bluuebunny/crossref_metadata_2025_split huggingface dataset:
Emerging therapies in Ewing sarcoma
Authors: Strauss Sandra J. , Berlanga Pablo , McCabe Martin G. 
Published: May 2024

Purpose of review
There is an unmet need to improve outcomes for patients for Ewing sarcoma, a rare, aggressive sarcoma with a peak incidence in adolescents and young adults (AYA). Current therapy at diagnosis involves multiagent chemotherapy and local therapy, but despite intensification of treatment, those with metastases at diagnosis and recurrent disease have poor outcomes.

Recent findings
Improved understanding of Ewing sarcoma biology has identified novel targets with promising activity in Ewing sarcoma patients, including tyrosine kinase inhibitors that are now undergoing evaluation as combination and maintenance therapy. Other emerging therapies include those that target the EWSR1::FLI1 fusion oncoprotein, and act on DNA damage, cell cycle and apoptotic pathways. Immunotherapeutic approaches, particularly CAR-T-cell therapy directed at GD2, also hold promise. Recent collaborative clinical trials that have defined an international standard of care for patients with newly diagnosed Ewing sarcoma and novel platform studies with adaptive designs offer unique opportunities to investigate these therapies inclusive of all ages.

Summary
Close international collaboration between clinicians and biologists will allow us to prioritize promising emerging therapies and develop biomarkers to facilitate their incorporation into standard of care and more rapidly translate into benefit for Ewing sarcoma patients.
Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation
Authors: Moore Mary P. , Wang Xiaobo , Kennelly John Paul , Shi Hongxue , Ishino Yuki , Kano Kuniyuki , Aoki Junken , Cherubini Alessandro , Ronzoni Luisa , Guo Xiuqing , Chalasani Naga P. , Khalid Shareef , Saleheen Danish , Mitsche Matthew A. , Rotter Jerome I. , Yates Katherine P. , Valenti Luca , Kono Nozomu , Tontonoz Peter , Tabas Ira 
Published: May 2024

Background and Aims:
The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction–associated steatotic liver disease and metabolic dysfunction–associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction–associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear.

Approach and Results:
We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity and increased IHH mRNA.

Conclusions:
This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis, adds new insight into an established genetic locus for MASH, and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7.
Autologous Platelet-rich Fibrin as a Three-dimensional Structural Scaffold in the Healing of Contracted Orbital Sockets
Authors: Bhattacharjee Kasturi , Venkatraman Vatsalya , Soni Deepak , Gaikwad Sonali 
Published: May 2024

Purpose:
Evaluation of platelet-rich fibrin as an adjuvant in surface healing of contracted orbital sockets.

Methods:
Prospective, interventional, and comparative study of 25 patients with moderate to severe contracted sockets conducted over 2 years (February 2020–February 2022). Group 1 underwent a dermis-fat graft with fornix forming sutures supplemented by a platelet-rich fibrin membrane, while group 2 received a dermis-fat graft with fornix forming sutures only. Patients over 18 years were evaluated as per prefixed inclusion and exclusion criteria. Assessments were conducted at 1, 3, and 12 months postsurgery, focusing on wound evaluation, socket epithelialization, postoperative pain, prosthesis rehabilitation, and complications, if any. Wound evaluation and pain intensity were assessed utilizing the wound evaluation score and visual analog scale, respectively. Socket epithelization was documented clinically at every visit.

Results:
The study showed a mean age of 38.8 ± 8.8 years, with a 2:1 male-to-female ratio. Group 1 consistently scored higher on wound evaluation score than group 2 at all follow-up points. In group 1, 81.8% achieved a maximum wound evaluation score at 4 weeks and 100% at 3 and 12 months, compared to group 2’s 42.8%, 50%, and 57.1%, respectively (p < 0.05). Postoperative contracture occurred in 3 group 2 patients at the final follow-up, with 6 showing unsatisfactory appearance. Group 1 demonstrated significantly lower pain intensity on postoperative day 1 (p = 0.03), and greater epithelization at 4 weeks.

Conclusion:
platelet-rich fibrin appears to be an effective solution for enhancing wound healing during socket reconstruction, attributed to its sustained release of growth factors and mesenchymal stem cells.
Unravelling the molecular landscape of endometrial cancer subtypes: insights from multiomics analysis
Authors: Shen Yufei , Tian Yan , Ding Jiashan , Chen Zhuo , Zhao Rong , Lu Yingnan , Li Lucia , Zhang Hui , Wu Haiyue , Li Xi , Zhang Yu 
Published: May 2024

Background:
Endometrial cancer (EC) as one of the most common gynecologic malignancies is increasing in incidence during the past 10 years. Genome-Wide Association Studies (GWAS) extended to metabolic and protein phenotypes inspired us to employ multiomics methods to analyze the causal relationships of plasma metabolites and proteins with EC to advance our understanding of EC biology and pave the way for more targeted approaches to its diagnosis and treatment by comparing the molecular profiles of different EC subtypes.

Methods:
Two-sample mendelian randomization (MR) was performed to investigate the effects of plasma metabolites and proteins on risks of different subtypes of EC (endometrioid and nonendometrioid). Pathway analysis, transcriptomic analysis, and network analysis were further employed to illustrate gene-protein-metabolites interactions underlying the pathogenesis of distinct EC histological types.

Results:
The authors identified 66 causal relationships between plasma metabolites and endometrioid EC, and 132 causal relationships between plasma proteins and endometrioid EC. Additionally, 40 causal relationships between plasma metabolites and nonendometrioid EC, and 125 causal relationships between plasma proteins and nonendometrioid EC were observed. Substantial differences were observed between endometrioid and nonendometrioid histological types of EC at both the metabolite and protein levels. The authors identified seven overlapping proteins (RGMA, NRXN2, EVA1C, SLC14A1, SLC6A14, SCUBE1, FGF8) in endometrioid subtype and six overlapping proteins (IL32, GRB7, L1CAM, CCL25, GGT2, PSG5) in nonendometrioid subtype and conducted network analysis of above proteins and metabolites to identify coregulated nodes.

Conclusions:
Our findings observed substantial differences between endometrioid and nonendometrioid EC at the metabolite and protein levels, providing novel insights into gene-protein-metabolites interactions that could influence future EC treatments.
Randomized, Assessor-Blinded Trial Comparing Highly Purified Human Menotropin and Recombinant Follicle-Stimulating Hormone in High Responders Undergoing Intracytoplasmic Sperm Injection
Authors: Witz Craig A. , Daftary Gaurang S. , Doody Kevin J. , Park John K. , Seifu Yodit , Yankov Vladimir I. , Heiser Patrick W. ,   On Behalf of the Menopur in GnRH Antagonist Cycles With Single Embryo Transfer–High Responder (MEGASET-HR) Trial Group
Published: May 2024

(Abstracted from Fertil Steril 2020;114:321–330
There exists considerable variation in patient’s response to gonadotropin stimulation when undergoing assisted reproductive technologies (ARTs). Serum anti-Müllerian hormone (AMH) level has been shown to be a robust predictor of ovarian response and is used to guide gonadotropin dosing.
Comparison of Multiparametric MRI and the Combination of PSMA Plus MRI for the Intraprostatic Diagnosis of Prostate Cancer
Authors: Brondani Torri Giovanni , Antune Pereira Pedro , Piovesan Wiethan Camila , Mesquita Yasmin , Mirshahvalad Seyed Ali , Veit-Haibach Patrick , Ghai Sangeet , Metser Ur , Altmayer Stephan , Dias Adriano Basso 
Published: May 2024

Purpose
The aim of this study was to perform a head-to-head comparison of multiparametric MRI (mpMRI) and the combination of prostate-specific membrane antigen (PSMA) PET plus MRI (PSMA + MRI) for detecting intraprostatic clinically significant prostate cancer (csPCa).

Patients and Methods
Relevant databases were searched through November 2023. Only studies directly comparing mpMRI and PSMA + MRI (PET/MRI or PET/CT + mpMRI) were included. A meta-analysis with a random-effects model was used to estimate pooled sensitivity, specificity, and area under the curve for each approach.

Results
A total of 19 studies were included. On a patient-level analysis, PSMA + MRI had higher sensitivity (9 studies) than mpMRI for csPCa detection (96% [95% confidence interval (CI): 92%, 98%] vs 89% [95% CI: 81%, 94%]; P = 0.04). The patient-level specificity (4 studies) of PSMA + MRI was 55% (95% CI: 31%–76%) compared with 50% (95% CI: 44%–57%) of mpMRI (P = 0.67). Region-level sensitivity (10 studies) was 85% (95% CI: 74%–92%) for PSMA + MRI and 71% (95% CI: 58%–82%) for mpMRI (P = 0.09), whereas specificity (4 studies) was 87% (95% CI: 76%–94%) and 90% (95% CI: 82%–95%), respectively (P = 0.59). Lesion-level sensitivity and specificity were similar between modalities with pooled data from less than 4 studies.

Conclusions
PSMA + MRI had superior pooled sensitivity and similar specificity for the detection of csPCa compared with mpMRI in this meta-analysis of head-to-head studies.
An Evaluation of Autologous Fat Injection as a Treatment for Velopharyngeal Insufficiency
Authors: Mirsky Nicholas A. , Slavin Blaire V. , Sheinberg Derek S. , Stauber Zachary M. , Parra Marcelo , Vivekanand Nayak Vasudev , Witek Lukasz , Coelho Paulo G. , Thaller Seth R. 
Published: May 2024

Background
Velopharyngeal insufficiency (VPI) is a condition characterized by incomplete separation of the oral and nasal cavities during speech production, thereby leading to speech abnormalities and audible nasal emissions. Subsequently, this adversely impacts communication and potentially interpersonal social interactions. Autologous fat grafting (AFG) to the velopharynx, a minimally invasive technique, aims to improve oronasal separation by providing bulk and advancing the posterior pharyngeal wall toward the soft palate. Despite its potential, the relative novelty of AFG in treating VPI has resulted in reporting of inconsistent indications, varied surgical techniques, and mixed outcomes across existing literature.

Methods
This systemic review examined the evidence of AFG for VPI treatment over the past decade (2013–2023). A thorough search across five electronic databases yielded 233 studies, with 20 meeting the inclusion criteria (e.g., utilized fat injection as their selected VPI treatment, conducted study in human subjects, did not perform additional surgical procedure at time of fat injection). Selected studies encompassed patient and surgical intervention characteristics, perceptual speech assessment (PSA) scores, gap sizes, nasalance measurements, and complications.

Results
The majority of patients had a prior cleft palate diagnosis (78.2%), in which nasoendoscopy was the prevalent method for visualizing the velopharyngeal port defect. Fat harvesting predominantly occurred from the abdomen (64.3%), with an average injection volume of 6.3 mL across studies. PSA and subjective gap size scores were consistently higher preoperatively than postoperatively. PSA score analysis from seven studies revealed significant and sustained improvements postoperatively. Gap size score analysis from four studies demonstrated similar preoperative and postoperative differences. Complications were reported in 17 studies, yielding a 2.7% summative complication rate among 594 cases.

Conclusions
Autologous fat grafting has emerged as a minimally invasive, safe, and effective treatment for mild to moderate VPI. However, challenges remain because of variability in patient selection criteria, diagnostic modalities, and outcome measurements. This review underscores the need for randomized control trials to directly compare AFG with standard-of-care surgical interventions, providing more conclusive evidence of its clinical efficacy.
Individuals with Methamphetamine Use Disorder Show Reduced Directed Exploration and Learning Rates Independent of an Aversive Interoceptive State Induction
Authors: Goldman Carter M. , Takahashi Toru , Lavalley Claire A. , Li Ning , Taylor Samuel , Chuning Anne E. , Hodson Rowan , Stewart Jennifer L. , Wilson Robert C. , Khalsa Sahib S. , Paulus Martin P. , Smith Ryan 
Published: May 2024

AbstractMethamphetamine Use Disorder (MUD) is associated with substantially reduced quality of life. Yet, decisions to use persist, due in part to avoidance of anticipated withdrawal states. However, the specific cognitive mechanisms underlying this decision process, and possible modulatory effects of aversive states, remain unclear. Here, 56 individuals with MUD and 58 healthy comparisons (HCs) performed a decision task, both with and without an aversive interoceptive state induction. Computational modeling measured the tendency to test beliefs about uncertain outcomes (directed exploration) and the ability to update beliefs in response to outcomes (learning rates). Compared to HCs, those with MUD exhibited less directed exploration and slower learning rates, but these differences were not affected by the aversive state induction. Follow-up analyses further suggested that reduced exploration in MUD was best explained by greater avoidance of uncertainty on the task, and that trait differences in cognitive reflectiveness might account for these differences in task behavior. These results suggest novel, state-independent computational mechanisms whereby individuals with MUD may have difficulties in testing beliefs about the tolerability of abstinence and in adjusting behavior in response to consequences of continued use.
Dynamic basis of lipopolysaccharide export by LptB2FGC
Authors: Dajka Marina , Rath Tobias , Morgner Nina , Joseph Benesh 
Published: May 2024

AbstractLipopolysaccharides (LPS) confer resistance against harsh conditions, including antibiotics, in Gram-negative bacteria. The lipopolysaccharide transport (Lpt) complex, consisting of seven proteins (A-G), exports LPS across the cellular envelope. LptB2FG forms an ATP-binding cassette transporter that transfers LPS to LptC. How LptB2FG couples ATP binding and hydrolysis with LPS transport to LptC remains unclear. We observed the conformational heterogeneity of LptB2FG and LptB2FGC in micelles and/or proteoliposomes using pulsed dipolar electron spin resonance spectroscopy. Additionally, we monitored LPS binding and release using laser-induced liquid bead ion desorption mass spectrometry. The β-jellyroll domain of LptF stably interacts with the LptG and LptC β-jellyrolls in both the apo and vanadate-trapped states. ATP binding at the cytoplasmic side is allosterically coupled to the selective opening of the periplasmic LptF β-jellyroll domain. In LptB2FG, ATP binding closes the nucleotide binding domains, causing a collapse of the first lateral gate as observed in structures. However, the second lateral gate, which forms the putative en try site for LPS, exhibits a heterogeneous conformation. LptC binding limits the flexibility of this gate to two conformations, likely representing the helix of LptC as either released from or inserted into the transmembrane domains. Our results reveal the regulation of the LPS entry gate through the dynamic behavior of the LptC transmembrane helix, while its β-jellyroll domain is anchored in the periplasm. This, combined with long-range ATP-dependent allosteric gating of the LptF β-jellyroll domain, may ensure efficient and unidirectional transport of LPS across the periplasm.
Histologic variants in bladder cancer harbor aggressive molecular features including TM4SF1 expression and a CA125+ cell state
Authors: Yang Heiko , Song Hanbing , Yip Elizabeth , Chang Kevin , Allegakoen Paul , Lu Kevin L. , Hui Keliana , Pham Julia , Kasap Corynn , Kumar Vipul , Gayle Janae , Stohr Bradley A. , Ding Chien-Kuang Cornelia , Wiita Arun P. , Meng Maxwell V. , Chou Jonathan , Porten Sima P. , Huang Franklin W. 
Published: May 2024

ABSTRACTHistologic variant (HV) subtypes of bladder cancer are clinically aggressive tumors that are more resistant to standard therapy compared to conventional urothelial carcinoma (UC). Little is known about the transcriptional programs that account for the morphological and biological differences in HV tumors. To investigate the tumor biology of HV bladder cancers, we generated a single cell RNA sequencing (scRNA- seq) atlas of nine HV tumors and three UC tumors. Our analyses revealed a tumor cell state specific to HVs that is characterized by expression ofMUC16(CA125), KRT24, andWISP2. This CA125+ cell state bears transcriptional hallmarks of epithelial-mesenchymal transition, is enriched in metastases, is predicted to be highly chemotherapy resistant, and is linked with poor survival, suggesting that this cell state plays an important role in the aggressive biology of HV tumors. Our analyses also provide novel evidence of transcriptional “mimicry” between HVs and histologically similar non-urothelial cell types. Lastly, we identified higher expression of TM4SF1, a cell surface protein associated with cancer metastasis, in HV tumor cells compared to UC tumor cells. Finally, CAR T cells engineered against TM4SF1 protein demonstratedin vitroandin vivoactivity against bladder cancer cell lines in aTM4SF1expression- dependent manner, highlighting its potential as a therapeutic target in bladder cancer.One sentence summarySingle cell RNA sequencing of primary bladder cancers identified a CA125+ cell state specific to histologic variants that is associated with aggressive biological features and TM4SF1 as a novel therapeutic target for histologic variant subtypes of bladder cancer which can be targeted by anti- TM4SF1 CAR T cells.
Blood- and brain-based genome-wide association studies of smoking
Authors: Chybowska Aleksandra D. , Bernabeu Elena , Yousefi Paul , Suderman Matthew , Hillary Robert F. , MacGillivray Louise , Murphy Lee , Harris Sarah E. , Corley Janie , Campbell Archie , Spires-Jones Tara L. , McCartney Daniel L. , Cox Simon R. , Price Jackie F. , Evans Kathryn L. , Marioni Riccardo E. 
Published: May 2024

AbstractBackgroundSelf-reported smoking is often incorporated into disease prediction tools but suffers from recall bias and does not capture passive exposure. Blood-based DNA methylation (DNAm) is an objective way to assess smoking. However, studies have not fully explored tissue-specificity or epigenome-wide coverage beyond array data. Here, we update the existing biomarkers of smoking and conduct a detailed analysis of the associations between blood DNAm and self-reported smoking.Methods and FindingsA blood-based Bayesian epigenome-wide association study (EWAS) of smoking was carried out in 17,865 Generation Scotland individuals at ∼850k CpG sites (Illumina EPIC array). For 24 pairs of smokers and non-smokers a high-resolution approach was implemented (∼4 million sites, TWIST methylome panel). A DNAm-derived biomarker of smoking (mCigarette) was tested in the independent Lothian Birth Cohort 1936 (n=882, Illumina 450k array) and in the ALSPAC parents and offspring at four time points (range n=496–1,207). To explore tissue specific signals, EWASs of smoking were run across five brain regions for 14 individuals using DNAm from the EPIC array. Lastly, genome-wide association studies (GWASs) of smoking pack years and an epigenetic score for smoking (GrimAge DNAm pack years) were conducted (n=17,105). The primary EWAS analyses identified two novel genome-wide significant loci, mapping to genes related to addiction and carcinogenesis. Associations with CpG sites which are currently absent from methylation arrays were identified by the high resolution EWAS of smoking (n=48). The mCigarette pack years biomarker showed excellent discrimination across all smoking categories (current, former, never), and outperformed existing predictors in associations with pack years in an external test dataset (Pearson r=0.75). Several CpGs showed near-perfect discrimination of smoking status in both blood and brain, but these loci did not overlap across tissues. The GWAS of DNAm (but not self-reported) pack years identified novel and established smoking-related loci. However, the self-reported phenotype GWAS had a higher genetic correlation with a large meta-analysis GWAS of self-reported pack years. Among the study shortcomings are its potential lack of generalizability to non-Europeans and the absence of serum cotinine data.ConclusionA multi-tissue, multi-cohort analysis of the relationship between smoking, DNA and DNAm (assessed via arrays and targeted sequencing) has improved our understanding of the biological consequences of smoking.
Apoptotic cells promote circulating tumor cell survival and metastasis
Authors: Hagan Cassidy E. , Snyder Annelise G. , Headley Mark , Oberst Andrew 
Published: May 2024

ABSTRACTDuring tumor progression and especially following cytotoxic therapy, cell death of both tumor and stromal cells is widespread. Despite clinical observations that high levels of apoptotic cells correlate with poorer patient outcomes, the physiological effects of dying cells on tumor progression remain incompletely understood. Here, we report that circulating apoptotic cells robustly enhance tumor cell metastasis to the lungs. Using intravenous metastasis models, we observed that the presence of apoptotic cells, but not cells dying by other mechanisms, supports circulating tumor cell (CTC) survival following arrest in the lung vasculature. Apoptotic cells promote CTC survival by recruiting platelets to the forming metastatic niche. Apoptotic cells externalize the phospholipid phosphatidylserine to the outer leaflet of the plasma membrane, which we found increased the activity of the coagulation initiator Tissue Factor, thereby triggering the formation of platelet clots that protect proximal CTCs. Inhibiting the ability of apoptotic cells to induce coagulation by knocking out Tissue Factor, blocking phosphatidylserine, or administering the anticoagulant heparin abrogated the pro-metastatic effect of apoptotic cells. This work demonstrates a previously unappreciated role for apoptotic cells in facilitating metastasis by establishing CTC-supportive emboli, and suggests points of intervention that may reduce the pro-metastatic effect of apoptotic cells.GRAPHICAL ABSTRACT