, while the HRs for glioma were generally below unity. Among new users, the HR with high intensity of current or recent vaginal oestradiol tablet use for 2+ years was 1.66 (95% CI 1.09–2.55) for meningioma and 0.77 (95% CI 0.41–1.44) for glioma.ConclusionUse of vaginal oestradiol tablets was associated with a slightly increased incidence of meningioma but not of glioma. Owing to the observational nature of the study, residual bias cannot be ruled out.
Three to four mRNA COVID‐19 vaccines in multiple sclerosis patients on immunosuppressive drugs: Seroconversion and variant neutralization
Authors: Louapre Céline , Belin Lisa , Marot Stéphane , Hippolyte Amandine , Januel Edouard , Ibrahim Michella , Jeantin Lina , Zafilaza Karen , Malet Isabelle , Charbonnier‐Beaupel Fanny , Rosenzwajg Michelle , Soulié Cathia , Marcelin Anne‐Geneviève , Pourcher Valérie 
Published: June 2023

AbstractBackground and purposeAn enhanced severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine regimen could improve humoral vaccine response in patients with multiple sclerosis (MS) treated by anti‐CD20. The aim was to evaluate the serological response and the neutralizing activity after BNT162b2 primary and booster vaccination in MS patients, including patients on anti‐CD20 receiving a primary vaccine regimen enhanced with three injections.MethodsIn this prospective longitudinal cohort study of 90 patients (47 on anti‐CD20, 10 on fingolimod, 33 on natalizumab, dimethylfumarate or teriflunomide), anti‐SARS‐CoV‐2 receptor binding domain (RBD) immunoglobulin G antibodies were quantified and their neutralization capacity was evaluated by enzyme‐linked immunosorbent assay (GenScript) and a virus neutralization test against B.1 historical strain, Delta and Omicron variants, before and after three to four BNT162b2 injections.ResultsAfter the primary vaccination scheme, the anti‐RBD positivity rate was strongly decreased in patients on anti‐CD20 (28% [15%; 44%] after two shots, 45% [29%; 62%] after three shots) and fingolimod (50% [16%; 84%]) compared to other treatments (100% [90%; 100%]). Neutralization activity was also decreased in patients on anti‐CD20 and fingolimod, and notably low for the Omicron variant in all patients (0%–22%). Delayed booster vaccination was performed in 54 patients, leading to a mild increase of anti‐RBD seropositivity in patients on anti‐CD20 although it was still lower compared to other treatments (65% [43%; 84%] vs. 100% [87%; 100%] respectively). After a booster, Omicron neutralization activity remained low on anti‐CD20 and fingolimod treated patients but was strongly increased in patients on other treatments (91% [72%; 99%]).DiscussionIn MS patients on anti‐CD20, an enhanced primary vaccination scheme moderately increased anti‐RBD seropositivity and anti‐RBD antibody titre, but neutralization activity remained modest even after a fourth booster injection.Trial registration informationCOVIVAC‐ID, NCT04844489, first patient included on 20 April 2021.
The reasonable citizen: A model for bridging ethics and politics in the EU
Authors: Mangini Michele 
Published: June 2023

AbstractThe ethical‐political model of the EU needs normative rethinking after the pandemic. Using Dworkin's ‘thesis of continuity’ between ethics and politics, I argue that a strong model of the citizen, called on to exercise duties and civic virtues, is badly needed by the EU. The legitimacy of EU political institutions is not enough, if we want to promote the participation of citizens to their functioning. The basic point is that of arguing in favour of the model of ‘the reasonable citizen’, aimed to overcome the dominant liberal model of ‘citizenship as rights’. This is shown by the ‘European Social Model’, but its weaknesses need to be supplemented by a republican conception. In order for the reasonable citizen not to be just an abstract ideal, some measure of operationalisation is proposed through ‘progressively increasing constellations of common identities’; these rely on and respect the multiple demoi of the EU.
Topical N‐phosphonacetyl‐l‐aspartate is a dual action candidate for treating non‐melanoma skin cancer
Authors: Mahen Kala K. , Markley Lilian , Bogart Jolie , Klatka Hope , Krishna Vijay , Maytin Edward V. , Stark George R. , McDonald Christine 
Published: June 2023

AbstractEach year, 3.3 million Americans are diagnosed with non‐melanoma skin cancers (NMSC) and an additional 40 million individuals undergo treatment of precancerous actinic keratosis lesions. The most effective treatments of NMSC (surgical excision and Mohs surgery) are invasive, expensive and require specialised training. More readily accessible topical therapies currently are 5‐fluorouracil (a chemotherapeutic agent) and imiquimod (an immune modulator), but these can have significant side effects which limit their efficacy. Therefore, more effective and accessible treatments are needed for non‐melanoma cancers and precancers. Our previous work demonstrated that the small molecule N‐phosphonacetyl‐L‐aspartate (PALA) both inhibits pyrimidine nucleotide synthesis and activates pattern recognition receptor nucleotide‐binding oligomerization domain 2. We propose that topical application of PALA would be an effective NMSC therapy, by combining the chemotherapeutic and immune modulatory features of 5‐fluorouracil and imiquimod. Daily topical application of PALA to mouse skin was well tolerated and resulted in less irritation, fewer histopathological changes, and less inflammation than caused by either 5‐fluorouracil or imiquimod. In an ultraviolet light‐induced NMSC mouse model, topical PALA treatment substantially reduced the numbers, areas and grades of tumours, compared to vehicle controls. This anti‐neoplastic activity was associated with increased expression of the antimicrobial peptide cathelicidin and increased recruitment of CD8+ T cells and F4/80+ macrophages to the tumours, demonstrating both immunomodulatory and anti‐proliferative effects. These findings indicate that topical PALA is an excellent candidate as an effective alternative to current standard‐of‐care NMSC therapies.
Effect of L‐T and S‐T orientations on fatigue crack growth in an aluminum 7050‐T7451 plate
Authors: Borges Micael F. , Antunes Fernando V. , Jesus Joel , Branco Ricardo , Prates Pedro , Neto Diogo M. 
Published: June 2023

AbstractThis study is focused on the anisotropic fatigue crack growth (FCG) behavior of an aluminum AA7050‐T7451 plate. L‐T and S‐T orientations were studied in M(T) samples with W = 50 mm, in mode I loading, with R‐ratio of +0.05. A numerical approach was used, assuming that crack tip plastic strain is the crack driving force. A purely kinematic elastic–plastic model was calibrated using experimental data from low cycle fatigue tests of smooth specimens in L and S orientations. The predicted FCG rates agree well with experimental trends in the Paris' regime, suggesting that cyclic plastic deformation is the main damage mechanism. The numerical model was used to estimate the stress ratio effect for both orientations, which was found to be linked with crack closure variations. However, the closure free predicted trends for both microstructural orientations at R = 0.05 are not overlapped, suggesting an effect of microstructure not linked to crack closure.
Interactions between intradialytic central venous oxygen saturation, relative blood volume, and all‐cause mortality in maintenance hemodialysis patients
Authors: Preciado Priscila , Rosales Merlo Laura , Zhang Hanjie , Kooman Jeroen P. , van der Sande Frank M. , Kotanko Peter 
Published: June 2023

AbstractIntroductionIn maintenance hemodialysis (HD) patients, low central venous oxygen saturation (ScvO2) and small decline in relative blood volume (RBV) have been associated with adverse outcomes. Here we explore the joint association between ScvO2 and RBV change in relation to all‐cause mortality.MethodsWe conducted a retrospective study in maintenance HD patients with central venous catheters as vascular access. During a 6‐month baseline period, Crit‐Line (Fresenius Medical Care, Waltham, MA) was used to measure continuously intradialytic ScvO2 and hematocrit‐based RBV. We defined four groups per median change of RBV and median ScvO2. Patients with ScvO2 above median and RBV change below median were defined as reference. Follow‐up period was 3 years. We constructed Cox proportional hazards model with adjustment for age, diabetes, and dialysis vintage to assess the association between ScvO2 and RBV and all‐cause mortality during follow‐up.FindingsBaseline comprised 5231 dialysis sessions in 216 patients. The median RBV change was −5.5% and median ScvO2 was 58.8%. During follow‐up, 44 patients (20.4%) died. In the adjusted model, all‐cause mortality was highest in patients with ScvO2 below median and RBV change above median (HR 6.32; 95% confidence interval [CI] 1.37–29.06), followed by patients with ScvO2 below median and RBV change below median (HR 5.04; 95% CI 1.14–22.35), and ScvO2 above median and RBV change above median (HR 4.52; 95% CI 0.95–21.36).DiscussionConcurrent combined monitoring of intradialytic ScvO2 and RBV change may provide additional insights into a patient's circulatory status. Patients with low ScvO2 and small changes in RBV may represent a specifically vulnerable group of patients at particularly high risk for adverse outcomes, possibly related to poor cardiac reserve and fluid overload.