bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gastrointestinal and genitourinary toxicity profiles of metformin versus placebo in men with prostate cancer receiving prostate radiotherapy: interim toxicity results of a double-blinded, multicenter, phase II randomized controlled trial
Authors: Kim Julian O. , McDonald Megan O. , Ong Aldrich , Koul Rashmi , Dubey Arbind , Hunter William , Ahmed Shahida , Quon Harvey , Yee Don , Parliament Matthew , Sivananthan Gokulan , Danielson Brita , Rowe Lindsay , Ghosh Sunita , Usmani Nawaid 
Published: November 2021

AbstractAndrogen deprivation therapy (ADT) used for prostate cancer (PCa) management is associated with metabolic and anthropometric toxicity. Metformin given concurrent to ADT is hypothesized to counteract these changes. This planned interim analysis reports the gastrointestinal and genitourinary toxicity profiles of PCa patients receiving ADT and prostate/pelvic radiotherapy plus metformin versus placebo as part of a phase 2 randomized controlled trial. Men with intermediate or high-risk PCa were randomized 1:1 to metformin versus placebo. Both groups were given ADT for 18–36 months with minimum 2-month neoadjuvant phase prior to radiotherapy. Acute gastrointestinal and genitourinary toxicities were quantified using CTCAE v4.0. Differences in ≥ grade 2 toxicities by treatment were assessed by chi-squared test. 83 patients were enrolled with 44 patients randomized to placebo and 39 randomized to metformin. There were no significant differences at any time point in ≥ grade 2 gastrointestinal toxicities or overall gastrointestinal toxicity. Overall ≥ grade 2 gastrointestinal toxicity was low prior to radiotherapy (7.9% (placebo) vs. 3.1% (metformin), p = 0.39) and at the end of radiotherapy (2.8% (placebo) vs 3.1% (metformin), p = 0.64). There were no differences in overall ≥ grade 2 genitourinary toxicity between treatment arms (19.0% (placebo) vs. 9.4% (metformin), p = 0.30). Metformin added to radiotherapy and ADT did not increase rates of ≥ grade 2 gastrointestinal or genitourinary toxicity and is generally safe and well-tolerated.
Characteristics and outcomes analysis of ovarian Sertoli–Leydig cell tumors (SLCTs): analysis of 15 patients
Authors: Wang Guangning , Zhang Ran , Li Chuan , Chen Aiping 
Published: November 2021

Abstract
Introduction
Because of limited information of Sertoli–Leydig cell tumors (SLCTs), the objective aimed to describe clinical parameters, management and treatment results of SLCTs.

Material and methods
We retrospectively reviewed 15 cases with SLCTs, who were treated in the Affiliated Hospital of Qingdao University between 2009 and 2020. Data of clinical parameters and treatment was studied.

Results
The age ranged 25–69 years. Elevated testosterone was observed in 4 patients. FIGO-stage: 14 were at Ia(10 moderately differentiated, 3 poorly differentiated, 5 retiform pattern).1 was at Ic. Patients with retiform pattern were more likely to exhibit endocrine function (p = 0.019, w = 0.61) and tumor diameter was significantly bigger in no endocrine function (p = 0.012, d = 1.52). All patients received surgical treatment. 8 received postoperative chemotherapy. The median follow-up was 66 months (20–112 months). 1 patient relapsed within 36 months and received cytoreductive surgery. She survived without disease after recurrence treatment. Of 5 patients who performed fertility sparing surgeries with the desire of childbirth, 3 had full-term pregnancy and 1 experienced a miscarriage. Another one has not tried to conceive.

Conclusion
The prognosis of SLCTs is good. Our data showed patients with retiform pattern were more likely to exhibit endocrine function. The diameter of tumor was significantly bigger in no endocrine function. Conservative surgery is the preferred option for patients with the desire of fertility at stage Ia. Postoperative chemotherapy is advised to cases with high-risk factors, but the most effective chemotherapy regimen is still uncertain.
Secreted indicators of androgen receptor activity in breast cancer pre-clinical models
Authors: Hanamura Toru , Christenson Jessica L. , O’Neill Kathleen I. , Rosas Emmanuel , Spoelstra Nicole S. , Williams Michelle M. , Richer Jennifer K. 
Published: November 2021

Abstract
Purpose
Accumulating evidence has attracted attention to the androgen receptor (AR) as a biomarker and therapeutic target in breast cancer. We hypothesized that AR activity within the tumor has clinical implications and investigated whether androgen responsive serum factors might serve as a minimally invasive indicator of tumor AR activity.

Methods
Based on a comprehensive gene expression analysis of an AR-positive, triple negative breast cancer patient-derived xenograft (PDX) model, 163 dihydrotestosterone (DHT)-responsive genes were defined as an androgen responsive gene set. Among them, we focused on genes that were DHT-responsive that encode secreted proteins, namely KLK3, AZGP1 and PIP, that encode the secreted factors prostate specific antigen (PSA), zinc-alpha-2-glycoprotein (ZAG) and prolactin induced protein (PIP), respectively. Using AR-positive breast cancer cell lines representing all breast cancer subtypes, expression of candidate factors was assessed in response to agonist DHT and antagonist enzalutamide. Gene set enrichment analysis (GSEA) was performed on publically available gene expression datasets from breast cancer patients to analyze the relationship between genes encoding the secreted factors and other androgen responsive gene sets in each breast cancer subtype.

Results
Anti-androgen treatment decreased proliferation in all cell lines tested representing various tumor subtypes. Expression of the secreted factors was regulated by AR activation in the majority of breast cancer cell lines. In GSEA, the candidate genes were positively correlated with an androgen responsive gene set across breast cancer subtypes.

Conclusion
KLK3, AZGP1 and PIP are AR regulated and reflect tumor AR activity. Further investigations are needed to examine the potential efficacy of these factors as serum biomarkers.
The design of a Bayesian adaptive clinical trial of tranexamic acid in severely injured children
Authors: VanBuren John M. , Casper T. Charles , Nishijima Daniel K. , Kuppermann Nathan , Lewis Roger J. , Dean J. Michael , McGlothlin Anna ,   For the TIC-TOC Collaborators of the Pediatric Emergency Care Applied Research Network (PECARN)
Published: November 2021

Abstract
Background
Trauma is the leading cause of death and disability in children in the USA. Tranexamic acid (TXA) reduces the blood transfusion requirements in adults and children during surgery. Several studies have evaluated TXA in adults with hemorrhagic trauma, but no randomized controlled trials have occurred in children with trauma. We propose a Bayesian adaptive clinical trial to investigate TXA in children with brain and/or torso hemorrhagic trauma.

Methods/design
We designed a double-blind, Bayesian adaptive clinical trial that will enroll up to 2000 patients. We extend the traditional Emax dose-response model to incorporate a hierarchical structure so multiple doses of TXA can be evaluated in different injury populations (isolated head injury, isolated torso injury, or both head and torso injury). Up to 3 doses of TXA (15 mg/kg, 30 mg/kg, and 45 mg/kg bolus doses) will be compared to placebo. Equal allocation between placebo, 15 mg/kg, and 30 mg/kg will be used for an initial period within each injury group. Depending on the dose-response curve, the 45 mg/kg arm may open in an injury group if there is a trend towards increasing efficacy based on the observed relationship using the data from the lower doses. Response-adaptive randomization allows each injury group to differ in allocation proportions of TXA so an optimal dose can be identified for each injury group. Frequent interim stopping periods are included to evaluate efficacy and futility. The statistical design is evaluated through extensive simulations to determine the operating characteristics in several plausible scenarios. This trial achieves adequate power in each injury group.

Discussion
This trial design evaluating TXA in pediatric hemorrhagic trauma allows for three separate injury populations to be analyzed and compared within a single study framework. Individual conclusions regarding optimal dosing of TXA can be made within each injury group. Identifying the optimal dose of TXA, if any, for various injury types in childhood may reduce death and disability.
The vaginal microbiota and innate immunity after local excisional treatment for cervical intraepithelial neoplasia
Authors: Mitra Anita , MacIntyre David A. , Paraskevaidi Maria , Moscicki Anna-Barbara , Mahajan Vishakha , Smith Ann , Lee Yun S. , Lyons Deirdre , Paraskevaidis Evangelos , Marchesi Julian R. , Bennett Phillip R. , Kyrgiou Maria 
Published: November 2021

Abstract
Background
Vaginal microbiota (VMB) composition is altered in women with cervical intra-epithelial neoplasia (CIN) compared to healthy controls and is associated with disease progression. However, the impact of CIN excision on the VMB and innate immunity is not known. This observational study aims to explore the impact of CIN excision on the VMB, antimicrobial peptides (AMP) and proinflammatory cytokines.

Methods
We sampled 103 non-pregnant, premenopausal women at the time of excisional treatment for CIN and at their 6-month follow-up visit. A further 39 untreated controls with normal cytology were also sampled. We used metataxonomics to group vaginal swab samples into community state types (CSTs) and ELISA to quantify cytokine and AMP levels in matched vaginal secretions. Analyses were performed to compare the bacterial composition and immune analyte levels before and after CIN excision and in healthy controls.

Results
Women with CIN had significantly higher rates of Lactobacillus species depletion pre-treatment compared to healthy controls (CST IV 21/103, 20% vs 1/39, 3%, p = 0.0081). Excision did not change the VMB composition, with CST IV remaining significantly more prevalent after excision compared to untreated, healthy controls (CST IV 19/103, 20% vs 1/39, 3%, p = 0.0142). Prevotella bivia and Sneathia amnii were significantly higher in samples before treatment compared to untreated controls, and Prevotella bivia remained significantly higher amongst the treated, with less Lactobacillus crispatus compared to untreated controls. IL-1β and IL-8 remained significantly elevated pre- (p < 0.0001 and p = 0.0014, respectively) and post-treatment (p < 0.0001 and p = 0.0035, respectively) compared to untreated controls. Levels of human beta-defensin-1 and secretory leukocyte protease inhibitor were both significantly reduced following CIN excision (p < 0.0001); however, their levels remained lower than controls post-treatment.

Conclusions
Women with CIN have an increased prevalence of Lactobacillus sp. depletion, high-diversity VMB composition, and higher levels of proinflammatory cytokines and AMPs compared to normal controls. Surgical excision of the disease reduces levels of vaginal AMPs but does not alter VMB composition or cytokine levels. These findings suggest that women with CIN have an inherent predisposition to a high-diversity proinflammatory environment that is not corrected by disease excision. The failure to re-establish a Lactobacillus-enriched CST may explain why women remain at high risk of pre-invasive and invasive disease recurrence.
Acute psychosis and serotonin syndrome in the setting of “Triple-C” overdose: a case report
Authors: Bachar Roudi , Majewski John Robert , Shrack Christopher , El-Khoury Anthony 
Published: November 2021

Abstract
Background
Over-the-counter medication overdose is a difficult diagnostic challenge for many physicians as common drug screening assays cannot detect these substances. We present a case of acute psychosis, serotonin syndrome, and anticholinergic overdose-like properties in the setting of Coricidin HBP Cough & Cold tablets, known by their street name Triple-C. This is the first case report we are aware of involving a patient presenting with these symptoms and requiring critical-care-level support.

Case presentation
A 31-year-old African American female with a past medical history of anxiety, childhood asthma, previous methamphetamine abuse, and coronavirus disease 2019 infection in August 2020 was brought to the emergency department by the local police department with altered mental status. Initial blood work, including extended drug screens, were unremarkable for a definitive diagnosis. This patient required critical-care-level support and high sedation because of her symptoms. Collateral history revealed the patient regularly consumed Triple-C daily for the 6 weeks prior to admission. A trial off sedation was attempted after 24 hours with no complications. The patient admitted to regular Triple-C consumption and auditory hallucinations since adolescence. She was discharged safely after 48 hours back into the community. She was lost to follow-up with psychiatry and internal medicine; however, she was evaluated in the emergency room 1 month later with a similar psychiatric presentation.

Conclusion
Overdose of Triple-C should be kept in the differential diagnosis of patients presenting with a triad of psychosis, serotonin syndrome, and anticholinergic overdose, in the setting of unknown substance ingestion.
Single-cell RNA-seq of out-of-thaw mesenchymal stromal cells shows tissue-of-origin differences and inter-donor cell-cycle variations
Authors: Medrano-Trochez Camila , Chatterjee Paramita , Pradhan Pallab , Stevens Hazel Y. , Ogle Molly E. , Botchwey Edward A. , Kurtzberg Joanne , Yeago Carolyn , Gibson Greg , Roy Krishnendu 
Published: November 2021

Abstract
Background
Human Mesenchymal stromal cells (hMSCs) from various tissue sources are widely investigated in clinical trials. These MSCs are often administered to patients immediately after thawing the cryopreserved product (out-of-thaw), yet little is known about the single-cell transcriptomic landscape and tissue-specific differences of out-of-thaw human MSCs.

Methods
13 hMSC samples derived from 10 “healthy” donors were used to assess donor variability and tissue-of-origin differences in single-cell gene expression profiles. hMSCs derived and expanded from the bone marrow (BM) or cord tissue (CT) underwent controlled-rate freezing for 24 h. Cells were then transferred to the vapor phase of liquid nitrogen for cryopreservation. hMSCs cryopreserved for at least one week, were characterized immediately after thawing using a droplet-based single-cell RNA sequencing method. Data analysis was performed with SC3 and SEURAT pipelines followed by gene ontology analysis.

Results
scRNA-seq analysis of the hMSCs revealed two major clusters of donor profiles, which differ in immune-signaling, cell surface properties, abundance of cell-cycle related transcripts, and metabolic pathways of interest. Within-sample transcriptomic heterogeneity is low. We identified numerous differentially expressed genes (DEGs) that are associated with various cellular functions, such as cytokine signaling, cell proliferation, cell adhesion, cholesterol/steroid biosynthesis, and regulation of apoptosis. Gene-set enrichment analyses indicated different functional pathways in BM vs. CT hMSCs. In addition, MSC-batches showed significant variations in cell cycle status, suggesting different proliferative vs. immunomodulatory potential. Several potential transcript-markers for tissue source differences were identified for further investigation in future studies. In functional assays, both BM and CT MSCs suppressed macrophage TNFα secretion upon interferon stimulation. However, differences between donors, tissue-of-origin, and cell cycle are evident in both TNF suppression and cytokine secretion.

Conclusions
This study shows that donor differences in hMSC transcriptome are minor relative to the intrinsic differences in tissue-of-origin. hMSCs with different transcriptomic profiles showed potential differences in functional characteristics. These findings contribute to our understanding of tissue origin-based differences in out-of-thaw therapeutic hMSC products and assist in the identification of cells with immune-regulatory or survival potential from a heterogeneous MSC population. Our results form the basis of future studies in correlating single-cell transcriptomic markers with immunomodulatory functions.
PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy
Authors: Chen Miao , Jing Dian , Ye Rui , Yi Jianru , Zhao Zhihe 
Published: November 2021

Abstract
Background
Diabetic patients are more vulnerable to skeletal complications. Peroxisome proliferators-activated receptor (PPAR) β/δ has a positive regulatory effect on bone turnover under physiologic glucose concentration; however, the regulatory effect in diabetes mellitus has not been investigated yet. Herein, we explored the effects of PPARβ/δ agonist on the regeneration of diabetic bone defects and the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) under a pathological high-glucose condition.

Methods
We detected the effect of PPARβ/δ agonist on osteogenic differentiation of rBMSCs in vitro and investigated the bone healing process in diabetic rats after PPARβ/δ agonist treatment in vivo. RNA sequencing was performed to detect the differentially expressed genes and enriched pathways. Western blot was performed to detect the autophagy-related protein level. Laser confocal microscope (LSCM) and transmission electron microscope (TEM) were used to observe the formation of autophagosomes.

Results
Our results demonstrated that the activation of PPARβ/δ can improve the osteogenic differentiation of rBMSCs in high-glucose condition and promote the bone regeneration of calvarial defects in diabetic rats, while the inhibition of PPARβ/δ alleviated the osteogenic differentiation of rBMSCs. Mechanistically, the activation of PPARβ/δ up-regulates AMPK phosphorylation, yielding mTOR suppression and resulting in enhanced autophagy activity, which further promotes the osteogenic differentiation of rBMSCs in high-glucose condition. The addition of AMPK inhibitor Compound C or autophagy inhibitor 3-MA inhibited the osteogenesis of rBMSCs in high-glucose condition, suggesting that PPARβ/δ agonist promotes osteogenic differentiation of rBMSCs through AMPK/mTOR-regulated autophagy.

Conclusion
In conclusion, our study demonstrates the potential role of PPARβ/δ as a molecular target for the treatment of impaired bone quality and delayed bone healing in diabetic patients for the first time.
Efficacy of posterior capsular release for flexion contracture in posterior-stabilized total knee arthroplasty
Authors: Kinoshita Tomofumi , Hino Kazunori , Kutsuna Tatsuhiko , Watamori Kunihiko , Tsuda Takashi , Miura Hiromasa 
Published: November 2021

Abstract
Purpose
Posterior capsular contracture causes stiffness during knee extension in knee osteoarthritis. Furthermore, in posterior-stabilized total knee arthroplasty (PS-TKA), a unique design such as the cam mechanism could conflict with the posterior capsule (PC) causing flexion contracture (FC). However, few studies have focused on the anatomical aspects of the PC. This study aimed to investigate the anatomical site and forms of posterior capsular attachment to the femoral cortex, and to evaluate the efficacy of posterior capsular release for FC by assessing changes in knee extension angles using a navigation system.

Methods
Attachment sites of the PC were investigated in 10 cadaveric knees using computed tomography. PS-TKA was performed in six cadaveric knees using a navigation system to evaluate the efficacy of posterior capsular release for FC. Posterior capsular release was performed stepwise at each part of the femoral condyle.

Results
The gastrocnemius tendon and PC were integrally attached to the femoral cortex at the medial and lateral condyles, whereas the PC at the intercondylar fossa was independently attached directly to the femoral cortex. Moreover, the PC at the intercondylar fossa was attached most distally among each femoral condyle. Posterior capsular release at the intercondylar fossa allowed 11.4° ± 2.8° improvement in knee extension. This angle was further improved by 5.5° ± 1.3°, after subsequent capsular release at the medial and lateral condyles.

Conclusion
The forms and sites of posterior capsular attachment differed based on the part of the femoral condyle. Stepwise posterior capsular release was effective for FC in PS-TKA.

Level of evidence
III.
Genome-wide identification and characteristic analysis of the downstream melatonin metabolism gene GhM2H in Gossypium hirsutum L.
Authors: Zhang Yuexin , Wang Jing , Chen Xiugui , Lu Xuke , Wang Delong , Wang Junjuan , Wang Shuai , Chen Chao , Guo Lixue , Malik Waqar Afzal , Fan Yapeng , Rui Cun , Cui Ruifeng , Wang Qinqin , Lei Yuqian , Ye Wuwei 
Published: November 2021

Abstract
Background
Melatonin 2-hydroxylase (M2H) is the first enzyme in the catabolism pathway of melatonin, which catalyzes the production of 2-hydroxymelatonin (2-OHM) from melatonin. The content of 2-hydroxymelatonin in plants is much higher than that of melatonin. So M2H may be a key enzyme in the metabolic pathway of melatonin.

Method
We conducted a systematic analysis of the M2H gene family in Gossypium hirsutum based on the whole genome sequence by integrating the structural characteristics, phylogenetic relationships, expression profile, and biological stress of the members of the Gossypium hirsutum M2H gene family.

Result
We identified 265 M2H genes in the whole genome of Gossypium hirsutum, which were divided into 7 clades (clades I-VII) according to phylogenetic analysis. Most M2H members in each group had similar motif composition and gene structure characteristics. More than half of GhM2H members contain ABA-responsive elements and MeJA-responsive elements. Under different stress conditions, the expression levels of the gene changed, indicating that GhM2H members were involved in the regulation of abiotic stress. Some genes in the GhM2H family were involved in regulating melatonin levels in cotton under salt stress, and some genes were regulated by exogenous melatonin.

Conclusion
This study is helpful to explore the function of GhM2H, the downstream metabolism gene of melatonin in cotton, and lay the foundation for better exploring the molecular mechanism of melatonin improving cotton's response to abiotic stress.