bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human umbilical cord mesenchymal stem cell‐derived exosomes ameliorate renal fibrosis in diabetic nephropathy by targeting Hedgehog/SMO signaling
Authors: Zhang Ke , Zheng Shuo , Wu Jiasheng , He Jing , Ouyang Yu , Ao Chunchun , Lang Ruibo , Jiang Yijia , Yang Yifan , Xiao Huan , Li Yu , Li Mao , Wang Huiming , Li Changyong , Wu Dongcheng 
Published: April 2024

AbstractDiabetic nephropathy (DN) is the leading cause of end‐stage renal disease globally. Currently, there are no effective drugs for the treatment of DN. Although several studies have reported the therapeutic potential of mesenchymal stem cells, the underlying mechanisms remain largely unknown. Here, we report that both human umbilical cord MSCs (UC‐MSCs) and UC‐MSC‐derived exosomes (UC‐MSC‐exo) attenuate kidney damage, and inhibit epithelial‐mesenchymal transition (EMT) and renal fibrosis in streptozotocin‐induced DN rats. Strikingly, the Hedgehog receptor, smoothened (SMO), was significantly upregulated in the kidney tissues of DN patients and rats, and positively correlated with EMT and renal fibrosis. UC‐MSC and UC‐MSC‐exo treatment resulted in decrease of SMO expression. In vitro co‐culture experiments revealed that UC‐MSC‐exo reduced EMT of tubular epithelial cells through inhibiting Hedgehog/SMO pathway. Collectively, UC‐MSCs inhibit EMT and renal fibrosis by delivering exosomes and targeting Hedgehog/SMO signaling, suggesting that UC‐MSCs and their exosomes are novel anti‐fibrotic therapeutics for treating DN.
Xbp1 promotes odontoblastic differentiation through modulating mitochondrial homeostasis
Authors: Huang Delan , Li Yuanyuan , Han Jiahao , Zuo Huanyan , Liu Huan , Chen Zhi 
Published: April 2024

AbstractOdontoblast differentiation depends on the orderly recruitment of transcriptional factors (TFs) in the transcriptional regulatory network. The depletion of crucial TFs disturbs dynamic alteration of the chromatin landscape and gene expression profile, leading to developmental defects. Our previous studies have revealed that the basic leucine zipper (bZIP) TF family is crucial in odontoblastic differentiation, but the function of bZIP TF family member XBP1 is still unknown. Here, we showed the stage‐specific expression patterns of the spliced form Xbp1s during tooth development. Elevated Xbp1 expression and nuclear translocation of XBP1S in mesenchymal stem cells (MSCs) were induced by differentiation medium in vitro. Diminution of Xbp1 expression impaired the odontogenic differentiation potential of MSCs. The further integration of ATAC‐seq and RNA‐seq identified Hspa9 as a direct downstream target, an essential mitochondrial chaperonin gene that modulated mitochondrial homeostasis. The amelioration of mitochondrial dysfunction rescued the impaired odontogenic differentiation potential of MSCs caused by the diminution of Xbp1. Furthermore, the overexpression of Hspa9 rescued Xbp1‐deficient defects in odontoblastic differentiation. Our study illustrates the crucial role of Xbp1 in odontoblastic differentiation via modulating mitochondrial homeostasis and brings evidence to the therapy of mitochondrial diseases caused by genetic defects.
Organ preservation in muscle-invasive urothelial bladder cancer
Authors: Niglio Scot A. , Purswani Juhi M. , Schiff Peter B. , Lischalk Jonathan W. , Huang William C. , Murray Katie S. , Apolo Andrea B. 
Published: April 2024

Purpose of review
The most common definitive treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. However, removing the bladder and surrounding organs poses risks of morbidity that can reduce quality of life, and raises the risk of death. Treatment strategies that preserve the organs can manage the local tumor and mitigate the risk of distant metastasis. Recent data have demonstrated promising outcomes in several bladder-preservation strategies.

Recent findings
Bladder preservation with trimodality therapy (TMT), combining maximal transurethral resection of the bladder tumor, chemotherapy, and radiotherapy (RT), was often reserved for nonsurgical candidates for radical cystectomy. Recent meta-analyses show that outcomes of TMT and radical cystectomy are similar. More recent bladder-preservation approaches include combining targeted RT (MRI) and immune checkpoint inhibitors (ICIs), ICIs and chemotherapy, and selecting patients based on genomic biomarkers and clinical response to systemic therapies. These are all promising strategies that may circumvent the need for radical cystectomy.

Summary
MIBC is an aggressive disease with a high rate of systemic progression. Current management includes neoadjuvant cisplatin-based chemotherapy and radical cystectomy with lymph node dissection. Novel alternative strategies, including TMT approaches, combinations with RT, chemotherapy, and/or ICIs, and genomic biomarkers, are in development to further advance bladder-preservation options for patients with MIBC.
Validation of Long-term Recall of Pregnancy-related Weight in the Life-course Experiences And Pregnancy Study
Authors: Farkas Kriszta , Bodnar Lisa M. , Emery Tavernier Rebecca L. , Friedman Jessica K. , Johnson Sydney T. , MacLehose Richard F. , Mason Susan M. 
Published: April 2024

Background:
Prepregnancy body mass index (BMI) and gestational weight gain (GWG) are determinants of maternal and child health. However, many studies of these factors rely on error-prone self-reported measures.

Methods:
Using data from Life-course Experiences And Pregnancy (LEAP), a US-based cohort, we assessed the validity of prepregnancy BMI and GWG recalled on average 8 years postpartum against medical record data treated as alloyed gold standard (“true”) values. We calculated probabilities of being classified into a self-reported prepregnancy BMI or GWG category conditional on one’s true category (analogous to sensitivities and specificities) and probabilities of truly being in each prepregnancy BMI or GWG category conditional on one’s self-reported category (analogous to positive and negative predictive values).

Results:
There was a tendency toward under-reporting prepregnancy BMI. Self-report misclassified 32% (95% confidence interval [CI] = 19%, 48%) of those in LEAP with truly overweight and 13% (5%, 27%) with obesity into a lower BMI category. Self-report correctly predicted the truth for 72% (55%, 84%) with self-reported overweight to 100% (90%, 100%) with self-reported obesity. For GWG, both under- and over-reporting were common; self-report misclassified 32% (15%, 55%) with truly low GWG as having moderate GWG and 50% (28%, 72%) with truly high GWG as moderate or low GWG. Self-report correctly predicted the truth for 45% (25%, 67%) with self-reported high GWG to 85% (76%, 91%) with self-reported moderate GWG. Misclassification of BMI and GWG varied across maternal characteristics.

Conclusion:
Findings can be used in quantitative bias analyses to estimate bias-adjusted associations with prepregnancy BMI and GWG.
A Revised System of Radiological Protection Is Needed
Authors: Scott Bobby R. 
Published: April 2024

AbstractThe system of radiological protection has been based on linear no-threshold theory and related dose-response models for health detriment (in part related to cancer induction) by ionizing radiation exposure for almost 70 y. The indicated system unintentionally promotes radiation phobia, which has harmed many in relationship to the Fukushima nuclear accident evacuations and led to some abortions following the Chernobyl nuclear accident. Linear no-threshold model users (mainly epidemiologists) imply that they can reliably assess the cancer excess relative risk (likely none) associated with tens or hundreds of nanogray (nGy) radiation doses to an organ (e.g., bone marrow); for 1,000 nGy, the excess relative risk is 1,000 times larger than that for 1 nGy. They are currently permitted this unscientific view (ignoring evolution-related natural defenses) because of the misinforming procedures used in data analyses of which many radiation experts are not aware. One such procedure is the intentional and unscientific vanishing of the excess relative risk uncertainty as radiation dose decreases toward assigned dose zero (for natural background radiation exposure). The main focus of this forum article is on correcting the serious error of discarding risk uncertainty and the impact of the correction. The result is that the last defense of the current system of radiological protection relying on linear no-threshold theory (i.e., epidemiologic studies implied findings of harm from very low doses) goes away. A revised system is therefore needed.
The Accumulative Effect of Intravenous Prostaglandin E1 over Nineteen Years to Treat the Ocular Ischemia in High Myopia Keywords: Ocular ischemia, high myopia, prostaglandin E1 (PGE1), extreme choroidal thinning Prostaglandin E1 in High Myopia
Authors: Steigerwalt Robert Davis 
Published: April 2024

Purpose:
The purpose of this paper is to present the clinical history of the use of intrarvenous (IV) prostaglandin E1(PGE1), a potent vasodilator of the peripheral vascular system, to treat the ischemia in high myopia. This was originally reported in 2009.

Methods:
Three patients with high myopia and progressive visual loss were seen. They all had documented ocular ischemia and were placed under treatment with IV PGE1 for the ischemia.

Results:
All 3 had central and peripheral visual improvement which initially lasted from 10-14 days after each treatment. PGE1 was well tollerated by all 3. One abbandoned treatment after 4 months because she did not want to be part of an experiment. A second patient had irregular treatments which became ineffective after 15 years. The third has had regular treatments for the last 19 and 1/2 years maintaining a good visual acuity allowing an independent life. He has been able to extend the intervals between treatments to 3- 4 months. He had occasional hypotensive episodes when the medicine was increased especially during the summer.

Conclusion:
High myopia can be associated with severe central and/or peripheral visual loss. This can be due to ischemia and can lead to NLP in severe cases if not treated. The author presents the use of IV PGE1 as a possible treatment which could be tried in these cases.
Effects of Aerobic Exercise Combined With Attentional Bias Modification in the Care of Male Patients With a Methamphetamine Use Disorder
Authors: Liu Xiao-xia , Huang Peng-hui , Wang Yong-jie , Gao Ying 
Published: April 2024

Abstract

Objective
It remains unclear which individual or combined strategies are most beneficial for methamphetamine use disorders (MUDs). We compared the effects of aerobic exercise, attentional bias modification, and combined intervention on male patients with MUD.

Method
One hundred male patients with MUD were randomly assigned to combined intervention, aerobic exercise, attentional bias modification, or control groups (25 patients per group). The 8-week intervention protocol included three 60-minute sessions of aerobic exercises per week. Primary outcomes included high- and low-frequency heart rate variability, executive function, and cardiorespiratory fitness measured by customized software, computerized tests, and the Harvard step test, respectively. Secondary outcomes included psychiatric symptoms, drug craving, training acceptability, and persistence.

Results
Participant characteristics were matched between groups at baseline. Executive function, heart rate variability, cardiorespiratory fitness, drug craving, and most psychiatric symptoms had significant time–group interactions at posttest (p < .05, η2 = .08–.28). Compared with the attentional bias modification and control groups, the combined intervention and aerobic exercise groups improved significantly in executive function, heart rate variability, cardiorespiratory fitness, and most secondary outcomes. In addition, high-frequency heart rate variability and cardiorespiratory fitness in the aerobic exercise group were significantly higher than those in the combined intervention group.

Conclusions
Combination strategies showed comparable efficacy to aerobic exercise alone in improving executive function, psychiatric symptoms, and drug craving and significantly exceeded other conditions. For heart rate variability and cardiorespiratory fitness, aerobic exercise alone was the most effective. For acceptability and persistence, combination strategies were preferred over single-domain training and health education intervention.
Cirrhosis and Portal Hypertension Worsen Bowel Preparation for Screening Colonoscopy
Authors: Gow-Lee Benjamin , Gaumnitz John , Alsadhan Muatassem , Garg Gauri , Amoafo Linda , Zhang Yue , Fang John , Rodriguez Eduardo 
Published: April 2024

Background:
Colonoscopy is a diagnostic and therapeutic procedure that reduces colorectal cancer incidence and mortality but requires adequate bowel cleansing for high-quality examination. Past studies have suggested cirrhosis as a risk factor for worse bowel preparation.

Methods:
We carried out a match-controlled retrospective study evaluating patients with and without cirrhosis who underwent outpatient screening colonoscopies to assess the effect of cirrhosis and portal hypertension complications on preparation quality and endoscopic measures. We also did a subgroup analysis excluding patients with obesity.

Results:
We examined 1464 patients with cirrhosis and matched controls. Cirrhotic patients had lower mean Boston Bowel Preparation Scale (BBPS) scores and slower cecal intubation times. We found a single point increase in the Model for End-stage Liver Disease (MELD) score, as well as ascites, hepatic encephalopathy, and variceal hemorrhage were all associated with a longer cecal intubation time. Subgroup analysis excluding patients with obesity again found a significantly lower BBPS score and longer cecal intubation time while also finding a 24% drop in polyp detection.

Conclusions:
Patients with cirrhosis have worse BBPS scores and longer cecal intubation times. Nonobese cirrhotic patients additionally have a lower polyp detection rate. Portal hypertension complications were associated with worsened preparation quality and longer cecal intubation times. Each incremental increase in MELD score lengthened cecal intubation time. These findings support a more aggressive bowel preparation strategy for patients with cirrhosis, especially patients with severe disease or portal hypertension complications.
Transcription factor regulation of ribosomal RNA in hematopoiesis
Authors: Paralkar Vikram R. 
Published: April 2024

Purpose of review
Ribosomal RNAs (rRNAs) are transcribed within nucleoli from rDNA repeats by RNA Polymerase I (Pol I). There is variation in rRNA transcription rates across the hematopoietic tree, and leukemic blast cells have prominent nucleoli, indicating abundant ribosome biogenesis. The mechanisms underlying these variations are poorly understood. The purpose of this review is to summarize findings of rDNA binding and Pol I regulation by hematopoietic transcription factors.

Recent findings
Our group recently used custom genome assemblies optimized for human and mouse rDNA mapping to map nearly 2200 ChIP-Seq datasets for nearly 250 factors to rDNA, allowing us to identify conserved occupancy patterns for multiple transcription factors. We confirmed known rDNA occupancy of MYC and RUNX factors, and identified new binding sites for CEBP factors, IRF factors, and SPI1 at canonical motif sequences. We also showed that CEBPA degradation rapidly leads to reduced Pol I occupancy and nascent rRNA in mouse myeloid cells.

Summary
We propose that a number of hematopoietic transcription factors bind rDNA and potentially regulate rRNA transcription. Our model has implications for normal and malignant hematopoiesis. This review summarizes the literature, and outlines experimental considerations to bear in mind while dissecting transcription factor roles on rDNA.
Early Interventional Treatment of High Output Chyle Leak following Esophagectomy is Associated with Improved Survival
Authors: Deboever Nathaniel , Correa Arlene M. , Feldman Hope , Eisenberg Michael , Antonoff Mara B. , Mehran Reza J. , Rajaram Ravi , Rice David C. , Roth Jack A. , Sepesi Boris , Swisher Stephen G. , Vaporciyan Ara A. , Walsh Garrett L. , Hofstetter Wayne L. 
Published: April 2024

Objectives:
Our objective was to investigate overall survival (OS) and length of stay (LOS) associated with differing management for high output (>1 liter over 24 h) leaks (HOCL) following cancer related esophagectomy.

Summary Background:
Although infrequent, chyle leak following esophagectomy is an event that can lead to significant perioperative sequelae. Low volume leaks appear to respond to non-operative measures, while HOCL often require invasive therapeutic interventions.

Methods:
From a prospective single-institution database, we retrospectively reviewed patients treated from 2001-2021 who underwent esophagectomy for esophageal cancer. Within that cohort, we focused on a subgroup of patients who manifested a HOCL postoperatively. Clinicopathologic and operative characteristics were collected, including hospital length of stay and survival data.

Results:
A total of 53/2299 patients manifested a HOCL. These were mostly males (77%), with a mean age of 62 years. Of this group, 15 patients received non-operative management, 15 patients received prompt (<72 h from diagnosis) interventional management, and 23 received late interventional management. Patients in the late intervention group had longer length of stay compared to early intervention (Slope=9.849, 95% Confidence Interval [CI] 3.431 to 16.267). Late intervention (Hazard Ratio (HR) 4.772, CI: 1.384 to 16.460) and non-operative management (HR 4.731, CI: 1.294 to 17.305) were associated with increased mortality compared to early intervention. Patients with early intervention for HOCL had an overall survival similar to patients without chyle leaks in survival analysis.

Conclusions:
Patients with HOCL should receive early intervention in order to possibly reverse the prognostic implications of this potentially detrimental complication.
Discovery of RdRp Thumb-1 as a novel broad-spectrum antiviral family of targets and MDL-001 as a potent broad-spectrum inhibitor thereof
Authors: Woods Virgil , Umansky Tyler , Russell Sean M. , Garvey David S. , Smith Davey , Haders Daniel 
Published: April 2024

ABSTRACTMultiple positive sense, single-stranded RNA (+ssRNA) viruses cause human diseases, ranging from mild colds to deadly pandemics. These viruses share a highly conserved RNA-dependent RNA polymerase (RdRp), but developing a non-nucleoside RdRp inhibitor with broad antiviral activity has been elusive. To this end, we first compared RdRp structures across +ssRNA viral families, including homology models created for critical viruses lacking solved crystal structures, and used multiple sequence alignments to observe key loop and pocket residues. Second, we used ChemPrint, a Molecular-Geometric Deep Learning (Mol-GDL) machine learning model, to predict drug inhibition of the Thumb-1 site in RdRp in a panel of +ssRNA viruses of concern. We identified pipendoxifene (MDL-001) as a promising broad-spectrum antiviral that in previous clinical studies has demonstrated safety and tolerability and sufficient evidence to support its oral administration and once a day dosing. These experiments also demonstrated how the Thumb-1 site has been hidden from conventional virtual screening techniques, like docking, and we demonstrated why beclabuvir, the only approved (Japan) Thumb-1 inhibitor, does not work as a broad-spectrum antiviral.
Exome sequencing identifiesHELBas a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer
Authors: Dicks Ed M. , Tyrer Jonthan P. , Ezquina Suzana , Jones Michelle , Baierl John , Peng Pei-Chen , Diaz Michael , Goode Ellen , Winham Stacey J , Dörk Thilo , Van Gorp Toon , De Fazio Ana , Bowtell David , Odunsi Kunle , Moysich Kirsten , Pavanello Marina , Campbell Ian , Brenton James D. , Ramus Susan J. , Gayther Simon A. , Pharoah Paul D. P. 
Published: April 2024

SummaryRare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls. Harmonised variant calling and quality control filtering was applied across the different data sets. We carried out a gene-by-gene simple burden test for association of rare loss-of-function variants (minor allele frequency < 0.1%) with all non-mucinous ovarian cancer, high grade serous ovarian cancer and non-high grade serous ovarian cancer using logistic regression adjusted for the top four principal components to account for cryptic population structure and genetic ancestry. Seven of the top 10 associated genes were associations of the known ovarian cancer susceptibility genesBRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6andPALB2(false discovery probability < 0.1). A further four genes (HELB, OR2T35, NBNandMYO1A) had a false discovery rate of less than 0.1. Of these,HELBwas most strongly associated with the non-high grade serous histotype (P = 1.3x10−6, FDR = 9.1x10−4). Further support for this association comes from the observation that loss of function variants in this gene are also associated with age at natural menopause and Mendelian randomisation analysis shows an association between genetically predicted age at natural menopause and endometrioid ovarian cancer, but not high-grade serous ovarian cancer.