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Pediatric brain cancer is the leading cause of disease-related mortality in children, and many aggressive tumors still lack effective treatment strategies. Despite extensive studies characterizing these tumor genomes, alternative transcriptional splicing patterns remain underexplored. Here, we systematically characterized aberrant alternative splicing across pediatric brain tumors, identifying pediatric high-grade gliomas (HGGs) among the most heterogeneous. Through integration with UniProt Knowledgebase annotations, we identified 12,145 splice events in 5,424 genes, leading to functional changes in protein activation, folding, and localization. We discovered that the master splicing factor and cell-cycle modulator, CDC-like kinase 1 (CLK1), is aberrantly spliced in HGGs to include exon 4, resulting in a gain of two phosphorylation sites and subsequent activation of CLK1. Inhibition of CLK1 with Cirtuvivint in the pediatric HGG KNS-42 cell line significantly decreased both cell viability and proliferation in a dose-dependent manner. Morpholino-mediated depletion of CLK1 exon 4 splicing reduced RNA expression, protein abundance, and cell viability. Notably, KNS-42 cells treated with the CLK1 exon 4 morpholino demonstrated differential expression impacting 78 genes and differential splicing with loss or gain of a functional site in 193 genes annotated as oncogene or tumor suppressor genes (TSGs). These genes were enriched for cancer-associated pathways, with 15 identified as significant gene dependencies in pediatric HGGs. Our findings highlight a dependency of pediatric HGGs on CLK1 and its roles contributing to tumor splicing heterogeneity through transcriptional dysregulation of splicing factors and transcriptional modulation of oncogenes. Overall, aberrant splicing in HGGs and other pediatric brain tumors represents a potentially targetable oncogenic pathway contributing to tumor growth and maintenance.
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Background: In 2019, the Open Pediatric Brain Tumor Atlas (OpenPBTA) was created as a global, collaborative open-science initiative to genomically characterize 1,074 pediatric brain tumors and 22 patient-derived cell lines. Here, we extend the OpenPBTA to create the Open Pediatric Cancer (OpenPedCan) Project, a harmonized open-source multi-omic dataset from 6,112 pediatric cancer patients with 7,096 tumor events across more than 100 histologies. Combined with RNA-Seq from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA), OpenPedCan contains nearly 48,000 total biospecimens (24,002 tumor and 23,893 normal specimens). Findings: We utilized Gabriella Miller Kids First (GMKF) workflows to harmonize WGS, WXS, RNA-seq, and Targeted Sequencing datasets to include somatic SNVs, InDels, CNVs, SVs, RNA expression, fusions, and splice variants. We integrated summarized CPTAC whole cell proteomics and phospho-proteomics data, miRNA-Seq data, and have developed a methylation array harmonization workflow to include m-values, beta-vales, and copy number calls. OpenPedCan contains reproducible, dockerized workflows in GitHub, CAVATICA, and Amazon Web Services (AWS) to deliver harmonized and processed data from over 60 scalable modules which can be leveraged both locally and on AWS. The processed data are released in a versioned manner and accessible through CAVATICA or AWS S3 download (from GitHub), and queryable through PedcBioPortal and the NCI's pediatric Molecular Targets Platform. Notably, we have expanded PBTA molecular subtyping to include methylation information to align with the WHO 2021 Central Nervous System Tumor classifications, allowing us to create research- grade integrated diagnoses for these tumors. Conclusions: OpenPedCan data and its reproducible analysis module framework are openly available and can be utilized and/or adapted by researchers to accelerate discovery, validation, and clinical translation.
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In most recent studies, long-term retention after orthodontic treatment has been hypothesized that may be necessary to maintain the stability of the dentition and avoid post-treatment changes. The bonded fixed retainer is characterized by its clinical effectiveness, patient acceptance, and lack of patient complaints as compared with a removable retainer. An electronic database (such as PubMed, PubMed Central, Web of Science, Science Direct, Cochrane Library, Scopus, and ResearchGate) has been collected using specific keywords. Of the 152 articles, only randomized clinical trials that investigated different types of fixed retainers or compared fixed with removable retainers were illustrated in tables and included in this review. The present review has gone some way towards enhancing our understanding of the bonded fixed retainer, types, material, bonding methods, and how to improve its the success rate, besides the importance of new technology in fixed orthodontic retention.
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Congenital syphilis, caused by the Gram-negative obligate bacterium Treponema pallidum, can manifest as early- or late-onset infection, typically exhibiting classic symptoms such as a maculopapular rash, failure to thrive, and hepatosplenomegaly. This case report presents rare clinical manifestations of congenital syphilis not typically observed during early onset infection in a newborn in Bahrain. Additionally, it details the physical findings and investigations conducted to diagnose the disease.
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SUMMARY: With the increasing rates of exome and whole genome sequencing, the ability to classify large sets of germline sequencing variants using up-to-date American College of Medical Genetics-Association for Molecular Pathology (ACMG-AMP) criteria is crucial. Here, we present Automated Germline Variant Pathogenicity (AutoGVP), a tool that integrates germline variant pathogenicity annotations from ClinVar and sequence variant classifications from a modified version of InterVar (PVS1 strength adjustments, removal of PP5/BP6). This tool facilitates large-scale, clinically focused classification of germline sequence variants in a research setting. AVAILABILITY AND IMPLEMENTATION: AutoGVP is an open source dockerized workflow implemented in R and freely available on GitHub at https://github.com/diskin-lab-chop/AutoGVP.
Subject(s)
Genetic Variation , Genomics , Humans , Workflow , Virulence , Software , Germ Cells , Genetic TestingABSTRACT
Standard bariatric surgeries include biliopancreatic diversion (BPD), sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and adjustable gastric banding (AGB). Laparoscopic sleeve gastrectomy (LSG) is currently favored due to safety, efficacy, and shorter operation time. However, previous literature shows 75.6% weight regain post LSG. Introducing Laparoscopic band sleeve gastrectomy (LBSG) to maintain pouch size is proposed to improve outcomes and reduce weight regain. This study aims to compare the safety and efficacy of LSG vs. LBSG in obese patients. A comprehensive search strategy was executed to identify pertinent literature comparing LBSG and LSG in obese patients. Eligible studies underwent independent screening, and pertinent data were systematically extracted. The analysis employed pooled risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous variables, each accompanied by their respective 95% confidence intervals (CI). Our systematic review and meta-analysis included 15 studies encompassing 3929 patients. Regarding body mass index (BMI), at six, 12, and 24 months, no substantial differences were found between LBSG and LSG groups (p < 0.05). Still, at 36 months, LBSG exhibited significantly lower BMI than LSG (MD = -2.07 [-3.84, -0.29], p = 0.02). Excess Weight Loss (EWL) favored LBSG at 12, 24, and 36 months with MD of 3.30 [0.42, 6.18], 4.13 [1.44, 6.81], and 18.43 [9.44, 27.42], p = 0.02, 0.003, < 0.00001, respectively). Operative time did not significantly differ between the procedures (MD = 2.95, 95%CI [-0.06, 5.95], p = 0.05). Resolution of comorbidities, overall complications, post-operative bleeding, reflux, and early complications did not significantly differ between LBSG and LSG. However, LBSG showed higher post-operative regurgitation than LSG (RR = 2.38, 95%CI [1.25, 4.54], p = 0.008). LBSG showed a substantial decrease in BMI at three-year follow-up and higher EWL at one, two, and three years. However, LBSG procedures exhibited a higher incidence of post-operative regurgitation symptoms than LSG. No substantial differences were noted in BMI at six, 12, or 24 months, EWL at six months, operative time, bleeding, reflux, or overall complications.
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BACKGROUND: Anterior chest wall defects have a wide range of etiologies in the pediatric population, ranging from infection, tumor, and trauma to congenital diseases. The reconstructive goals include restoring skeletal stability, obliterating dead space, preserving cardiopulmonary mechanics, and protecting vital underlying mediastinal organs. Although various reconstructive methods have been described in the literature, selecting the optimal method is challenging for the growing pediatric skeleton. Here, we report a case of previously thoraco-omphalopagus twins who underwent successful separation and reconstruction and presented for definitive anterior chest wall reconstruction. METHODS: A pair of previously thoraco-omphalopagus conjoined twins underwent definitive anterior chest wall defect reconstruction using cadaveric ribs and omental flap. Twin A received 2 cadaveric ribs, whereas twin B had a much larger sternal defect that required 3 cadaveric ribs combined with an omental flap for soft tissue chest coverage. Both twins were followed up for 8 months. RESULTS: Twin A's postoperative course was uneventful, and she was discharged on postoperative day 6. Twin B's course was complicated, and she was discharged on supported ventilation on postoperative day 10. At 8 months postoperatively, both twins healed well, and chest radiographs confirmed the stability of the chest reconstructions. The rib grafts in the twin with a tracheostomy were not mobile, and the patient had a solid sternum with adequate pulmonary expansion. The construct initially did not facilitate pulmonary functioning, but after a healing process, it eventually allowed for the twin with the tracheostomy who required pulmonary assistance to no longer need this device. CONCLUSIONS: Cryopreserved cadaveric ribs and omental flaps offer safe and reliable reconstructive methods to successfully reconstruct congenital anterior chest wall skeletal defects in the growing pediatric population. The involvement of multidisciplinary team care is key to optimizing the outcomes.
Subject(s)
Musculoskeletal Diseases , Plastic Surgery Procedures , Thoracic Wall , Twins, Conjoined , Female , Humans , Child , Thoracic Wall/surgery , Twins, Conjoined/surgery , Ribs , CadaverABSTRACT
Introduction Diabetic foot ulcer (DFU) is a prevalent complication of diabetes mellitus (DM), affecting approximately 15% of all diabetic patients. This condition poses significant challenges due to its association with major morbidity, mortality, high costs, and diminished quality of life. The incidence of diabetic foot complications among diagnosed diabetes cases is alarming, making it a primary concern in diabetes management. Diabetes mellitus, a chronic metabolic disorder, impacts nearly every system in the body. Methods In this study, a cross-sectional design was employed to assess the level of knowledge, attitude, and practices related to foot care among 432 diabetic patients in Tabuk City, Saudi Arabia. Results The participants' ages ranged from 18 to above 60 years, with (n = 206, 47.69%) being male and (n = 226, 52.31%) female. Type 2 diabetes was prevalent, constituting (n = 277, 64.12%) of cases, whereas (n = 187, 38.29%) had type 1 diabetes. Approximately (n= 224, 51.9%) of patients had been diagnosed with diabetes for less than 10 years. A significant portion (n= 302, 69.91%) of patients did not report any foot complaints. However, (n= 88, 20.37%) had a history of healed ulcers, and (n= 21, 4.9%) had undergone amputation due to diabetes. The majority of patients (n = 228, 52.78%) were under oral agent treatment. Conclusion The study population demonstrated adequate knowledge about diabetes management and exhibited positive attitudes toward diabetes and its related complications, particularly concerning foot care. While most patients displayed appropriate practices related to diabetic foot care, some participants showed inadequate adherence to essential procedures. Addressing these gaps in knowledge and practices is crucial for enhancing the overall management of diabetic foot complications among patients.
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With the increasing rates of exome and whole genome sequencing, the ability to classify large sets of germline sequencing variants using up-to-date American College of Medical Genetics - Association for Molecular Pathology (ACMG-AMP) criteria is crucial. Here, we present Automated Germline Variant Pathogenicity (AutoGVP), a tool that integrates germline variant pathogenicity annotations from ClinVar and sequence variant classifications from a modified version of InterVar (PVS1 strength adjustments, removal of PP5/BP6). This tool facilitates large-scale, clinically-focused classification of germline sequence variants in a research setting.
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Although many published studies have investigated the benefits of tranexamic acid (TXA) in reducing perioperative bleeding, no large meta-analysis has been conducted to demonstrate its overall benefit. Methods: A systematic review was performed by following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. PubMed, Cochrane, Ovid, Embase, Web of Science, ClinicalTraisl.Gov, and Scopus databases were searched for articles reporting the benefit of TXA in reducing perioperative bleeding in craniosynostosis surgery from establishment through October 2022. The results of our meta-analysis were pooled across the studies using a random-effects model, and presented as a weighted mean difference with 95% confidence interval (95% CI). Results: The database search yielded 3207 articles, of which 27 studies with a corresponding number of 9696 operations were eligible. The meta-analysis included only 18 studies, accounting for 1564 operations. Of those operations, 882 patients received systemic TXA, whereas 682 patients received placebo (normal saline), no intervention, low dose TXA, or other control substances. This meta-analysis demonstrated a significant beneficial effect of TXA in reducing perioperative bleeding, particularly when compared with other controlled substances, with a weighted mean difference of -3.97 (95% CI = -5.29 to -2.28). Conclusions: To our knowledge, this is the largest meta-analysis in the literature investigating the benefit of TXA in reducing perioperative blood loss in craniosynostosis surgery. We encourage implementing TXA-protocol systems in hospitals after the appraisal of the data presented in this study.
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BACKGROUND: SARS-CoV-2 (COVID-19) is considered a highly infectious and life threatening disease. OBJECTIVE: The present paper aims to evaluate various aspects of preventive measures and clinical management of the scheduled visits for orthodontic patients to the dental clinics during the outbreak of COVID-19, and to assess how orthodontists dealt with this challenge. METHODS: Orthodontists in private and public clinics were invited to fill a questionnaire that addressed infection control protocols and concerns about clinical management of patients in the clinics during the pandemic. Frequncies and percentages of the responses were obtained and compared using Chi-square tests. RESULTS: About 77% of those working in private clinics, and 63% of those working in private and governmental clinics performed room disinfection following each patient. In case of patients needing urgent management and have active infection, 56% of the participants provided care under high infection control measures; on the contrary, 64% provided symptomatic intervention including orthodontic wax, analgesics and sometimes mouthwash. CONCLUSION: The COVID-19 pandemic has had a negative impact on the orthodontic treatments. All pre-cautionary measures have to be made available in the clinic in order to minimize the spread of viral infection with continuous dental health care training.
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COVID-19 , Humans , COVID-19/epidemiology , SARS-CoV-2 , Pandemics/prevention & control , Infection Control/methods , Surveys and QuestionnairesABSTRACT
Aim The eye is a vital and extraordinarily perceptive part of the human body. A wide spectrum of possible outcomes from eye injuries, from temporary vision loss to permanent blindness. There is a lack of information about how to handle an eye injury. Education and raising awareness are the best way to prevent severe complications and eventual loss of vision. Therefore, the purpose of this study is to evaluate and assess general population knowledge and first aid practices regarding eye injuries in the Western Region of Saudi Arabia, focusing on the importance of early management. Methodology A cross-sectional questionnaire was administered among residents of western Saudi Arabia using a validated questionnaire. One thousand two hundred seventy-nine adults of both genders were randomly chosen to represent the sample. In December 2022, we used a web-based survey to gather our data. Result This study analyzed data from 1279 responses on the online platform. Results showed that good knowledge was significantly higher among females than males, those without a history of eye injury than their peers with injuries, and those with higher educational levels than those with lower educational levels. Additionally, good knowledge was predicted by the female gender (OR = 1.6, 95% CI, 1.3 to 2.1, p < 0.001). Conclusion The study found that public awareness of eye injury first aid was good in the western region. The role of physicians should be expanded and health education campaigns and social media are recommended to achieve the goal of reduction and limiting the most crucial damage to the most sensitive organ in the body.
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Introduction Herpes zoster (HZ) is a viral infection that occurs due to the reactivation of the varicella-zoster virus. The vaccination against herpes zoster to prevent its complications has been approved for individuals 50 years of age and older. This study aims to evaluate the knowledge, attitudes, and habits of at-risk populations about the varicella-zoster virus and its vaccination. Methodology A quantitative, observational, cross-sectional study was conducted among 500 adults over 50 years of age. Participants were selected by non-probability, convenience sampling from public places. RStudio (R version 4.1.1) was used to analyze the data. Result Eighty-three percent (n = 416) of participants had heard of herpes zoster (HZ). Seventy-four percent of respondents (n = 368) did not recognize the link between varicella and herpes zoster. Multiple linear regression showed that individuals who had varicella and heard about herpes zoster were the only positive predictors of herpes zoster knowledge. Out of all the respondents, 55.8% (n = 279) had heard of the herpes zoster vaccine, but 94.6% (n = 473) had not taken it. Among the respondents, 28.1% (n = 118) were unwilling to take optional vaccines; 77.4% (n = 387) agreed to take the HZ vaccine if recommended by a healthcare professional. Conclusion The general Saudi population had a good understanding of HZ and its vaccine. Their attitudes toward the HZ vaccine were generally positive; however, poor practices were observed. We recommend that arranging national campaigns targeting at-risk populations can enhance awareness about herpes zoster and its vaccine, subsequently increasing the rate of HZ immunization.
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Noncanonical exon usage plays many important roles in cellular phenotypes, but its contribution to human B-cell development remains sketchily understood. To fill this gap, we collected various B-cell fractions from bone marrow (BM) and tonsil donors, performed RNA sequencing, and examined transcript variants. We identified 150 genes that harbor local splicing variations in all pairwise comparisons. One of them encodes FBXW7, an E3 ubiquitin ligase implicated as a driver in several blood cancers. Surprisingly, we discovered that in normal human pro-B cells, the predominant transcript used an alternative first exon to produce the poorly characterized FBXW7ß isoform, previously thought to be restricted to neural tissues. The FBXW7ß transcript was also abundant in cell lines and primary samples of pediatric B-cell acute lymphoblastic leukemia (B-ALL), which originates in the BM. When overexpressed in a heterologous cell system, this transcript yielded the expected protein product, as judged by anti-FLAG immunoblotting and mass spectrometry. Furthermore, in REH B-ALL cells, FBXW7ß mRNA was the only FBXW7 isoform enriched in the polyribosome fraction. To shed light on possible functions of FBXW7ß, we used gain- and loss-of-function approaches and identified an FBXW7-dependent inflammatory gene signature, apparent in a subset of B-ALL with high FBXW7ß expression. This signature contained several members of the tumor necrosis factor superfamily, including those comprising the HLA Class III cluster (LTB, LST1, NCR3, LTA, and NFKBIL1). Our findings suggest that FBXW7ß expression drives proinflammatory responses, which could contribute to normal B-cell development, leukemogenesis, and responses to anticancer therapies.
Subject(s)
F-Box-WD Repeat-Containing Protein 7 , Precursor Cells, B-Lymphoid , Child , Humans , Cell Line , F-Box-WD Repeat-Containing Protein 7/genetics , F-Box-WD Repeat-Containing Protein 7/metabolism , Precursor Cells, B-Lymphoid/metabolism , Protein Isoforms/genetics , Protein Isoforms/metabolism , Transcriptional ActivationABSTRACT
Objective: This study aimed to evaluate and compare the force degradation of two types of elastomeric chains following different periods of immersion in zinc-containing mouthwashes. Materials and Methods: Four hundred and forty pieces of Elasto-Force and Super Elasto-Force elastomeric chains were divided into two control and eight experimental groups. The pieces were stretched to 25 mm on pins mounted on an acrylic block and stored in distilled water at 37°C. The experimental groups were immersed in four different types of mouthwash for one minute twice a day throughout the test period. Ten continuous thermocycles per day between cold and hot water baths (5-55°C) were carried out. Forces were measured at six-time intervals (initial, 24 hours, 1, 3, 6, and 8 weeks). The mean force was calculated and compared among different elastomeric chains, mouthwashes, and times using the t-test and one-way ANOVA test followed by Tukey's HSD test. The level of significance was set at 0.05. Results: Both types of elastomeric chains had significant force degradation over time (74-79% at 8 weeks). The Super Elasto-Force generated a higher force level than the Elasto-Force elastomeric chain at all time points. SmartMouth Clinical DDS mouthwash had a significantly lower effect on force degradation than other mouthwashes with no significant difference compared to control groups. Conclusions: Depending on these results: there is no clinically significant difference between both types of elastomeric chains, although Super Elasto-Force delivered a higher force level. The pH of the mouthwashes could play a role in force degradation over time, rather than other ingredients including zinc. The SmartMouth mouthwash had the minimum effect on force degradation of elastomeric chains, followed by Halita, Listerine Total Care Zero, and Breath Rx, respectively.
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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN® nucleases. In this study, we examine the antitumor activity of UCART123 in preclinical models of BPDCN. We report that UCART123 have selective antitumor activity against CD123-positive primary BPDCN samples (while sparing normal hematopoietic progenitor cells) in the in vitro cytotoxicity and T cell degranulation assays; supported by the increased secretion of IFNγ by UCART123 cells when cultured in the presence of BPDCN cells. UCART123 eradicate BPDCN and result in long-term disease-free survival in a subset of primary patient-derived BPDCN xenograft mouse models. One potential challenge of CD123 targeting therapies is the loss of CD123 antigen through diverse genetic mechanisms, an event observed in one of three BPDCN PDX studied. In summary, these results provide a preclinical proof-of-principle that allogeneic UCART123 cells have potent anti-BPDCN activity.