bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of relapsed clinical stage I versus de novo metastatic testicular cancer patients: an analysis of the IGCCCG Update database
Authors: Lauritsen Jakob , Sauvé Nicolas , Tryakin Alexey , Jiang Di Maria , Huddart Robert , Heng Daniel Y. C. , Terbuch Angelika , Winquist Eric , Chovanec Michal , Hentrich Marcus , Fankhauser Christian D. , Shamash Jonathan , del Muro Xavier Garcia , Vaughn David , Heidenreich Axel , Sternberg Cora N. , Sweeney Christopher , Necchi Andrea , Bokemeyer Carsten , Bandak Mikkel , Jandari Abolghassem , Collette Laurence , Gillessen Silke , Beyer Joerg , Daugaard Gedske 
Published: September 2023

Abstract
Background
Active surveillance after orchiectomy is the preferred management in clinical stage I (CSI) germ-cell tumours (GCT) associated with a 15 to 30% relapse rate.

Patients and methods
In the IGCCCG Update database, we compared the outcomes of gonadal disseminated GCT relapsing from initial CSI to outcomes of patients with de novo metastatic GCT.

Results
A total of 1014 seminoma (Sem) [298 (29.4%) relapsed from CSI, 716 (70.6%) de novo] and 3103 non-seminoma (NSem) [626 (20.2%) relapsed from CSI, 2477 (79.8%) de novo] were identified. Among Sem, no statistically significant differences in PFS and OS were found between patients relapsing from CSI and de novo metastatic disease [5-year progression-free survival (5y-PFS) 87.6% versus 88.5%; 5-year overall survival (5y-OS) 93.2% versus 96.1%). Among NSem, PFS and OS were higher overall in relapsing CSI patients (5y-PFS 84.6% versus 80.0%; 5y-OS 93.3% versus 88.7%), but there were no differences within the same IGCCCG prognostic groups (HR = 0.89; 95% CI: 0.70–1.12). Relapses in the intermediate or poor prognostic groups occurred in 11/298 (4%) Sem and 112/626 (18%) NSem.

Conclusion
Relapsing CSI GCT patients expect similar survival compared to de novo metastatic patients of the same ICCCCG prognostic group. Intermediate and poor prognosis relapses from initial CSI expose patients to unnecessary toxicity from more intensive treatments.
DNA damage response inhibitors enhance tumour treating fields (TTFields) potency in glioma stem-like cells
Authors: Vanderlinden Aurelie , Jones Callum G. , Myers Katie N. , Rominiyi Ola , Collis Spencer J. 
Published: September 2023

Abstract
Background
High-grade gliomas are primary brain cancers with unacceptably low and persistent survival rates of 10–16 months for WHO grade 4 gliomas over the last 40 years, despite surgical resection and DNA-damaging chemo-radiotherapy. More recently, tumour-treating fields therapy (TTFields) has demonstrated modest survival benefit and been clinically approved in several countries. TTFields is thought to mediate anti-cancer activity by primarily disrupting mitosis. However, recent data suggest that TTFields may also attenuate DNA damage repair and replication fork dynamics, providing a potential platform for therapeutic combinations incorporating standard-of-care treatments and targeted DNA damage response inhibitors (DDRi).

Methods
We have used patient-derived, typically resistant, glioma stem-like cells (GSCs) in combination with the previously validated preclinical Inovitro™ TTFields system together with a number of therapeutic DDRi.

Results
We show that TTFields robustly activates PARP- and ATR-mediated DNA repair (including PARylation and CHK1 phosphorylation, respectively), whilst combining TTFields with PARP1 or ATR inhibitor treatment leads to significantly reduced clonogenic survival. The potency of each of these strategies is further enhanced by radiation treatment, leading to increased amounts of DNA damage with profound delay in DNA damage resolution.

Conclusion
To our knowledge, our findings represent the first report of TTFields applied with clinically approved or in-trial DDRi in GSC models and provides a basis for translational studies toward multimodal DDRi/TTFields-based therapeutic strategies for patients with these currently incurable tumours.
SIRT2 alleviated renal fibrosis by deacetylating SMAD2 and SMAD3 in renal tubular epithelial cells
Authors: Yang Shu , Yang Guangyan , Wang Xinyu , Xiang Jiaqing , Kang Lin , Liang Zhen 
Published: September 2023

AbstractTransforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease. In kidneys that are obstructed, specific deletion of Sirt2 in renal tubule epithelial cells (TEC) has been shown to aggravate renal fibrosis, while renal tubule specific overexpression of Sirt2 has been shown to ameliorate renal fibrosis. Similarly, specific deletion of Sirt2 in hepatocyte aggravated CCl4-induced hepatic fibrosis. In addition, we have demonstrated that SIRT2 overexpression and knockdown restrain and enhance TGF-β-induced fibrotic gene expression, respectively, in TEC. Mechanistically, SIRT2 reduced the phosphorylation, acetylation, and nuclear localization levels of SMAD2 and SMAD3, leading to inhibition of the TGF-β signaling pathway. Further studies have revealed that that SIRT2 was able to directly interact with and deacetylate SMAD2 at lysine 451, promoting its ubiquitination and degradation. Notably, loss of SMAD specific E3 ubiquitin protein ligase 2 abolishes the ubiquitination and degradation of SMAD2 induced by SIRT2 in SMAD2. Regarding SMAD3, we have found that SIRT2 interact with and deacetylates SMAD3 at lysine 341 and 378 only in the presence of TGF-β, thereby reducing its activation. This study provides initial indication of the anti-fibrotic role of SIRT2 in renal tubules and hepatocytes, suggesting its therapeutic potential for fibrosis.
Engineered small extracellular vesicles loaded with miR-654-5p promote ferroptosis by targeting HSPB1 to alleviate sorafenib resistance in hepatocellular carcinoma
Authors: Sun Jiao , Liu Qi , Jiang Yanfang , Cai Zhihui , Liu Hui , Zuo Huaiwen 
Published: September 2023

AbstractSorafenib (sora) is the initial therapy for patients with progressive hepatocellular carcinoma (HCC), but the emergence of drug resistance has seriously impacted its therapeutic efficacy. However, the mechanism of sora resistance remains unclear, and effective strategies to overcome drug resistance are still lacking. By establishing a sora-resistant hepatocellular carcinoma cell line, we found that Heat Shock Protein Family B (small) Member 1 (HSPB1) was markedly upregulated in sora-resistant HCC cells. Further research revealed that the ferroptosis resistance induced by HSPB1 upregulation plays a crucial role in sora resistance. In addition, we confirmed that miR-654-5p enhances sora-induced ferroptosis by binding to HSPB1 and reducing its protein levels. To enhance miRNA stability and delivery efficiency in vivo, we used small extracellular vesicles (sEV) derived from human adipose mesenchymal stem cells as miR-654-5p carriers, creating engineered sEV (m654-sEV). The research demonstrated that m654-sEV effectively delivers miR-654-5p to HCC cells, targeting HSPB1 and enhancing sora-induced ferroptosis. This improves therapeutic effects on sora-resistant HCC cells and xenograft tumors, restoring their sensitivity to sora. In summary, m654-sEV, which targets HSPB1 via miR-654-5p delivery, represents a promising strategy for addressing sora-resistant issue. The combined use of m654-sEV and sora has the potential to significantly enhance therapeutic efficacy for patients with sora-resistant HCC.
Myelination and excitation-inhibition balance synergistically shape structure-function coupling across the human cortex
Authors: Fotiadis Panagiotis , Cieslak Matthew , He Xiaosong , Caciagli Lorenzo , Ouellet Mathieu , Satterthwaite Theodore D. , Shinohara Russell T. , Bassett Dani S. 
Published: September 2023

AbstractRecent work has demonstrated that the relationship between structural and functional connectivity varies regionally across the human brain, with reduced coupling emerging along the sensory-association cortical hierarchy. The biological underpinnings driving this expression, however, remain largely unknown. Here, we postulate that intracortical myelination and excitation-inhibition (EI) balance mediate the heterogeneous expression of structure-function coupling (SFC) and its temporal variance across the cortical hierarchy. We employ atlas- and voxel-based connectivity approaches to analyze neuroimaging data acquired from two groups of healthy participants. Our findings are consistent across six complementary processing pipelines: 1) SFC and its temporal variance respectively decrease and increase across the unimodal-transmodal and granular-agranular gradients; 2) increased myelination and lower EI-ratio are associated with more rigid SFC and restricted moment-to-moment SFC fluctuations; 3) a gradual shift from EI-ratio to myelination as the principal predictor of SFC occurs when traversing from granular to agranular cortical regions. Collectively, our work delivers a framework to conceptualize structure-function relationships in the human brain, paving the way for an improved understanding of how demyelination and/or EI-imbalances induce reorganization in brain disorders.
A CK2 and SUMO-dependent, PML NB-involved regulatory mechanism controlling BLM ubiquitination and G-quadruplex resolution
Authors: Liu Shichang , Atkinson Erin , Paulucci-Holthauzen Adriana , Wang Bin 
Published: September 2023

AbstractThe Boom syndrome helicase (BLM) unwinds a variety of DNA structures such as Guanine (G)-quadruplex. Here we reveal a role of RNF111/Arkadia and its paralog ARKL1, as well as Promyelocytic Leukemia Nuclear Bodies (PML NBs), in the regulation of ubiquitination and control of BLM protein levels. RNF111 exhibits a non-canonical SUMO targeted E3 ligase (STUBL) activity targeting BLM ubiquitination in PML NBs. ARKL1 promotes RNF111 localization to PML NBs through SUMO-interacting motif (SIM) interaction with SUMOylated RNF111, which is regulated by casein kinase 2 (CK2) phosphorylation of ARKL1 at a serine residue near the ARKL1 SIM domain. Upregulated BLM in ARKL1 or RNF111-deficient cells leads to a decrease of G-quadruplex levels in the nucleus. These results demonstrate that a CK2- and RNF111-ARKL1-dependent regulation of BLM in PML NBs plays a critical role in controlling BLM protein levels for the regulation of G-quadruplex.
Fast, multiplexable and efficient somatic gene deletions in adult mouse skeletal muscle fibers using AAV-CRISPR/Cas9
Authors: Thürkauf Marco , Lin Shuo , Oliveri Filippo , Grimm Dirk , Platt Randall J. , Rüegg Markus A. 
Published: September 2023

AbstractMolecular screens comparing different disease states to identify candidate genes rely on the availability of fast, reliable and multiplexable systems to interrogate genes of interest. CRISPR/Cas9-based reverse genetics is a promising method to eventually achieve this. However, such methods are sorely lacking for multi-nucleated muscle fibers, since highly efficient nuclei editing is a requisite to robustly inactive candidate genes. Here, we couple Cre-mediated skeletal muscle fiber-specific Cas9 expression with myotropic adeno-associated virus-mediated sgRNA delivery to establish a system for highly effective somatic gene deletions in mice. Using well-characterized genes, we show that local or systemic inactivation of these genes copy the phenotype of traditional gene-knockout mouse models. Thus, this proof-of-principle study establishes a method to unravel the function of individual genes or entire signaling pathways in adult skeletal muscle fibers without the cumbersome requirement of generating knockout mice.
Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality
Authors: Hong Yun Soo , Battle Stephanie L. , Shi Wen , Puiu Daniela , Pillalamarri Vamsee , Xie Jiaqi , Pankratz Nathan , Lake Nicole J. , Lek Monkol , Rotter Jerome I. , Rich Stephen S. , Kooperberg Charles , Reiner Alex P. , Auer Paul L. , Heard-Costa Nancy , Liu Chunyu , Lai Meng , Murabito Joanne M. , Levy Daniel , Grove Megan L. , Alonso Alvaro , Gibbs Richard , Dugan-Perez Shannon , Gondek Lukasz P. , Guallar Eliseo , Arking Dan E. 
Published: September 2023

AbstractMitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia.
Heat-inactivated Bifidobacterium adolescentis ameliorates colon senescence through Paneth-like-cell-mediated stem cell activation
Authors: Qi Yadong , He Jiamin , Zhang Yawen , Ge Qiwei , Wang Qiwen , Chen Luyi , Xu Jilei , Wang Lan , Chen Xueqin , Jia Dingjiacheng , Lin Yifeng , Xu Chaochao , Zhang Ying , Hou Tongyao , Si Jianmin , Chen Shujie , Wang Liangjing 
Published: September 2023

AbstractDeclined numbers and weakened functions of intestinal stem cells (ISCs) impair the integrity of the intestinal epithelium during aging. However, the impact of intestinal microbiota on ISCs in this process is unclear. Here, using premature aging mice (telomerase RNA component knockout, Terc−/−), natural aging mice, and in vitro colonoid models, we explore how heat-inactivated Bifidobacterium adolescentis (B. adolescentis) affects colon senescence. We find that B. adolescentis could mitigate colonic senescence-related changes by enhancing intestinal integrity and stimulating the regeneration of Lgr5+ ISCs via Wnt/β-catenin signaling. Furthermore, we uncover the involvement of Paneth-like cells (PLCs) within the colonic stem-cell-supporting niche in the B. adolescentis-induced ISC regeneration. In addition, we identify soluble polysaccharides (SPS) as potential effective components of B. adolescentis. Overall, our findings reveal the role of heat-inactivated B. adolescentis in maintaining the ISCs regeneration and intestinal barrier, and propose a microbiota target for ameliorating colon senescence.
Proof-of-concept study linking ex vivo sensitivity testing to neoadjuvant anthracycline-based chemotherapy response in breast cancer patients
Authors: Ladan Marjolijn M. , Meijer Titia G. , Verkaik Nicole S. , de Monye Cecile , Koppert Linetta B. , Oomen-de Hoop Esther , van Deurzen Carolien H. M. , Kanaar Roland , Nonnekens Julie , van Gent Dik C. , Jager Agnes 
Published: September 2023

AbstractWe developed a functional ex vivo anthracycline-based sensitivity test. Surgical resection material of primary breast cancer (BC) was used to determine criteria for the ex vivo sensitivity assay based on morphology, proliferation and apoptosis. Subsequently, a proof-of-concept study was performed correlating results of this assay on primary BC biopsies with in vivo response after treatment with anthracycline-containing neoadjuvant chemotherapy (NAC). Cut off values for the ex vivo anthracycline-based sensitivity test were established based on analysis of 21 primary breast tumor samples obtained after surgery. In the proof-of-concept study based on a new set of tumor biopsies, 41 patients were included. Eight biopsies did not contain tumor cells and three patients could not be biopsied for various reasons. In the remaining 30 biopsies, the success rate of the ex vivo test was 77% (23/30); six out of seven failed tests were due to excessive apoptosis, our pre-specified test criteria. Of the 23 patients with a successful ex vivo test result, three patients did not undergo NAC after the biopsy. Here we report the ex vivo anthracycline-based sensitivity assay is feasible on biopsy material and shows 75% concordance between ex vivo outcomes and in vivo MRI response. Unfortunately, the percentage of unsuccessful tests is rather high. This study provides the foundation for further development of ex vivo sensitivity assays.
Spirometry practice by French general practitioners between 2010 and 2018 in adults aged 40 to 75 years
Authors: Chapron A. , Lemée T. , Pau G. , Jouneau S. , Kerbrat S. , Balusson F. , Oger E. 
Published: September 2023

AbstractIn France, most spirometries are performed by pneumologists. Spirometry is difficult to access due to the distance to medical office and long delays for appointments. This lack of accessibility contributes to the underdiagnosis of chronic obstructive pulmonary disease (COPD) among patients aged between 40 and 75 years. In recent years, general practitioners (GPs) have been performing spirometry in private practice. However, the extent of this practice is unknown. A French retrospective, repetitive transversal study analysed data from the “Système National des Données de Santé” (SNDS) database. The targeted population was GPs in primary care that performed spirometries between 2010 and 2018, in patients aged between 40 and 75 years. Between 2010 and 2018, 302,674 (7.2%) spirometries were performed in France by GPs in private practices, in patients 40 to 75 years old. 5.4% by “expert GPs” (>60 spirometries/year) and 1.8% by “non-expert GPs”. In “non-expert GPs” (2.8% of French GPs in 2018), the annual number of spirometries increased by 701 each year (p < 2.104), the annual number of GPs performing spirometries increased by 114 each year (p < 2.10−5). Overall, 24.9% of the spirometries performed by GPs were referrals from other GPs. The number of spirometries performed by GPs and the number of GPs performing spirometries has gradually increased over time. However, this increase is inadequate considering the need to early detect and follow up respiratory disorders.
Satisfaction with cognitive remediation therapy: its effects on implementation and outcomes using the cognitive remediation satisfaction scale
Authors: Evans Joanne , Tinch-Taylor Rose , Csipke Emese , Cella Matteo , Pickles Andrew , McCrone Paul , Stringer Dominic , Oliver Abigail , Reeder Clare , Birchwood Max , Fowler David , Greenwood Kathryn , Johnson Sonia , Perez Jesus , Ritunnano Rosa , Thompson Andrew , Upthegrove Rachel , Wilson Jon , Kenny Alex , Isok Iris , Joyce Eileen M. , Wykes Til 
Published: September 2023

AbstractCognitive Remediation (CR) improves cognition and functioning but is implemented in a variety of ways (independent, group and one-to-one). There is no information on whether service users find these implementation methods acceptable or if their satisfaction influences CR outcomes. We used mixed participatory methods, including focus groups, to co-develop a CR satisfaction scale. This was refined using three psychometric criteria (Cronbach’s alpha, item discrimination, test-retest agreement) to select items. Factor analysis explored potential substructures. The refined measure was used in structural equation joint modelling to evaluate whether satisfaction with CR is affected by implementation method and treatment engagement or influences recovery outcome, using data from a randomised controlled trial. Four themes (therapy hours, therapist, treatment effects, computer use) generated a 31-item Cognitive Remediation Satisfaction scale (CRS) that reduced to 18 Likert items, 2 binary and 2 open-ended questions following psychometric assessment. CRS had good internal consistency (Alpha = 0.814), test-retest reliability (r= 0.763), and concurrent validity using the Working Alliance Inventory (r = 0.56). A 2-factor solution divided items into therapy engagement and therapy effects. Satisfaction was not related to implementation method but was significantly associated with CR engagement. Therapy hours were significantly associated with recovery, but there was no direct effect of satisfaction on outcome. Although satisfaction is important to therapy engagement, it has no direct effect on outcome. CR therapy hours directly affect outcome irrespective of which implementation model is used, so measuring satisfaction early might help to identify those who are likely to disengage. The study has mixed methods design.
Assessing immunogenicity barriers of the HIV-1 envelope trimer
Authors: Maliqi Liridona , Friedrich Nikolas , Glögl Matthias , Schmutz Stefan , Schmidt Daniel , Rusert Peter , Schanz Merle , Zaheri Maryam , Pasin Chloé , Niklaus Cyrille , Foulkes Caio , Reinberg Thomas , Dreier Birgit , Abela Irene , Peterhoff David , Hauser Alexandra , Kouyos Roger D. , Günthard Huldrych F. , van Gils Marit J. , Sanders Rogier W. , Wagner Ralf , Plückthun Andreas , Trkola Alexandra 
Published: September 2023

AbstractUnderstanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing.
Episodic and semantic feeling-of-knowing in aging: a systematic review and meta-analysis
Authors: Devaluez Méline , Mazancieux Audrey , Souchay Céline 
Published: September 2023

AbstractA complex pattern of preservation and deterioration in metacognition in aging is found, especially regarding predicting future memory retrieval (i.e., feeling-of-knowing, FOK). While semantic FOK (sFOK) is preserved with age, studies on episodic tasks (eFOK) produce equivocal findings. We present a meta-analysis of 20 studies on eFOK and sFOK, analyzing the difference in metacognitive sensitivity between 922 younger and 966 older adults, taking into account the difference in memory performance. The sFOK studies yielded no overall age effect (8 effects, g = −0.10 [−0.29, 0.10]). However, we found a reliable age-group difference on eFOK (22 effects, g = 0.53 [0.28, 0.78]), which was moderated when considering recognition performance. Moreover, using aggregated data of 134 young and 235 older adults from published and unpublished studies from our lab, we investigated memory performance as an explanation of the eFOK deficit. We show that older adults are less metacognitively sensitive than younger adults for eFOKs which is, at least partly, due to the age-related memory decline. We highlight two non-exclusive explanations: a recollection deficit at play in the first and second order tasks, and a confound between first order performance and the measure used to assess metacognitive sensitivity.