DigitalCommons@The Texas Medical Center
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Proxy Panels Enable Privacy-Aware Outsourcing of Genotype Imputation
Get PDFOne of the major challenges in genomic data sharing is protecting participants\u27 privacy in collaborative studies and in cases when genomic data are outsourced to perform analysis tasks, for example, genotype imputation services and federated collaborations genomic analysis. Although numerous cryptographic methods have been developed, these methods may not yet be practical for population-scale tasks in terms of computational requirements, rely on high-level expertise in security, and require each algorithm to be implemented from scratch. In this study, we focus on outsourcing of genotype imputation, a fundamental task that utilizes population-level reference panels, and develop protocols that rely on using proxy panels to protect genotype panels, whereas the imputation task is being outsourced at servers. The proxy panels are generated through a series of protection mechanisms such as haplotype sampling, allele hashing, and coordinate anonymization to protect the underlying sensitive panel\u27s genetic variant coordinates, genetic maps, and chromosome-wide haplotypes. Although the resulting proxy panels are almost distinct from the sensitive panels, they are valid panels that can be used as input to imputation methods such as Beagle. We demonstrate that proxy-based imputation protects against well-known attacks with a minor decrease in imputation accuracy for variants in a wide range of allele frequencies
Identification and Catalog of Viral Transcriptional Regulators in Human Diseases
Get PDFViral genomes encode viral transcriptional regulators (vTRs) that manipulate host gene expression to facilitate replication and evade immune detection. Nevertheless, their role in non-cancerous diseases remains largely underexplored. Here, we unveiled 268 new candidate vTRs from 14 of the 20 viral families we investigated. We mapped vTRs\u27 genome-wide binding profiles and identified their potential human targets, which were enriched in immune-mediated pathways, neurodegenerative disorders, and cancers. Through vTR DNA-binding preference analysis, 283 virus-specific and human-like motifs were identified. Prioritized Epstein-Barr virus (EBV) vTR target genes were associated with multiple sclerosis (MS), rheumatoid arthritis, and systemic lupus erythematosus. The partitioned heritability study among 19 diseases indicated significant enrichment of these diseases in EBV vTR-binding sites, implicating EBV vTRs\u27 roles in immune-mediated disorders. Finally, drug repurposing analysis pinpointed candidate drugs for MS, asthma, and Alzheimer disease. This study enhances our understanding of vTRs in diverse human diseases and identifies potential therapeutic targets for future investigation
ERK Activation Dynamics in Maturing Oocyte Controls Embryonic Nuclear Divisions in Caenorhabditis elegans
Get PDFERK activity oscillates between sustained activation during oocyte formation and transient inactivation during oocyte maturation, fertilization, and early embryogenesis. Consequences of ectopic ERK activity upon oocyte maturation and in early embryogenesis are unknown. We show, in Caenorhabditis elegans, that ectopic ERK activity upon oocyte maturation (metaphase I oocytes) results in embryos with abnormalities in nuclear divisions leading to embryonic death. We uncover that ERK directly phosphorylates Polo-like kinase I (PLK-1), on Serine 404, to inhibit nuclear envelope breakdown (NEBD) in early embryogenesis. The RAS/ERK/PLK-1 pathway poisons zygotic NEBD and inhibits the merging of parental genomes, underlining the importance of turning off ERK prior to embryogenesis. Given the conserved nature of both ERK signaling to oocyte development and PLK1 to embryonic divisions, this work has implications for women undergoing in vitro fertilization (IVF) where ectopic ERK activation during superovulation through hormonal stimulation may diminish oocyte quality and influence zygotic development
Optimal Timing of Organs-at-Risk-Sparing Adaptive Radiation Therapy for Head-and-Neck Cancer Under Re-Planning Resource Constraints
Get PDFBackground and purpose: Prior work on adaptive organ-at-risk (OAR)-sparing radiation therapy has typically reported outcomes based on fixed-number or fixed-interval re-planning, which represent one-size-fits-all approaches and do not account for the variable progression of individual patients\u27 toxicities. The purpose of this study was to determine the personalized optimal timing of re-planning in adaptive OAR-sparing radiation therapy, considering limited re-planning resources, for patients with head and neck cancer (HNC).
Materials and methods: A novel Markov decision process (MDP) model was developed to determine optimal timing of re-planning based on the patient\u27s expected toxicity, characterized by normal tissue complication probability (NTCP), for four toxicities. The MDP parameters were derived from a dataset comprising 52 HNC patients treated between 2007 and 2013. Kernel density estimation was used to smooth the sample distributions. Optimal re-planning strategies were obtained when the permissible number of re-plans throughout the treatment was limited to 1, 2, and 3, respectively.
Results: The MDP (optimal) solution recommended re-planning when the difference between planned and actual NTCPs (ΔNTCP) was greater than or equal to 1%, 2%, 2%, and 4% at treatment fractions 10, 15, 20, and 25, respectively, exhibiting a temporally increasing pattern. The ΔNTCP thresholds remained constant across the number of re-planning allowances (1, 2, and 3).
Conclusion: In limited-resource settings that impeded high-frequency adaptations, ΔNTCP thresholds obtained from an MDP model could derive optimal timing of re-planning to minimize the likelihood of treatment toxicities
Hsa-miR-214-3p Inhibits Breast Cancer Cell Growth and Improves the Tumor Immune Microenvironment by Downregulating B7H3
Get PDFBACKGROUND: Immune checkpoint inhibitors play an important role in the treatment of solid tumors, but the currently used immune checkpoint inhibitors targeting programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) show limited clinical efficacy in many breast cancers. B7H3 has been widely reported as an immunosuppressive molecule, but its immunological function in breast cancer patients remains unclear.
METHODS: We analyzed the expression of B7H3 in breast cancer samples using data from the Cancer Genome Atlas Program (TCGA) and the Gene Expression Omnibus (GEO) databases. MicroRNAs were selected using the TarBase, miRTarBase, and miRBase databases. The regulatory role of the microRNA hsa-miR-214-3p on B7H3 was investigated through dual-luciferase reporter assays, which identified the specific action sites of interaction. The expression levels of B7H3 and hsa-miR-214-3p in human breast cancer tissues and adjacent normal tissues were quantified using Western blotting and quantitative PCR (qPCR).
RESULTS: In breast cancer tissues, the expression level of B7H3 is inversely correlated with that of hsa-miR-214-3p, as well as with the regulatory effects on breast cancercell behavior. Hsa-miR-214-3p was found to inhibit breast cancer cell growth by downregulating B7H3. Importantly, our research identified, for the first time, two binding sites for hsa-miR-214-3p on the 3\u27 UTR of B7H3, both of which exert similar effects independently. Co-culture experiments revealed that hsa-miR-214-3p obstructs the suppressive function of B7H3 on CD8
CONCLUSIONS: This study confirms the existence of two hsa-miR-214-3p binding sites on the 3\u27 UTR of B7H3, reinforcing the role of hsa-miR-214-3p as a regulatory factor for B7H3. In breast cancer, hsa-miR-214-3p reduces tumor cell proliferation and enhances the tumor immune microenvironment by downregulating B7H3. These findings suggest new potential targets for the clinical treatment of breast cancer
An Automated Treatment Planning Portfolio for Whole Breast Radiotherapy
Get PDFBackground: Automation in radiotherapy presents a promising solution to the increasing cancer burden and workforce shortages. However, existing automated methods for breast radiotherapy lack a comprehensive, end-to-end solution that meets varying standards of care.
Purpose: This study aims to develop a complete portfolio of automated radiotherapy treatment planning for intact breasts, tailored to individual patient factors, clinical approaches, and available resources.
Methods: We developed five automated conventional treatment approaches and utilized an established RapidPlan model for volumetric arc therapy. These approaches include conventional tangents for whole breast treatment, two variants for supraclavicular nodes (SCLV) treatment with/without axillary nodes, and two options for comprehensive regional lymph nodes treatment. The latter consists of wide tangents photon fields with a SCLV field, and a photon tangents field with a matched electron field to treat the internal mammary nodes (IMNs), and a SCLV field. Each approach offers the choice of a single or two isocenter setup (with couch rotation) to accommodate a wide range of patient sizes. All algorithms start by automatically generating contours for breast clinical target volume, regional lymph nodes, and organs at risk using an in-house nnU-net deep learning models. Gantry angles and field shapes are then automatically generated and optimized to ensure target coverage while limiting the dose to nearby organs. The dose is optimized using field weighting for the lymph nodes fields and an automated field-in-field approach for the tangents. These algorithms were integrated into the RayStation treatment planning system and tested for clinical acceptability on 15 internal whole breast patients (150 plans) and 40 external patients from four different institutions in Switzerland, Argentina, Iran, and the USA (360 plans). Evaluation criteria included ensuring adequate coverage of targets and adherence to dose constraints for normal structures. A breast radiation oncologist reviewed the single institution dataset for clinical acceptability (5-point scale) and a physicist evaluated the multi-institutional dataset (use as is or edit).
Results: The dosimetric evaluation across all datasets (510 plans) showed that 100% of the automated plans met the dose coverage requirements for the breast, 99% for the SCLV, 98% for the axillary nodes, and 91% for the IMN. As expected, hot spots were more prevalent when multiple fields were combined. For the heart, ipsilateral lung, and contralateral breast, automated plans met constraints for 95%, 92%, and 95% of the plans, respectively. Physician evaluation of the 15 internal patients indicated that all automated plans were clinically acceptable with minor edits. Notably, the use of automated contours with the RapidPlan model resulted in plans that were immediately ready for use in 73% of cases (95% confidence interval, 95% CI [51- 96]) of patients, with the remaining cases requiring minor stylistic edits. Similarly, the physicist\u27s review of the 40 multi-institution patients showed that the auto-plans were ready for use 79% (95% CI [73,85]) of the time (95% CI [73,85]), with edits needed for the remaining cases.
Conclusion: This study demonstrates the feasibility of a comprehensive automated treatment planning model for whole breast radiotherapy, effectively accommodating diverse treatment paradigms
Altered Thermal Preference by Preoptic Estrogen Receptor Alpha Neurons in Postpartum Females
Get PDFOBJECTIVE: This study aims to investigate how reproductive experience (RE) alters thermal preference and thermoregulation in female mice, with a focus on estrogen receptor alpha (ERα)-expressing neurons in the preoptic area (POA).
METHODS: Thermal preference and body temperature were measured in female mice with and without RE, and virgin female mice with selective deletion of ERα from the POA (ERα
RESULTS: We showed that female mice prefer a cooler environment starting from late pregnancy and persisting long term postpartum. Female mice with RE (\u3e4 weeks post-weaning) displayed lower body temperature and a lower thermal preferred temperature, and lost preference for warm environments (30 °C) but preserved avoidance of cold environments (15 °C). This was associated with a significant decrease in the number of ERα
CONCLUSION: Our results support that the thermosensing ability and estrogenic effects in ER
American Cochlear Implant Alliance Position Statement on Newborn Congenital Cytomegalovirus Screening
Get PDFIt is estimated that 1 in every 200 US newborns has congenital cytomegalovirus (cCMV). Delayed identification of cCMV in newborns precludes timely intervention to mitigate sequelae of the infection such as hearing loss and other neurological complications. Newborn testing for cCMV enables appropriate diagnosis and intervention by multidisciplinary teams to properly manage the immediate sequelae of cCMV, avoid unnecessary additional testing that can result from delayed diagnosis, and monitor for future complications. It is the position of the American Cochlear Implant Alliance, the National CMV Foundation, and the American Academy of Otolaryngology-Head and Neck Surgery that universal newborn cCMV screening is necessary to best accomplish these goals
From Bench to Bedside: Murine Models of Inherited and Sporadic Brain Arteriovenous Malformations
Get PDFBrain arteriovenous malformations are abnormal vascular structures in which an artery shunts high pressure blood directly to a vein without an intervening capillary bed. These lesions become highly remodeled over time and are prone to rupture. Historically, brain arteriovenous malformations have been challenging to treat, using primarily surgical approaches. Over the past few decades, the genetic causes of these malformations have been uncovered. These can be divided into (1) familial forms, such as loss of function mutations in TGF-β (BMP9/10) components in hereditary hemorrhagic telangiectasia, or (2) sporadic forms, resulting from somatic gain of function mutations in genes involved in the RAS-MAPK signaling pathway. Leveraging these genetic discoveries, preclinical mouse models have been developed to uncover the mechanisms underlying abnormal vessel formation, and thus revealing potential therapeutic targets. Impressively, initial preclinical studies suggest that pharmacological treatments disrupting these aberrant pathways may ameliorate the abnormal pathologic vessel remodeling and inflammatory and hemorrhagic nature of these high-flow vascular anomalies. Intriguingly, these studies also suggest uncontrolled angiogenic signaling may be a major driver in bAVM pathogenesis. This comprehensive review describes the genetics underlying both inherited and sporadic bAVM and details the state of the field regarding murine models of bAVM, highlighting emerging therapeutic targets that may transform our approach to treating these devastating lesions
