bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparative, observational study evaluating dosing characteristics and ovarian response using the recombinant human follicle-stimulating hormone pen injector with small-dose dial in assisted reproductive technologies treatment in Asia: IMPROVE study
Authors: Choi Bum Chae , Zhou Canquan , Ye Hong , Sun Yun , Zhong Ying , Gong Fei , Sini Ivan , Abramova Nadezda , Longobardi Salvatore , Hickey Miranda , D’Hooghe Thomas 
Published: January 2022

Abstract
Background
Ovarian stimulation during medically assisted reproduction treatment should be individualized to optimize outcomes and reduce complications. This study assessed whether use of the recombinant human follicle-stimulating hormone (r-hFSH) pen injector allowing small 12.5 IU dose increments resulted in lower r-hFSH dose per oocyte retrieved in a subgroup of patients at risk of OHSS, compared with r-hFSH injection devices allowing only 37.5 IU increments.

Methods
This multicenter, comparative, observational study evaluated patients from a prospective (study group) and historical (control group) cohort. The study group enrolled 1783 patients using the redesigned r-hFSH pen injector (GONAL-f®, Merck Healthcare KGaA, Darmstadt, Germany) from a prospective phase IV, non-interventional, open-label study, conducted in Korea, Vietnam, Indonesia, and China. The control group consisted of 1419 patients from a historical study using r-hFSH devices allowing 37.5 IU increments. In the study group, 397 patients were considered at risk of OHSS; this information was unavailable for the control group, so biomarkers and patient characteristics were used to match 123 patients from the study group and control group. Each center adhered to standard practice; starting dose and intra-cycle dose adjustments were allowed at any point. The primary endpoint, amount of r-hFSH (IU) administered per oocyte retrieved, was assessed in matched patients only. Additional outcomes and safety were assessed in the overall populations.

Results
Baseline characteristics were comparable between groups. Mean (SD) total dose of r-hFSH administered per oocyte retrieved in patients at risk of OHSS, was significantly lower in the study group compared with the control group (132.5 [85.2] vs. 332.7 [371.6] IU, P < 0.0001, n = 123). Implantation rate, clinical pregnancy rate, and live birth rates in the overall study and control groups were 30.0 vs. 20.6%, 50.3 vs. 40.7%, and 43.8 vs. 34.0%, respectively. OHSS incidence was significantly lower in the study group compared with the control group (27/1783 [1.5%] vs. 57/1419 [4.0%] patients, P < 0.0001). AEs were reported by 5.0% of patients in the study group.

Conclusions
A significantly lower r-hFSH dose per oocyte retrieved and lower OHSS incidence were observed in patients using the redesigned injector compared with patients using other injection devices.
Radiotherapy-induced toxicity in prostate cancer patients with hip prostheses
Authors: Fischer Andrea M. , Hoskin Peter J. 
Published: January 2022

Abstract
Introduction
Acute and late toxicity was analysed for prostate cancer patients with bilateral hip prostheses, who received fixed field intensity modulated radiotherapy (IMRT). The aims were (1) to establish whether toxicity rates differed from those of a control group with normal hips, (2) to develop a volumetric modulated arc therapy (VMAT) approach for patients with prostheses and (3) to compare doses to bladder and rectum for the control group, prostheses group and VMAT replans for the prostheses group.

Methods
Genitourinary (GU) and gastrointestinal (GI) toxicity was scored using Common Terminology Criteria for Adverse Events version 5.0. The incidence of grade 2 or worse (G2+) toxicity was compared using Fisher’s exact test. Dose volume histograms (DVHs) and mean doses to organs at risk (OARs) were compared using signed rank tests.

Results
There were 17 patients in the prostheses group and 50 in the control group. Acute and late GU toxicity was similar. G2+ late GI toxicity incidence was 31% for the prostheses group and 14% for the control group (p = 0.14). Significant differences (p < 0.05) were seen between the OAR DVHs of the prostheses group who had IMRT and the control group for a range of intermediate doses. The rectum mean dose was significantly different (p < 0.001), but no difference was seen for the bladder mean dose (p = 0.08).

Conclusions
No significant differences were seen in GU and GI toxicity incidence between patients with bilateral hip prostheses and a control group. The DVHs for bladder and rectum were significantly higher for patients with prostheses planned with IMRT. Replanning using a VMAT technique significantly reduced doses to the OARs, whilst maintaining good planning target volume coverage.
Comparison of blood tonic efficacy and chemical constituents of Kadsura interior A.C. Smith and its closely related species
Authors: Xu Jing , Liu Jiushi , Li Bin , Wei Xueping , Qi Yaodong , Zhang Bengang , Liu Haitao , Xiao Peigen 
Published: January 2022

Abstract
Background
The stems of Kadsura interior A. C. Smith are used as traditional Chinese medicine (TCM) Kadsurae Caulis, with the traditional efficacy of tonifying and invigorating the blood, therefore being favored to treat blood deficiency (BD) widely. However, the stems of K. interior and its closely related species are morphologically similar and they may readily be misused as Kadsurae Caulis, thus likely to exert negative effects on clinical efficacy and clinical medication safety.

Methods
Firstly, blood tonic efficacies of the stems of K. interior (KIS) and its closely related species were compared using BD mouse model induced by 1-acetyl-2-phenylhydrazine (APH) and cyclophosphamide (CTX). Secondly, the chemical constituents from the stems of K. interior and its closely related species were evaluated and compared using a plant metabolomics approach. Plant metabolomics in this study aims at discovering differential metabolites and comprehensively assessing the chemical constituents by combining state-of-the-art high-resolution UPLC-Q/TOF–MS/MS technique and multivariate data analysis. Finally, based on the pharmacological data and the chemical constituents in UPLC-Q/TOF–MS fingerprints, the potential blood tonic active markers were screened by the spectrum-effect relationship analysis and quantified by UPLC-UV-DAD.

Results
The ethanol extract of the stems of K. interior significantly increased the levels of hematocrit (HCT), hemoglobin (HGB), and red blood cells (RBC) in BD mice. In addition, it significantly increased the serum levels of interleukin 3 (IL-3), granulocyte–macrophage colony-stimulating factor (GM-CSF), and macrophage-stimulating factor (M-CSF) in BD mice (P < 0.01). The blood tonic efficacy of the stems of K. interior was superior to those of its closely related species, especially at the dose of 200 mg/kg. Six differential compounds in the stems of K. interior were screened out to distinguish it from its closely related species. In combination with the results of the spectrum-effect relationship analysis, heteroclitin D, interiorin C, and heteroclitin G were identified as potential bioactive markers. The contents of heteroclitin D and heteroclitin G in the freeze-dried powder of KIS were 15.90 and 3.74 μg/mg.

Conclusions
This study illustrated the differences in the blood tonic efficacies and the chemical constituents of the stems of K. interior and its closely related species, and pinpointed the potential bioactive markers of K. interior.
Metabolic synthetic lethality by targeting NOP56 and mTOR in KRAS-mutant lung cancer
Authors: Yang Zhang , Liang Shun-Qing , Zhao Liang , Yang Haitang , Marti Thomas M. , Hegedüs Balazs , Gao Yanyun , Zheng Bin , Chen Chun , Wang Wenxiang , Dorn Patrick , Kocher Gregor J. , Schmid Ralph A. , Peng Ren-Wang 
Published: January 2022

Abstract
Background
Oncogenic KRAS mutations are prevalent in human cancers, but effective treatment of KRAS-mutant malignancies remains a major challenge in the clinic. Increasing evidence suggests that aberrant metabolism plays a central role in KRAS-driven oncogenic transformation. The aim of this study is to identify selective metabolic dependency induced by mutant KRAS and to exploit it for the treatment of the disease.

Method
We performed an integrated analysis of RNAi- and CRISPR-based functional genomic datasets (n = 5) to identify novel genes selectively required for KRAS-mutant cancer. We further screened a customized library of chemical inhibitors for candidates that are synthetic lethal with NOP56 depletion. Functional studies were carried out by genetic knockdown using siRNAs and shRNAs, knockout using CRISPR/Cas9, and/or pharmacological inhibition, followed by cell viability and apoptotic assays. Protein expression was determined by Western blot. Metabolic ROS was measured by flow cytometry-based quantification.

Results
We demonstrated that nucleolar protein 5A (NOP56), a core component of small nucleolar ribonucleoprotein complexes (snoRNPs) with an essential role in ribosome biogenesis, confers a metabolic dependency by regulating ROS homeostasis in KRAS-mutant lung cancer cells and that NOP56 depletion causes synthetic lethal susceptibility to inhibition of mTOR. Mechanistically, cancer cells with reduced NOP56 are subjected to higher levels of ROS and rely on mTOR signaling to balance oxidative stress and survive. We also discovered that IRE1α-mediated unfolded protein response (UPR) regulates this process by activating mTOR through p38 MAPK. Consequently, co-targeting of NOP56 and mTOR profoundly enhances KRAS-mutant tumor cell death in vitro and in vivo.

Conclusions
Our findings reveal a previously unrecognized mechanism in which NOP56 and mTOR cooperate to play a homeostatic role in the response to oxidative stress and suggest a new rationale for the treatment of KRAS-mutant cancers.
The SF3B1R625H mutation promotes prolactinoma tumor progression through aberrant splicing of DLG1
Authors: Guo Jing , Li Chuzhong , Fang Qiuyue , Liu Yulou , Wang Dawei , Chen Yiyuan , Xie Weiyan , Zhang Yazhuo 
Published: January 2022

Abstract
Background
Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1R625H), but its functional effects and underlying molecular mechanisms remain largely unexplored.

Methods
Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1R625H mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1-wild-type versus mutant human prolactinoma samples and GH3 cells. RT-PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1R625H were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components were detected using western blot, immunohistochemistry, and immunofluorescence. Suppressing proteins was achieved using siRNA.

Results
Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1R625H allele led to different alterations in splicing properties, affecting different genes in different species. SF3B1R625H promoted aberrant splicing and DLG1 suppression in both rat cells and human tumors. In addition, SF3B1R625H and knocking down DLG1 promoted cell migration, invasion, and epithelial-mesenchymal transition through PI3K/Akt pathway.

Conclusions
Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1R625H mutation.
Effects of the addition of transcutaneous electrical stimulation to non-pharmacological measures in labor pain: study protocol for a randomized controlled trial
Authors: Dias Naiara Toledo , Santos Patrícia Roberta , Cândido Thais Alves , Pinto Rogério de Melo Costa , Resende Ana Paula Magalhães , Pereira-Baldon Vanessa Santos 
Published: January 2022

Abstract
Background
Labor, although natural and physiological, is a period that can be marked by stress, pain, anxiety, suffering, fear, and anguish for a woman. Thus, non-pharmacological methods that reduce pain during labor are important to allow a better experience without the use of medications. Therefore, the aim of this study is to evaluate the effects of non-pharmacological pain relief methods, added or not to the application of transcutaneous electrical stimulation (TENS), on pain, satisfaction with the childbirth, duration of labor, and newborn conditions.

Methods
This is a randomized controlled clinical trial, with a non-probabilistic convenience sample, composed of women in the first active stage of labor, admitted to a public institution. The parturients will be divided into 3 groups: group 1 (n = 36) composed of parturients who will have continuous support and will be encouraged to walk, adopting different positions with the use of the Swiss ball and receiving back massage for 30 min; group 2 (n = 36) composed of parturients who will also have continuous support and will be encouraged to walk, adopt different positions using the Swiss ball, and will receive the application of TENS for 30 min; and group 3 (n = 36) composed of parturients who will have continuous support and will be encouraged to walk, adopting different positions with the use of the Swiss ball, and will receive placebo TENS application for 30 min. The outcomes evaluated in the study will be pain intensity assessed by the visual analog scale of pain applied before, immediately after, and 30 min and 1 h after the interventions; Experience and Satisfaction with Childbirth Questionnaire (QESP) applied 12 to 24 h after delivery; and data regarding delivery (type of delivery, total duration of labor, and possible obstetric complications) and neonate (weight, height, possible complications, Apgar score in the first and fifth minutes).

Discussion
With this research, it is expected to understand the effects of the intervention through TENS electrostimulation added to other non-pharmacological methods for pain management during labor.

Trial registration
Brazilian Registry of Clinical Trials (REBEC) RBR-68kh6j. Registered on March 17, 2020
Effectiveness of a high-intensive trauma-focused, family-based therapy for youth exposed to family violence: study protocol for a randomized controlled trial
Authors: Fictorie Valerie , Jonkman Caroline , Visser Margreet , Vandenbosch Marjolein , Steketee Majone , Schuengel Carlo 
Published: January 2022

Abstract
Background
Family violence is a common problem with direct adverse effects on children as well as indirect effects through disruption of parenting and parent-child relationships. The complex interrelationships between family violence, parenting, and relationships make recovery from psychological responses difficult. In more than half of the families referred to mental health care after family violence, the violence continues. Also, the effect sizes of “golden standard” treatments are generally lower for complex trauma compared to other forms of trauma. In the treatment of complex trauma, trauma-focused therapies including cognitive restructuring and imaginal exposure are most effective, and intensifying therapy results in faster symptom reduction. Furthermore, there is promising evidence that adding a parental component to individual trauma treatment increases treatment success. In family-based intensive trauma treatment (FITT), these factors are addressed on an individual and family level in a short period of time to establish long-term effects on the reduction of trauma symptoms and recovery of security in the family. This randomized controlled multicentre study tests if FITT is an effective treatment for concurrent reduction of trauma symptoms of children, improvement of parenting functioning, and increasing emotional and physical security in children, through the improvement of parent-child relationships.

Methods
The effectiveness of FITT will be tested by a RCT design. A total of 120 adolescents with a history of family violence and PTS symptoms will be randomized to (a) an intensive trauma treatment with a parent and systemic component (FITT), (b) an intensive trauma treatment without these components (ITT), and (c) treatment as usual (TAU, low-frequency trauma treatment with parent therapy and family sessions). Changes in children’s trauma symptoms, child and parent functioning, and emotional and physical security in the family will be monitored before, during, after, and at 3 months follow-up.

Discussion
Comparing these interventions with and without a high intensive frequency and parenting and family components can help to understand if and how these interventions work and can contribute to the ambition to recover from the impact of family violence and restore emotional and physical security for children and young people.

Trial registration
Netherlands Trial Register Trial NL8592. Registered on 4 May 2020
Boosting the acetol production in methanotrophic biocatalyst Methylomonas sp. DH-1 by the coupling activity of heteroexpressed novel protein PmoD with endogenous particulate methane monooxygenase
Authors: Chau Tin Hoang Trung , Nguyen Anh Duc , Lee Eun Yeol 
Published: January 2022

Abstract
Background
Methylacidiphilum sp. IT6 has been validated its C3 substrate assimilation pathway via acetol as a key intermediate using the PmoCAB3, a homolog of the particulate methane monooxygenase (pMMO). From the transcriptomic data, the contribution of PmoD of strain IT6 in acetone oxidation was questioned. Methylomonas sp. DH-1, a type I methanotroph containing pmo operon without the existence of its pmoD, has been deployed as a biocatalyst for the gas-to-liquid bioconversion of methane and propane to methanol and acetone. Thus, Methylomonas sp. DH-1 is a suitable host for investigation. The PmoD-expressed Methylomonas sp. DH-1 can also be deployed for acetol production, a well-known intermediate for various industrial applications. Microbial production of acetol is a sustainable approach attracted attention so far.

Results
In this study, bioinformatics analyses elucidated that novel protein PmoD is a C-terminal transmembrane–helix membrane with the proposed function as a transport protein. Furthermore, the whole-cell biocatalyst was constructed in Methylomonas sp. DH-1 by co-expression the PmoD of Methylacidiphilum sp. IT6 with the endogenous pMMO to enable acetone oxidation. Under optimal conditions, the maximum accumulation, and specific productivity of acetol were 18.291 mM (1.35 g/L) and 0.317 mmol/g cell/h, respectively. The results showed the first coupling activity of pMMO with a heterologous protein PmoD, validated the involvement of PmoD in acetone oxidation, and demonstrated an unprecedented production of acetol from acetone in type I methanotrophic biocatalyst. From the data achieved in batch cultivation conditions, an assimilation pathway of acetone via acetol as the key intermediate was also proposed.

Conclusion
Using bioinformatics tools, the protein PmoD has been elucidated as the membrane protein with the proposed function as a transport protein. Furthermore, results from the assays of PmoD-heteroexpressed Methylomonas sp. DH-1 as a whole-cell biocatalyst validated the coupling activity of PmoD with pMMO to convert acetone to acetol, which also unlocks the potential of this recombinant biocatalyst for acetol production. The proposed acetone-assimilated pathway in the recombinant Methylomonas sp. DH-1, once validated, can extend the metabolic flexibility of Methylomonas sp. DH-1.
Epigenetics of single-site and multi-site atherosclerosis in African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA)
Authors: Ammous Farah , Zhao Wei , Lin Lisha , Ratliff Scott M. , Mosley Thomas H. , Bielak Lawrence F. , Zhou Xiang , Peyser Patricia A. , Kardia Sharon L. R. , Smith Jennifer A. 
Published: January 2022

AbstractBackgroundDNA methylation, an epigenetic mechanism modulated by lifestyle and environmental factors, may be an important biomarker of complex diseases including cardiovascular diseases (CVD) and subclinical atherosclerosis.MethodsDNA methylation in peripheral blood samples from 391 African-Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) was assessed at baseline, and atherosclerosis was assessed 5 and 12 years later. Using linear mixed models, we examined the association between previously identified CpGs for coronary artery calcification (CAC) and carotid plaque, both individually and aggregated into methylation risk scores (MRSCACand MRScarotid), and four measures of atherosclerosis (CAC, abdominal aorta calcification (AAC), ankle–brachial index (ABI), and multi-site atherosclerosis based on gender-specific quartiles of the single-site measures). We also examined the association between four epigenetic age acceleration measures (IEAA, EEAA, PhenoAge acceleration, and GrimAge acceleration) and the four atherosclerosis measures. Finally, we characterized the temporal stability of the epigenetic measures using repeated DNA methylation measured 5 years after baseline (N = 193).ResultsAfter adjusting for CVD risk factors, four CpGs (cg05575921(AHRR), cg09935388 (GFI1), cg21161138 (AHRR), and cg18168448 (LRRC52)) were associated with multi-site atherosclerosis (FDR < 0.1). cg05575921 was also associated with AAC and cg09935388 with ABI. MRSCACwas associated with ABI (Beta = 0.016,P = 0.006), and MRScarotidwas associated with both AAC (Beta = 0.605, equivalent to approximately 1.8-fold increase in the Agatston score of AAC,P = 0.004) and multi-site atherosclerosis (Beta = 0.691,P = 0.002). A 5-year increase in GrimAge acceleration (~ 1 SD) was associated with a 1.6-fold (P = 0.012) increase in the Agatston score of AAC and 0.7 units (P = 0.0003) increase in multi-site atherosclerosis, all after adjusting for CVD risk factors. All epigenetic measures were relatively stable over 5 years, with the highest intraclass correlation coefficients observed for MRScarotidand GrimAge acceleration (0.87 and 0.89, respectively).ConclusionsWe found evidence of an association between DNA methylation and atherosclerosis at multiple vascular sites in a sample of African-Americans. Further evaluation of these potential biomarkers is warranted to deepen our understanding of the relationship between epigenetics and atherosclerosis.