bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic monitoring of UBA1 somatic mutations in patients with relapsing polychondritis
Authors: Duan Suying , Luo Haiyang , Wang Yunchao , Jiang Dongbin , Liu Jiajia , Li Jiaqi , Zheng Honglin , Zhao Taiqi , Liu Chenyang , Zhang Hang , Mao Chengyuan , Zhang Lei , Xu Yuming 
Published: January 2024

Abstract
Background
Commonly clinically diagnosed with relapsing polychondritis (RP), vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS) is a recently identified autoinflammatory disease caused by UBA1 somatic mutations. The low frequency and dynamic changes challenge the accurate detection of somatic mutations. The present study monitored these mutations in Chinese patients with RP. We included 44 patients with RP. Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood. Droplet digital polymerase chain reaction (ddPCR) was performed to screen low-prevalence somatic variants.

Results
Multiple ddPCR detections were performed using available blood samples collected at different follow-up time points. Three male patients were UBA1 somatic mutation carriers. Sanger sequencing detected the somatic UBA1 variant c.122T > C (p.Met41Thr) in two male patients. Initial ddPCR confirmed the variant in the two patients, with allele fractions of 73.75% and 88.46%, respectively, while yielding negative results in other patients. Subsequent ddPCR detected the somatic variant (c.122T > C) with low prevalence (1.02%) in another male patient from blood samples collected at a different time point, and confirmed dynamically fractional abundance in one patient with VEXAS, with allele fractions of 73.75%, 61.28%, 65.01%, and 73.75%. Nine patients assessed by ddPCR at different time points remained negative.

Conclusion
We report UBA1 variants in patients with RP in the Chinese population for the first time. Multiple ddPCR detections from samples collected at different time points can enhance sensitivity and should be considered for patients with initial negative ddPCR results.
Development and validation of TreatHSP-QoL: a patient-reported outcome measure for health-related quality of life in hereditary spastic paraplegia
Authors: Malina Jekaterina , Huessler Eva-Maria , Jöckel Karl-Heinz , Boog-Whiteside Eva , Jeschonneck Nicole , Schröder Bernadette , Schüle Rebecca , Kühl Tobias , Klebe Stephan 
Published: January 2024

Abstract
Background
Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disease that lacks specific and validated patient-centered outcome measures (PCOMs). We aimed to develop and validate a health-related quality of life (HRQoL) questionnaire specific to HSP (“TreatHSP-QoL”) that could be used as a PCOM.

Results
The pilot-items of the TreatHSP-QoL (45 five-level Likert scale items, with values per item between 0 and 4) were developed based on a qualitative data analysis of 54 semi-structured interviews, conducted in person with 36 HSP patients and 18 caregivers. It was then reduced and modified through the validation process to 25 items. The main validation was performed using the online questionnaire in 242 HSP patients and 56 caregivers. The exploratory factor analysis defined five subdomains. Cronbach’s alpha ranged from 0.57 to 0.85 for the subdomains and reached 0.85 for the total score. The test–retest Pearson correlation reached 0.86 (95% Confidence Interval (CI) [0.79, 0.91]). Pearson correlations with the EuroQol-5 Dimension (5 levels) (EQ-5D-5L) and Friedreich Ataxia Rating Scale-Activities of Daily Living (FARS-ADL) questionnaires varied strongly among the subdomains, with the total scores reaching 0.53 (95% CI [0.42, 0.61]) and -0.45 (95% CI [− 0.55, − 0.35]), respectively. The caregiver-patient response Pearson correlation ranged between 0.64 and 0.82 for subdomains and reached 0.65 (95% CI [0.38, 0.81]) for the total score.

Conclusions
TreatHSP-QoL can be used in high-quality clinical trials and clinical practice as a disease-specific PCOM (i.e., HRQoL measure) and is also applicable as a proxy questionnaire. Score values between 0 and 100 can be reached, where higher value represents better HRQoL. The Pearson correlations to the EQ-5D-5L and FARS-ADL support the additional value and need of HSP-specific PCOM, while non-specific QoL-assessment and specific clinical self-assessment tools already exist. All in all, the results demonstrate good validity and reliability for this new patient-centered questionnaire for HSP.
Healthcare provider recognition of pregnancy related risks and management considerations in patients with tuberous sclerosis complex
Authors: Rose Meredith , Ritter David , Gupta Nishant , Tolusso Leandra , Horn Paul , Wakefield Emily , Glass Jennifer 
Published: January 2024

Abstract
Background
Patients with tuberous sclerosis complex (TSC) face an increased risk of maternal health complications and worsening disease manifestations during pregnancy. There are no established consensus guidelines that address the management of pregnancy in patients with TSC and healthcare providers rely on their individual experiences and preferences to derive treatment decisions. We sought to obtain provider opinion of pregnancy related maternal complications in patients with TSC, and the common evaluation and management strategies used to address these issues.

Methods
We conducted a cross-sectional survey of healthcare providers with diverse areas of expertise related to the multisystem nature of involvement in TSC. Descriptive analyses were used to analyze our three primary variables: (1) provider recognition of maternal risks/complications; (2) provider recommendations before and during pregnancy; and (3) provider/clinic protocols.

Results
We received responses from 87 providers from 11 countries, with 40.7% (n = 35) seeing > 30 TSC patients yearly. The majority of providers (n = 70, 88.6%) deemed that a patient with TSC needed expert care beyond the standard of care for a typical pregnancy, with over 25% of providers reporting that they have seen lymphangioleiomyomatosis (LAM) exacerbation, seizures, and preterm labor in pregnant patients with TSC. Providers who managed patients treated with mTOR inhibitors (mTORi) also agreed that mTORi use should be stopped prior to pregnancy (n = 45, 68.2%) but there was uncertainty about when to stop the mTORi (one month 28.9%, two months 11.1%, three months 42.2%, and 6–12 months 2.2%). Additionally, there were mixed opinions on restarting mTORi in response to disease progression during pregnancy. When asked about provider or clinic specific protocols, 71.6% (n = 53) of providers stated that they do not have a clear protocol for management decisions for patients with TSC before or during pregnancy.

Conclusion
Healthcare providers recognize that patients with TSC are at an increased risk for maternal health complications during pregnancy. However, there are wide inter-individual variances in practice, especially pertaining to decisions regarding mTORi use. There is a critical need to better understand the implications of pregnancy for patients with TSC, and to draft consensus recommendations to guide management decisions.
The feedback loop of EFTUD2/c-MYC impedes chemotherapeutic efficacy by enhancing EFTUD2 transcription and stabilizing c-MYC protein in colorectal cancer
Authors: Zhu Xiaojian , Li Changxue , Gao Yunfei , Zhang Qingyuan , Wang Tao , Zhou Huaixiang , Bu Fanqin , Chen Jia , Mao Xinjun , He Yulong , Wu Kaiming , Li Ningning , Luo Hongliang 
Published: January 2024

Abstract
Background
Chemoresistance presents a significant obstacle in the treatment of colorectal cancer (CRC), yet the molecular basis underlying CRC chemoresistance remains poorly understood, impeding the development of new therapeutic interventions. Elongation factor Tu GTP binding domain containing 2 (EFTUD2) has emerged as a potential oncogenic factor implicated in various cancer types, where it fosters tumor growth and survival. However, its specific role in modulating the sensitivity of CRC cells to chemotherapy is still unclear.

Methods
Public dataset analysis and in-house sample validation were conducted to assess the expression of EFTUD2 in 5-fluorouracil (5-FU) chemotherapy-resistant CRC cells and the potential of EFTUD2 as a prognostic indicator for CRC. Experiments both in vitro, including MTT assay, EdU cell proliferation assay, TUNEL assay, and clone formation assay and in vivo, using cell-derived xenograft models, were performed to elucidate the function of EFTUD2 in sensitivity of CRC cells to 5-FU treatment. The molecular mechanism on the reciprocal regulation between EFTUD2 and the oncogenic transcription factor c-MYC was investigated through molecular docking, ubiquitination assay, chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, and co-immunoprecipitation (Co-IP).

Results
We found that EFTUD2 expression was positively correlated with 5-FU resistance, higher pathological grade, and poor prognosis in CRC patients. We also demonstrated both in vitro and in vivo that knockdown of EFTUD2 sensitized CRC cells to 5-FU treatment, whereas overexpression of EFTUD2 impaired such sensitivity. Mechanistically, we uncovered that EFTUD2 physically interacted with and stabilized c-MYC protein by preventing its ubiquitin-mediated proteasomal degradation. Intriguingly, we found that c-MYC directly bound to the promoter region of EFTUD2 gene, activating its transcription. Leveraging rescue experiments, we further confirmed that the effect of EFTUD2 on 5-FU resistance was dependent on c-MYC stabilization.

Conclusion
Our findings revealed a positive feedback loop involving an EFTUD2/c-MYC axis that hampers the efficacy of 5-FU chemotherapy in CRC cells by increasing EFTUD2 transcription and stabilizing c-MYC oncoprotein. This study highlights the potential of EFTUD2 as a promising therapeutic target to surmount chemotherapy resistance in CRC patients.
ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells
Authors: Bergonzini Cecilia , Gregori Alessandro , Hagens Tessa M. S. , van der Noord Vera E. , van de Water Bob , Zweemer Annelien J. M. , Coban Bircan , Capula Mjriam , Mantini Giulia , Botto Asia , Finamore Francesco , Garajova Ingrid , McDonnell Liam A. , Schmidt Thomas , Giovannetti Elisa , Danen Erik H. J. 
Published: January 2024

Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and the chemotherapies such as gemcitabine/nab-paclitaxel are confronted with intrinsic or acquired resistance. The aim of this study was to investigate mechanisms underlying paclitaxel resistance in PDAC and explore strategies to overcome it.

Methods
Three paclitaxel (PR) and gemcitabine resistant (GR) PDAC models were established. Transcriptomics and proteomics were used to identify conserved mechanisms of drug resistance. Genetic and pharmacological approaches were used to overcome paclitaxel resistance.

Results
Upregulation of ABCB1 through locus amplification was identified as a conserved feature unique to PR cells. ABCB1 was not affected in any of the GR models and no cross resistance was observed. The ABCB1 inhibitor verapamil or siRNA-mediated ABCB1 depletion sensitized PR cells to paclitaxel and prevented efflux of ABCB1 substrates in all models. ABCB1 expression was associated with a trend towards shorter survival in patients who had received gemcitabine/nab-paclitaxel treatment. A pharmacological screen identified known and novel kinase inhibitors that attenuate efflux of ABCB1 substrates and sensitize PR PDAC cells to paclitaxel.

Conclusion
Upregulation of ABCB1 through locus amplification represents a novel, conserved mechanism of PDAC paclitaxel resistance. Kinase inhibitors identified in this study can be further (pre) clinically explored as therapeutic strategies to overcome paclitaxel resistance in PDAC.
Caloric restriction and metformin selectively improved LKB1-mutated NSCLC tumor response to chemo- and chemo-immunotherapy
Authors: Ndembe Gloriana , Intini Ilenia , Moro Massimo , Grasselli Chiara , Panfili Andrea , Panini Nicolò , Bleve Augusto , Occhipinti Mario , Borzi Cristina , Garassino Marina Chiara , Marabese Mirko , Canesi Simone , Scanziani Eugenio , Sozzi Gabriella , Broggini Massimo , Ganzinelli Monica 
Published: January 2024

Abstract
Background
About 10% of NSCLCs are mutated in KRAS and impaired in STK11/LKB1, a genetic background associated with poor prognosis, caused by an increase in metastatic burden and resistance to standard therapy. LKB1 is a protein involved in a number of biological processes and is particularly important for its role in the regulation of cell metabolism. LKB1 alterations lead to protein loss that causes mitochondria and metabolic dysfunction that makes cells unable to respond to metabolic stress. Different studies have shown how it is possible to interfere with cancer metabolism using metformin and caloric restriction (CR) and both modify the tumor microenvironment (TME), stimulating the switch from “cold” to “hot”.
Given the poor therapeutic response of KRASmut/LKB1mut patients, and the role of LKB1 in cell metabolism, we examined whether the addition of metformin and CR enhanced the response to chemo or chemo-immunotherapy in LKB1 impaired tumors.

Methods
Mouse cell lines were derived from lung nodules of transgenic mice carrying KRASG12D with either functional LKB1 (KRASG12D/LKB1wt) or mutated LKB1 (KRASG12D/LKB1mut). Once stabilized in vitro, these cell lines were inoculated subcutaneously and intramuscularly into immunocompetent mice. Additionally, a patient-derived xenograft (PDX) model was established by directly implanting tumor fragments from patient into immunocompromised mice.
The mice bearing these tumor models were subjected to treatment with chemotherapy or chemo-immunotherapy, both as standalone regimens and in combination with metformin and CR.

Results
Our preclinical results indicate that in NSCLC KRASmut/LKB1mut tumors, metformin and CR do enhance the response to chemo and chemo-immunotherapy, inducing a metabolic stress condition that these tumors are not able to overcome. Analysis of immune infiltrating cells did not bring to light any strong correlation between the TME immune-modulation and the tumor response to metformin and CR.

Conclusion
Our in vitro and in vivo preliminary studies confirm our hypothesis that the addition of metformin and CR is able to improve the antitumor activity of chemo and chemoimmunotherapy in LKB1 impaired tumors, exploiting their inability to overcome metabolic stress.
Tumor immune microenvironment-based therapies in pancreatic ductal adenocarcinoma: time to update the concept
Authors: Luo Wenyu , Wen Ti , Qu Xiujuan 
Published: January 2024

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. The tumor immune microenvironment (TIME) formed by interactions among cancer cells, immune cells, cancer-associated fibroblasts (CAF), and extracellular matrix (ECM) components drives PDAC in a more immunosuppressive direction: this is a major cause of therapy resistance and poor prognosis. In recent years, research has advanced our understanding of the signaling mechanism by which TIME components interact with the tumor and the evolution of immunophenotyping. Through revolutionary technologies such as single-cell sequencing, we have gone from simply classifying PDACs as “cold” and “hot” to a more comprehensive approach of immunophenotyping that considers all the cells and matrix components. This is key to improving the clinical efficacy of PDAC treatments. In this review, we elaborate on various TIME components in PDAC, the signaling mechanisms underlying their interactions, and the latest research into PDAC immunophenotyping. A deep understanding of these network interactions will contribute to the effective combination of TIME-based therapeutic approaches, such as immune checkpoint inhibitors (ICI), adoptive cell therapy, therapies targeting myeloid cells, CAF reprogramming, and stromal normalization. By selecting the appropriate integrated therapies based on precise immunophenotyping, significant advances in the future treatment of PDAC are possible.
DCAF13 inhibits the p53 signaling pathway by promoting p53 ubiquitination modification in lung adenocarcinoma
Authors: Wei Shan , Xing Jing , Chen Jia , Chen Liping , Lv Jiapei , Chen Xiaofei , Li Tang , Yu Tao , Wang Huaying , Wang Kai , Yu Wanjun 
Published: January 2024

Abstract
Background
Lung cancer is a malignant tumor with the highest mortality worldwide. Abnormalities in the ubiquitin proteasome system are considered to be contributed to lung cancer progression with deleterious effects. DDB1 and CUL4 associated factor 13 (DCAF13) is a substrate receptor of the E3 ubiquitin ligase CRL4, but its role in lung cancer remains unknown. In this study, we aimed to investigate the regulatory mechanisms of DCAF13 in lung adenocarcinoma (LUAD).

Methods
So as to investigate the effect of DCAF13 on lung adenocarcinoma cell function using in vivo and in vitro. Mechanistically, we have identified the downstream targets of DCAF13 by using RNA-sequencing, as well as ubiquitination assays, co-immunoprecipitation, immunofluorescence, immunohistochemistry and chromatin immunoprecipitation - qPCR experiments.

Results
Our findings reveal that DCAF13 is a carcinogenic factor in LUAD, as it is highly expressed and negatively correlated with clinical outcomes in LUAD patients. Through RNA-sequencing, it has been shown that DCAF13 negatively regulates the p53 signaling pathway and inhibits p53 downstream targets including p21, BAX, FAS, and PIDD1. We also demonstrate that DCAF13 can bind to p53 protein, leading to K48-linked ubiquitination and degradation of p53. Functionally, we have shown that DCAF13 knockdown inhibits cell proliferation and migration. Our results highlight the significant role of DCAF13 in promoting LUAD progression by inhibiting p53 protein stabilization and the p53 signaling pathway. Furthermore, our findings suggest that high DCAF13 expression is a poor prognostic indicator in LUAD, and DCAF13 may be a potential therapeutic target for treating with this aggressive cancer.

Conclusions
The DCAF13 as a novel negative regulator of p53 to promote LUAD progression via facilitating p53 ubiquitination and degradation, suggesting that DCAF13 might be a novel biomarker and therapeutical target for LUAD.
Do we overlook predictive factors in Poseidon 1 patients? A retrospective analysis co-evaluating antral follicle counts & diameters
Authors: Uncu Gürkan , Aslan Kiper , Cakir Cihan , Avci Berrin , Kasapoglu Isil , Alviggi Carlo 
Published: January 2024

Abstract
Background
An unexpected impaired ovarian response pertains to an insufficient reaction to controlled ovarian hyperstimulation. This deficient reaction is identified by a reduced count of mature follicles and retrieved oocytes during an IVF cycle, potentially diminishing the likelihood of a successful pregnancy. This research seeks to examine whether the characteristics of antral follicles can serve as predictive indicators for the unexpected impaired ovarian response to controlled ovarian stimulation (COS).

Methods
This retrospective cohort study was conducted at a tertiary university hospital. The electronic database of the ART (assisted reproductive technologies) center was screened between the years 2012–2022. Infertile women under 35 years, with normal ovarian reserve [anti-Müllerian hormone (AMH) > 1.2 ng/ml, antral follicle count (AFC) > 5] who underwent their first controlled ovarian stimulation (COS) cycle were selected. Women with < 9 oocytes retrieved (group 1 of the Poseidon classification) constituted the group A, whereas those with ≥ 9 oocytes severed as control (normo-responders) one (group B). Demographic, anthropometric and hormonal variables together with COS parameters of the two groups were compared.

Results
The number of patients with < 9 oocytes (group A) was 404, and those with ≥ 9 oocytes were 602 (group B). The mean age of the group A was significantly higher (30.1 + 2.9 vs. 29.4 + 2.9, p = 0.01). Group A displayed lower AMH and AFC [with interquartile ranges (IQR); AMH 1.6 ng/ml (1-2.6) vs. 3.5 ng/ml (2.2–5.4) p < 0.01, AFC 8 (6–12) vs. 12 (9–17), p < 0.01]. The number of small antral follicles (2–5 mm) of the group A was significantly lower [6 (4–8) vs. 8 (6–12) p < 0.01), while the larger follicles (5–10 mm) remained similar [3 (1–5) vs. 3(1–6) p = 0.3] between the groups.

Conclusion
The propensity of low ovarian reserve and higher age are the main risk factors for the impaired ovarian response. The proportion of the small antral follicles may be a predictive factor for ovarian response to prevent unexpected poor results.
MiR-134-3p targets HMOX1 to inhibit ferroptosis in granulosa cells of sheep follicles
Authors: Abudureyimu Gulimire , Wu Yangsheng , Chen Ying , Wang Liqin , Hao Geng , Yu Jianguo , Wang Jianguo , Lin Jiapeng , Huang Juncheng 
Published: January 2024

Abstract
Background
The intricate interplay of gene expression within ovarian granulosa cells (GCs) is not fully understood. This study aimed to investigate the miRNA regulatory mechanisms of ferroptosis during the process of follicle development in lamb GCs.

Methods
Employing transcriptome sequencing, we compared differentially expressed mRNAs (DE-mRNAs) and miRNAs (DE-miRNAs) in GCs from lambs treated with follicle-stimulating hormone (FL) to untreated controls (CL). We further screened differentially expressed ferroptosis-related genes and identified potential miRNA regulatory factors. The expression patterns of HMOX1 and miRNAs in GCs were validated using qRT‒PCR and Western blotting. Additionally, we investigated the regulatory effect of oar-miR-134-3p on HMOX1 and its function in ferroptosis through cell transfection and erastin treatment.

Results
We identified a total of 4,184 DE-mRNAs and 304 DE-miRNAs. The DE-mRNAs were mainly enriched in ferroptosis, insulin resistance, and the cell cycle. Specifically, we focused on the differential expression of ferroptosis-related genes. Notably, the ferroptosis-related genes HMOX1 and SLC3A2, modulated by DE-miRNAs, were markedly suppressed in FLs. Experimental validation revealed that HMOX1 was significantly downregulated in FL and large follicles, while oar-miR-134-3p was significantly upregulated compared to that in the CLs. HMOX1 expression was regulated by the targeting effect of oar-miR-134-3p. Functional assays further revealed that modulation of oar-miR-134-3p influenced HMOX1 expression and altered cellular responses to ferroptosis induction by erastin.

Conclusion
This study suggested that oar-miR-134-3p and HMOX1 may be one of the pathways regulating ferroptosis in GCs. This finding provides new clues to understanding the development and regulatory process of follicles.