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WNT4 Deficiency Impacts Heart, Diaphragm, and Palate Development: Insights From Human Genetics, Machine Learning, and Mouse Models
No full textWNT4 is a secreted protein that plays a critical role in the regulation of cell fate and embryogenesis. Biallelic variants in WNT4 have been linked to SERKAL syndrome, an autosomal recessive disorder characterized by 46,XX sex reversal and dysgenesis of the kidneys, adrenals, and lungs. SERKAL syndrome has only been described in a single consanguineous kindred with four affected fetuses. Additional features seen in a subset of affected fetuses included ventricular septal defect (VSD), congenital diaphragmatic hernia (CDH), and orofacial clefting (OFC). To determine if these additional features were likely to be caused by WNT4 deficiency, we used machine learning to compare WNT4 to genes known to cause VSD, CDH, and OFC. When compared to all RefSeq genes, WNT4\u27s rank annotation scores for these congenital anomalies were 94%, 99%, and 98.5%, respectively, indicating a high level of similarity. We subsequently identified a second consanguineous family with SERKAL syndrome in which an affected fetus had CDH and an affected child had OFC. We then demonstrated that a subset of Wnt4 null embryos have perimembranous VSDs, anterior and posterior sac CDH, and soft palate clefts. These findings suggest that WNT4 deficiency can cause VSD, CDH, and palatal anomalies in mice and humans with SERKAL syndrome. These studies also suggest that our machine learning approach can be used as a candidate gene prioritization tool, and that targeted mouse phenotyping can serve as a means of confirming the roles of candidate genes in mammalian development
Improving the Quality of Bone Marrow Specimen Collection Through Powered Bone Marrow Device Simulation and Supervised Procedures
No full textImproving the Quality of Bone Marrow Specimen Collection Through Powered Bone Marrow Device Simulation and Supervised Procedures
Purpose
This quality improvement (QI) project aimed to implement powered bone marrow simulation training and supervised procedures for the Advanced Practice Provider (APP) proceduralists to increase proceduralists\u27 use of powered bone marrow devices and reduce poor bone marrow sampling.
Background
This project was implemented within the Bone Marrow Aspiration Clinic (BMAC) of an academic cancer center in Houston, Texas.
Methodology
Five APP proceduralists completed powered bone marrow device simulation training on the Bone Marrow (BM) Skills Simulator, followed by supervised procedures. Data were collected for six weeks post-intervention.
Results
Results showed that the poor BM sampling mean post-intervention decreased by 4.82% (mean=22.16%, median=22.5%, n=20). The pre-intervention\u27s mean was 26.98% (median=27.93%, n=44). Post-intervention use of powered bone marrow devices had a mean of 6.42% (n=7) with a baseline of 0%.
Implications
Powered bone marrow device simulation training using a BM Skills Simulator and supervised procedures can enhance APP proceduralists\u27 ability to collect better quality samples and improve BMAC patient outcomes by reducing unfavorable consequences related to poor BM sampling. Additional participants, time for intervention, and data collection are needed to mitigate the project\u27s limitations and provide better insight into the effectiveness of this intervention
Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers
No full textThe senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30%-70% of SCs, act by transiently disabling the senescent cell antiapoptotic pathways (SCAPs), which defend those SCs that are proapoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become senolytic-resistant . Administering senolytics to obese mice selectively decreased the abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30%-70% of human senescent preadipocytes or human umbilical vein endothelial cells (HUVECs) that are senolytic-resistant (to Dasatinib or Quercetin, respectively) had increased p1
Gallbladder Decompression and Hydrodissection as Adjuncts for Ablation of Pericholecystic Hepatocellular Carcinomas
No full textMicrowave ablation is an effective treatment for hepatocellular carcinoma, but tumors adjacent to extrahepatic organs carry a higher risk for thermal injury. Thermoprotective techniques such as hydrodissection and gallbladder decompression can reduce this risk and expand the range of lesions amenable to percutaneous treatment. We present a case of a 68-year-old woman with hepatocellular carcinoma in hepatic segment V, with partial treatment response from prior transarterial chemoembolization. Due to the lesion\u27s proximity to the gallbladder and transverse colon, microwave ablation was performed with concurrent ultrasound- and CT-guided gallbladder decompression and hydrodissection. The ablation was technically successful without post-procedural complications. At 12-month follow-up, MRI demonstrated no residual tumor. This case highlights the feasibility of microwave ablation in anatomically challenging locations using thermoprotective strategies, overcoming technical challenges that may otherwise preclude minimally invasive treatment
AI Tools for Research Teams
No full textJoin us for a fast-paced, practical session on using free and low-cost AI tools to save hours on your research workflow, from initial discovery to final synthesis. We\u27ll have an overview of tools like Rayyan, ResearchRabbit, and Elicit
Getting to Know Scholarly Publishing Benefits
No full textUnderstand the basics of scholarly publishing. Learn the differences between traditional publishing and open access journals. We will present the benefits offered by available vendors
Anti-Csf-1R Therapy With Combined Immuno-Chemotherapy Coordinate an Adaptive Immune Response to Eliminate Macrophage Enriched Triple Negative Breast Cancers
No full textWomen diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory low-dose Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic Trp53 null TNBC transplantable syngeneic models that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along with CTX disrupted the M-CSF/CSF-1R axis which upregulated IL-17, IL-5 and type II interferon resulting in elevated B- and T cell infiltration. Addition of an anti-PD-1 maintenance dose helped overcome de novo PD-L1 intra-tumoral heterogeneity (ITH) associated recurrence in lung and liver mTNBC
VACmap: An Accurate Long-Read Aligner for Unraveling Complex Genomic Rearrangements
No full textSequence alignment is essential for genomic research and clinical diagnostics, yet detecting complex rearrangements such as inversions, duplications, and gene conversions remains challenging due to allele complexity and limitations of current methods. We introduce VACmap, a non-linear mapping approach to enhance the detection and representation of all genetic variations. VACmap improves duplication detection from 20% to 90% in the Challenging Medically-Relevant Genes (CMRG) benchmark and improves characterization of complex inversions in repetitive regions and gene conversion events. It improves resolving clinically significant loci, including the LPA gene (with repetitive KIV-2 units linked to coronary heart disease), GBA1 and STRC genes (risk factors for Parkinson\u27s disease and hearing loss, respectively, affected by pseudogene recombination with GBAP1 and STRCP1). Here, we show that VACmap delivers better alignment accuracy and SV detection, providing a robust tool for genomic analysis and clinical insights, with potential to advance understanding of genetic diversity and disease mechanisms
miR-302 Regulates Pancreatic Progenitor Pool and Pancreatic Size
No full textDisruptions in pancreatic development can lead to health issues such as pancreatic agenesis and congenital diabetes mellitus. Understanding pancreatic organogenesis is critical for elucidating disease mechanisms and developing regenerative therapies. The pancreas consists of endocrine and exocrine cells, both of which are derived from multipotent progenitor cells (MPCs). MPC proliferation and differentiation are tightly controlled by multiple mechanisms, including post-transcriptional regulation by miRNAs. However, these regulatory factors are not fully understood. Here, we profiled miRNA expression in MPCs and identified that mir-302 was highly enriched during the earliest stages of pancreatic development. Loss of mir-302 resulted in reduced pancreatic size without altering the proportions of endocrine and exocrine cells at E17.5, suggesting that mir-302 regulates the number of MPCs rather than their differentiation. Transcriptomic analysis at E10.5 revealed that mir-302 modulates genes associated with the Wnt signaling pathway and cell cycle progression. Notably, loss of mir-302 prolonged the S phase in MPCs, resulting in slower cell proliferation and a smaller MPC pool at E10.5. These findings provide the first comprehensive miRNA profile during early pancreatic development and establish mir-302 as a critical regulator of MPC number and pancreas size
Lysine Demethylase 4A Is a Centrosome-Associated Protein Required for Centrosome Integrity and Genomic Stability
No full textCentrosomes play a fundamental role in nucleating and organizing microtubules in the cell and are vital for faithful chromosome segregation and maintenance of genomic stability. Loss of structural or functional integrity of centrosomes causes genomic instability and is a driver of oncogenesis. Here we identify lysine demethylase 4A (KDM4A), an epigenetic \u27eraser\u27 of chromatin methyl marks, as a centrosome-localized protein, visualized at the nanometer-scale resolution. We additionally uncovered that KDM4A demethylase enzymatic activity is required to maintain centrosome homeostasis and integrity; a previously unknown functionality unlinked to altered expression of genes regulating centrosome number. We find that KDM4A interacts with and localizes to the centrosome in all stages of mitosis, where it maintains centrosome numbers and centriole engagement during mitosis. Loss of KDM4A results in supernumerary centrosomes and accrual of chromosome segregation errors including chromatin bridges and micronuclei, markers of genomic instability. In summary, these data highlight a previously unknown role for an epigenetic \u27eraser\u27 regulating centrosome integrity, mitotic fidelity, and genomic stability at the centrosome