bluuebunny/crossref_metadata_2025 huggingface dataset:
Protocol for a hybrid type 3 effectiveness-implementation trial of a pragmatic individual-level implementation strategy for supporting school-based prevention programming
Authors: Lyon Aaron R. , Cook Clayton R. , Larson Madeline , Hugh Maria L. , Dopp Alex , Hamlin Corinne , Reinke Peter , Bose Mahasweta , Law Amy , Goosey Roger , Goerdt Annie , Morrell Nicole , Wackerle-Hollman Alisha , Pullmann Michael D.
Published: January 2024

Background

For approximately one in five children who have social, emotional, and behavioral (SEB) challenges, accessible evidence-based prevention practices (EBPPs) are critical. In the USA, schools are the primary setting for children’s SEB service delivery. Still, EBPPs are rarely adopted and implemented by front-line educators (e.g., teachers) with sufficient fidelity to see effects. Given that individual behavior change is ultimately required for successful implementation, focusing on individual-level processes holds promise as a parsimonious approach to enhance impact. Beliefs and Attitudes for Successful Implementation in Schools for Teachers (BASIS-T) is a pragmatic, multifaceted pre-implementation strategy targeting volitional and motivational mechanisms of educators’ behavior change to enhance implementation and student SEB outcomes. This study protocol describes a hybrid type 3 effectiveness-implementation trial designed to evaluate the main effects, mediators, and moderators of the BASIS-T implementation strategy as applied to Positive Greetings at the Door, a universal school-based EBPP previously demonstrated to reduce student disruptive behavior and increase academic engagement.

Methods

This project uses a blocked randomized cohort design with an active comparison control (ACC) condition. We will recruit and include approximately 276 teachers from 46 schools randomly assigned to BASIS-T or ACC conditions. Aim 1 will evaluate the main effects of BASIS-T on proximal implementation mechanisms (attitudes, subjective norms, self-efficacy, intentions to implement, and maintenance self-efficacy), implementation outcomes (adoption, reach, fidelity, and sustainment), and child outcomes (SEB, attendance, discipline, achievement). Aim 2 will examine how, for whom, under what conditions, and how efficiently BASIS-T works, specifically by testing whether the effects of BASIS-T on child outcomes are (a) mediated via its putative mechanisms of behavior change, (b) moderated by teacher factors or school contextual factors, and (c) cost-effective.

Discussion

This study will provide a rigorous test of BASIS-T—a pragmatic, theory-driven, and generalizable implementation strategy designed to target theoretically-derived motivational mechanisms—to increase the yield of standard EBPP training and support strategies.

Trial registration

ClinicalTrials.gov ID: NCT05989568. Registered on May 30, 2023.
Effectiveness of pleurodesis for postoperative air leaks after lung resection
Authors: Tsubokawa Norifumi , Mimae Takahiro , Ito Risa , Sasai Ryuma , Hirano Kouichi , Kamigaichi Atsushi , Kawamoto Nobutaka , Miyata Yoshihiro , Okada Morihito
Published: January 2024

Background

Pleurodesis is often performed for air leaks; however, the ideal materials and timing of the procedure remain controversial. We investigated the efficacy of pleurodesis using different materials and timing.

Methods

We retrospectively reviewed 913 consecutive patients who underwent segmentectomy or lobectomy for non-small cell lung cancer between 2014 and 2021. Pleurodesis efficacy was assessed on the day of chest tube removal.

Results

Eighty-six patients (9%) underwent pleurodesis for postoperative air leaks. Pleurodesis was performed on a median of postoperative day (POD) 5. Talc was the most frequently used material (n = 52, 60%), followed by autologous blood patches (n = 20, 23%), OK-432 (n = 12, 14%), and others (n = 2, 2%). No difference existed in the number of days from initial pleurodesis to chest tube removal among the three groups (talc, 3 days; autologous blood patch, 3 days; OK-432, 2 days; P = 0.55). No difference in patient background, except for sex, was observed between patients who underwent pleurodesis within 4 PODs and those who underwent pleurodesis on POD 5 or later. Drainage time was significantly shorter in patients who underwent pleurodesis within 4 PODs (median, 7 vs. 9 days; P = 0.004).

Conclusions

The efficacies of autologous blood patch, talc, and OK-432 would be considered comparable and early postoperative pleurodesis could shorten drainage time. Prospective studies are required.
Machine learning integration of multi-modal analytical data for distinguishing abnormal botanical drugs and its application in Guhong injection
Authors: Han Zhu , Zhao Jiandong , Tang Yu , Wang Yi
Published: January 2024

Background

Determination of batch-to-batch consistency of botanical drugs (BDs) has long been the bottleneck in quality evaluation primarily due to the chemical diversity inherent in BDs. This diversity presents an obstacle to achieving comprehensive standardization for BDs. Basically, a single detection mode likely leads to substandard analysis results as different classes of structures always possess distinct physicochemical properties. Whereas representing a workaround for multi-target standardization using multi-modal data, data processing for information from diverse sources is of great importance for the accuracy of classification.

Methods

In this research, multi-modal data of 78 batches of Guhong injections (GHIs) consisting of 52 normal and 26 abnormal samples were acquired by employing HPLC-UV, -ELSD, and quantitative 1H NMR (q1HNMR), of which data obtained was then individually used for Pearson correlation coefficient (PCC) calculation and partial least square-discriminant analysis (PLS-DA). Then, a mid-level data fusion method with data containing qualitative and quantitative information to establish a support vector machine (SVM) model for evaluating the batch-to-batch consistency of GHIs.

Results

The resulting outcomes showed that datasets from one detection mode (e.g., data from UV detectors only) are inadequate for accurately assessing the product's quality. The mid-level data fusion strategy for the quality evaluation enabled the classification of normal and abnormal batches of GHIs at 100% accuracy.

Conclusions

A quality assessment strategy was successfully developed by leveraging a mid-level data fusion method for the batch-to-batch consistency evaluation of GHIs. This study highlights the promising utility of data from different detection modes for the quality evaluation of BDs. It also reminds manufacturers and researchers about the advantages of involving data fusion to handle multi-modal data. Especially when done jointly, this strategy can significantly increase the accuracy of product classification and serve as a capable tool for studies of other BDs.
Father-to-daughter transmission in late-onset OTC deficiency: an underestimated mechanism of inheritance of an X-linked disease
Authors: Siri Barbara , Olivieri Giorgia , Lepri Francesca Romana , Poms Martin , Goffredo Bianca Maria , Commone Anna , Novelli Antonio , Häberle Johannes , Dionisi-Vici Carlo
Published: January 2024

Background

Ornithine Transcarbamylase Deficiency (OTCD) is an X-linked urea cycle disorder characterized by acute hyperammonemic episodes. Hemizygous males are usually affected by a severe/fatal neonatal-onset form or, less frequently, by a late-onset form with milder disease course, depending on the residual enzymatic activity. Hyperammonemia can occur any time during life and patients could remain non- or mis-diagnosed due to unspecific symptoms. In heterozygous females, clinical presentation varies based on the extent of X chromosome inactivation. Maternal transmission in X-linked disease is the rule, but in late-onset OTCD, due to the milder phenotype of affected males, paternal transmission to the females is possible. So far, father-to-daughter transmission of OTCD has been reported only in 4 Japanese families.

Results

We identified in 2 Caucasian families, paternal transmission of late-onset OTCD with severe/fatal outcome in affected males and 1 heterozygous female. Furthermore, we have reassessed the pedigrees of other published reports in 7 additional families with evidence of father-to-daughter inheritance of OTCD, identifying and listing the family members for which this transmission occurred.

Conclusions

Our study highlights how the diagnosis and pedigree analysis of late-onset OTCD may represent a real challenge for clinicians. Therefore, the occurrence of paternal transmission in OTCD should not be underestimated, due to the relevant implications for disease inheritance and risk of recurrence.
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

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

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

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

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

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

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

Pancreatic 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

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

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

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.
Protein disulfide isomerase family member 4 promotes triple-negative breast cancer tumorigenesis and radiotherapy resistance through JNK pathway
Authors: Tao Jinqiu , Xue Cailin , Cao Meng , Ye Jiahui , Sun Yulu , Chen Hao , Guan Yinan , Zhang Wenjie , Zhang Weijie , Yao Yongzhong
Published: January 2024

Background

Despite radiotherapy ability to significantly improve treatment outcomes and survival in triple-negative breast cancer (TNBC) patients, acquired resistance to radiotherapy poses a serious clinical challenge. Protein disulfide isomerase exists in endoplasmic reticulum and plays an important role in promoting protein folding and post-translational modification. However, little is known about the role of protein disulfide isomerase family member 4 (PDIA4) in TNBC, especially in the context of radiotherapy resistance.

Methods

We detected the presence of PDIA4 in TNBC tissues and paracancerous tissues, then examined the proliferation and apoptosis of TNBC cells with/without radiotherapy. As part of the validation process, xenograft tumor mouse model was used. Mass spectrometry and western blot analysis were used to identify PDIA4-mediated molecular signaling pathway.

Results

Based on paired clinical specimens of TNBC patients, we found that PDIA4 expression was significantly higher in tumor tissues compared to adjacent normal tissues. In vitro, PDIA4 knockdown not only increased apoptosis of tumor cells with/without radiotherapy, but also decreased the ability of proliferation. In contrast, overexpression of PDIA4 induced the opposite effects on apoptosis and proliferation. According to Co-IP/MS results, PDIA4 prevented Tax1 binding protein 1 (TAX1BP1) degradation by binding to TAX1BP1, which inhibited c-Jun N-terminal kinase (JNK) activation. Moreover, PDIA4 knockdown suppressed tumor growth xenograft model in vivo, which was accompanied by an increase in apoptosis and promoted tumor growth inhibition after radiotherapy.

Conclusions

The results of this study indicate that PDIA4 is an oncoprotein that promotes TNBC progression, and targeted therapy may represent a new and effective anti-tumor strategy, especially for patients with radiotherapy resistance.
Tissue-specific RNA Polymerase II promoter-proximal pause release and burst kinetics in a Drosophila embryonic patterning network
Authors: Hunt George , Vaid Roshan , Pirogov Sergei , Pfab Alexander , Ziegenhain Christoph , Sandberg Rickard , Reimegård Johan , Mannervik Mattias
Published: January 2024

Background

Formation of tissue-specific transcriptional programs underlies multicellular development, including dorsoventral (DV) patterning of theDrosophilaembryo. This involves interactions between transcriptional enhancers and promoters in a chromatin context, but how the chromatin landscape influences transcription is not fully understood.

Results

Here we comprehensively resolve differential transcriptional and chromatin states duringDrosophilaDV patterning. We find that RNA Polymerase II pausing is established at DV promoters prior to zygotic genome activation (ZGA), that pausing persists irrespective of cell fate, but that release into productive elongation is tightly regulated and accompanied by tissue-specific P-TEFb recruitment. DV enhancers acquire distinct tissue-specific chromatin states through CBP-mediated histone acetylation that predict the transcriptional output of target genes, whereas promoter states are more tissue-invariant. Transcriptome-wide inference of burst kinetics in different cell types revealed that while DV genes are generally characterized by a high burst size, either burst size or frequency can differ between tissues.

Conclusions

The data suggest that pausing is established by pioneer transcription factors prior to ZGA and that release from pausing is imparted by enhancer chromatin state to regulate bursting in a tissue-specific manner in the early embryo. Our results uncover how developmental patterning is orchestrated by tissue-specific bursts of transcription from Pol II primed promoters in response to enhancer regulatory cues.
Circ_MAPK9 promotes STAT3 and LDHA expression by silencing miR-642b-3p and affects the progression of hepatocellular carcinoma
Authors: Wang Kunyuan , Lu Qianting , Luo Yufeng , Yu Ganxiang , Wang Zhilei , Lin Jiaen , Tan Zhenlin , Lao Yueqiong , Liu Shiming , Yang Hui
Published: January 2024

Background

Aberrant expression and activation of circular RNAs (circRNAs) are closely associated with various cancers. The role of circ_MAPK9 (hsa_circ_0001566) in cancer progression remains unknown. This study aims to investigate the function, mechanism and clinical significance of circ_MAPK9 in hepatocellular carcinoma (HCC).

Methods

Circ_MAPK9 expression on the microarray of tumor from clinical HCC patients was detected by in situ hybridization (ISH). Circ_MAPK9 knockdown was achieved with siRNAs in SMMC-7721 and SK-Hep1 HCC cell lines. The biological function of circ_MAPK9 was verified in vitro by CCK8 test, colony formation assay, transwell assay, PI-Annexin V staining, and in vivo by xenograft tumor in nude mice. Fluorescent in situ hybridization (FISH), subcellular fractionation assay, a dual-luciferase reporter assay and rescue experiments were employed for further mechanistic investigation.

Results

The expression of circ_MAPK9 was significantly up-regulated in HCC tissues and cells, which was found to be associated with poor prognosis. Patients with high expression of circ_MAPK9 had a shorter overall survival and disease-free survival in comparison to those with low circ_MAPK9 expression. Functional assays showed that circ_MAPK9 knockdown suppressed cellular proliferation, migration, invasion and tumor growth in vivo, and promoted apoptosis in HCC cells. Moreover, we found that circ_MAPK9 knockdown could inhibit aerobic glycolysis by decreasing the production of adenosine triphosphate (ATP) and lactic acid, which was mediated by lactate dehydrogenase (LDHA). Mechanistically, circ_MAPK9 functioned as ceRNA via sponging miR-642b-3p and alleviated the inhibitory effect of miR-642b-3p on its target signal transducer and activator of transcription 3 (STAT3) and LDHA, thereby leading to STAT3 activation and LDHA expression.

Conclusions

Circ_MAPK9, as an oncogene, promotes HCC growth and metastasis through miR-642b-3p/STAT3-LDHA axis. Circ_MAPK9 could serve as a potential biomarker for HCC poor prognosis and diagnosis.
The oncogenic role and regulatory mechanism of PGK1 in human non-small cell lung cancer
Authors: Tian Tian , Leng Yahui , Tang Bingbing , Dong Xiaoxia , Ren Qiulei , Liang Jingyin , Liu Tianhui , Liu Yanni , Feng Wenxiao , Liu Song , Zhou Yang , Zhao Hongyan , Shen Li
Published: January 2024

Background

Phosphoglycerate kinase 1 (PGK1) is a metabolic enzyme that participates in various biological and pathological processes. Dysregulated PGK1 has been observed in numerous malignancies. However, whether and how PGK1 affects non-small cell lung cancer (NSCLC) is not yet fully elucidated.

Methods

Herein, the non-metabolic function of PGK1 in NSCLC was explored by integrating bioinformatics analyses, cellular experiments, and nude mouse xenograft models. The upstream regulators and downstream targets of PGK1 were examined using multiple techniques such as RNA sequencing, a dual-luciferase reporter assay, Co-immunoprecipitation, and Western blotting.

Results

We confirmed that PGK1 was upregulated in NSCLC and this upregulation was associated with poor prognosis. Further in vitro and in vivo experiments demonstrated the promoting effects of PGK1 on NSCLC cell growth and metastasis. Additionally, we discovered that PGK1 interacted with and could be O-GlcNAcylated by OGT. The inhibition of PGK1 O-GlcNAcylation through OGT silencing or mutation at the T255 O-GlcNAcylation site could weaken PGK1-mediated NSCLC cell proliferation, colony formation, migration, and invasion. We also found that a low miR-24-3p level led to an increase in OGT expression. Additionally, PGK1 exerted its oncogenic properties by augmenting ERK phosphorylation and MCM4 expression.

Conclusions

PGK1 acted as a crucial mediator in controlling NSCLC progression. The miR-24-3p/OGT axis was responsible for PGK1 O-GlcNAcylation, and ERK/MCM4 were the downstream effectors of PGK1. It appears that PGK1 might be an attractive therapeutic target for the treatment of NSCLC.
GPR137 inactivates Hippo signaling to promote gastric cancer cell malignancy
Authors: Li Lin , Tang Jinlong , Cao Bin , Xu Qiang , Xu Shouying , Lin Chao , Tang Chao
Published: January 2024

As the fifth most common cancer in the world, gastric cancer (GC) ranks as the third major cause of cancer-related death globally. Although surgical resection and chemotherapy still remains the mainstay of potentially curative treatment for GC, chemotherapy resistance and adverse side effects limit their clinical applications. Thus, further investigation of the mechanisms of carcinogenesis in GC and discovery of novel biomarkers is of great concern. We herein report that the elevated expression of GPR137 is correlated with GC. Overexpression of GPR137 potentiates human gastric cancer AGS cell malignancy, including proliferation, migration, invasion, colony formation and xenograft growth in nude mice in vivo, whereas knockout of GPR137 by CRISPR/Cas9 gene editing exerts the opposite effects. Mechanistically, GPR137 could bind to MST, the upstream kinases in Hippo pathway, which disrupts the association of MST with LATS, subsequently activating the transcriptional co-activators, YAP and TAZ, and thereby triggering the target transcription and the alterations in GC cell biological actions consequently. Therefore, our findings may provide with the evidence of developing a potentially novel treatment method with specific target for GC.
Risk assessment of transgender people: implementation of a demasculinizing–feminizing rodent model including the evaluation of thyroid homeostasis
Authors: Tammaro Alessia , Lori Gabriele , Martinelli Andrea , Cancemi Luigia , Tassinari Roberta , Maranghi Francesca
Published: January 2024

Background

Individuals whose gender identity differs from the biological sex and the social norms are defined as transgender. Sometimes transgender undergo gender affirming hormone therapy, which lasts for the entire life making essential to evaluate its potential long-term effects. Moreover, transgender can represent a susceptible sub-group of population and specific attention is needed in risk assessment, including the development of targeted animal models. Aim of the study is the implementation of a rodent demasculinizing–feminizing model through the setting of appropriate dose of hormone therapy and the selection of specific biomarkers to evaluate the sex transition. Specific attention is paid to thyroid homeostasis due to the close link with reproductive functions. Four male adult rats/group were subcutaneously exposed to three doses plus control of β-estradiol valerate plus cyproterone acetate at: 0.045 + 0.2 (low), 0.09 + 0.2 (medium) and 0.18 + 0.2 (high) mg/dose, five times/week. The doses were selected considering the most recent recommendations for transgender woman. Sperm count, histopathological analysis (testis, liver, thyroid), testosterone, estradiol, triiodothyronine and thyroid-stimulating hormone serum levels and gene expression of sex dimorphic CYP450 were evaluated.

Results

The doses induced feminizing–demasculinizing effects: decreased testosterone serum levels at the corresponding cisgender, increased estradiol, impairment of male reproductive function and reversal of sex-specific CYP liver expression. However, the medium and high doses induced marked liver toxicity and the low dose is considered the best choice, also for long-term studies in risk assessment. The alterations of thyroid indicated follicular cell hypertrophy supported by increased thyroid-stimulating hormone serum levels at the higher doses.

Conclusions

The implementation of animal models that mimic the effects of gender affirming hormone therapy is essential for supporting clinical studies in transgender people and filling data gap in order to ensure an appropriate risk assessment and a more accurate, personalized care for transgender people.
Comparison between the mesenteric fixation method (MEFIX) and conventional methods at preventing the occurrence of Petersen’s hernia: a study protocol for a multicenter randomized controlled trial
Authors: Park Jae Kyun , Kim Dae Hwan , Jeon Tae-Yong , Jeong Sang-Ho , Kim Tae Han , Min Jae-Seok , Kim Rock Bum , Lee Young Joon , Park Ji Ho , Son Young Gil , Yoon Ki Young , Seo Kyung Won , Kim Ki Hyun , Kim Yoonhong , Chae Hyun Dong , Hwang Sun Hwi , Lee Si-Hak , Chung Jae Hun , Kim Hyoung-Il , Park Dong Jin , Kim Kwang Hee , Seo Sang Hyuk , Oh Sung Jin , Lee Woo Yong , In Choi Chang
Published: January 2024

Background

Petersen’s hernia, which occurs after Billroth-II (B-II) or Roux-en-Y (REY) anastomosis, can be reduced by defect closure. This study aims to compare the incidence of bowel obstruction above Clavien–Dindo classification grade III due to Petersen’s hernia between the mesenteric fixation method and the conventional methods after laparoscopic or robotic gastrectomy.

Methods

This study was designed as prospective, single-blind, non-inferiority randomized controlled multicenter trial in Korea. Patients with histologically diagnosed gastric cancer of clinical stages I, II, or III who underwent B-II or REY anastomosis after laparoscopic or robotic gastrectomy are enrolled in this study. Participants who meet the inclusion criteria are randomly assigned to two groups: a CLOSURE group that underwent conventional Petersen’s defect closure method and a MEFIX group that underwent the mesenteric fixation method. The primary endpoint is the number of patients who underwent surgery for bowel obstruction caused by Petersen’s hernia within 3 years after laparoscopic or robotic gastrectomy.

Discussion

This trial is expected to provide high-level evidence showing that the MEFIX method can quickly and easily close Petersen’s defect without increased postoperative complications compared to the conventional method.

Trial registration

ClinicalTrials.gov NCT05105360. Registered on November 3, 2021.
Internet-based transdiagnostic treatment for emotional disorders in Arabic- and Farsi-speaking refugees: study protocol of a randomized controlled trial
Authors: Boettcher Johanna , Heinrich Manuel , Boettche Maria , Burchert Sebastian , Glaesmer Heide , Gouzoulis-Mayfrank Euphrosyne , Heeke Carina , Hernek Martina , Knaevelsrud Christine , Konnopka Alexander , Muntendorf Louisa , Nilles Hannah , Nohr Laura , Pohl Steffi , Paskuy Sophia , Reinhardt Isabelle , Sierau Susan , Stammel Nadine , Wirz Christina , Renneberg Babette , Wagner Birgit
Published: January 2024

Background

Refugee populations have an increased risk for mental disorders, such as depression, anxiety, and posttraumatic stress disorders. Comorbidity is common. At the same time, refugees face multiple barriers to accessing mental health treatment. Only a minority of them receive adequate help. The planned trial evaluates a low-threshold, transdiagnostic Internet-based treatment. The trial aims at establishing its efficacy and cost-effectiveness compared with no treatment.

Methods

N = 131 treatment-seeking Arabic- or Farsi-speaking patients, meeting diagnostic criteria for a depressive, anxiety, and/or posttraumatic stress disorder will be randomized to either the intervention or the waitlist control group. The intervention group receives an Internet-based treatment with weekly written guidance provided by Arabic- or Farsi-speaking professionals. The treatment is based on the Common Elements Treatment Approach (CETA), is tailored to the individual patient, and takes 6–16 weeks. The control group will wait for 3 months and then receive the Internet-based treatment.

Discussion

The planned trial will result in an estimate of the efficacy of a low-threshold and scalable treatment option for the most common mental disorders in refugees.

Trial registration

German Registry for Clinical Trials DRKS00024154. Registered on February 1, 2021.