DigitalCommons@The Texas Medical Center
Not a member yet
41791 research outputs found
Sort by
Dissecting the Effects of 223Radium on the Bone Microenvironment
No full textRadium-223 (223Ra) is a bone-seeking, alpha-particle-emitting radionuclide that is approved for the treatment of patients with metastatic prostate cancer and is currently being tested in clinical trials for primary and metastatic cancers to the bone. 223Ra accumulates in mineralized bone areas with high bone turnover, where its effects are confined within 100 μm of the bone–marrow interface due to the short tissue penetrance of the alpha particles. A recent clinical study has shown a significantly increased fracture rate associated with the administration of 223Ra, mostly in tumor-free bones. Importantly, the biological mechanisms underlying this bone fragility remain unclear. In this work, we combined micro-computed tomography and mechanical studies with ex vivo spatial biology analysis based on 3D fluorescence microscopy to clarify the effects of 223Ra on bone and key bone stromal cell components. We found that 223Ra caused major trabecular bone loss with no detectable impact on cortical bone. In addition, 223Ra impaired osteoblast bone-forming activity, which was paralleled by a transient increase in osteoclast number and long-term adipocyte formation. Overall, these results suggest that the impact of 223Ra on bone health is orchestrated by multiple bone stromal cell components. 223Ra-mediated trabecular bone loss was prevented by administration of zoledronic acid, which should always be combined with 223Ra
Genomics and Multiomics in the Age of Precision Medicine
No full textPrecision medicine is a transformative healthcare model that utilizes an understanding of a person\u27s genome, environment, lifestyle, and interplay to deliver customized healthcare. Precision medicine has the potential to improve the health and productivity of the population, enhance patient trust and satisfaction in healthcare, and accrue health cost-benefits both at an individual and population level. Through faster and cost-effective genomics data, next-generation sequencing has provided us the impetus to understand the nuances of complex interactions between genes, diet, and lifestyle that are heterogeneous across the population. The emergence of multiomics technologies, including transcriptomics, proteomics, epigenomics, metabolomics, and microbiomics, has enhanced the knowledge necessary for maximizing the applicability of genomics data for better health outcomes. Integrative multiomics, the combination of multiple \u27omics\u27 data layered over each other, including the interconnections and interactions between them, helps us understand human health and disease better than any of them separately. Integration of these multiomics data is possible today with the phenomenal advancements in bioinformatics, data sciences, and artificial intelligence. Our review presents a broad perspective on the utility and feasibility of a genomics-first approach layered with other omics data, offering a practical model for adopting an integrated multiomics approach in pediatric health care and research. IMPACT: Precision medicine provides a paradigm shift from a conventional, reactive disease control approach to proactive disease prevention and health preservation. Phenomenal advancements in bioinformatics, data sciences, and artificial intelligence have made integrative multiomics feasible and help us understand human health and disease better than any of them separately. The genotype-first approach or reverse phenotyping has the potential to overcome the limitations of the phenotype-first approach by identifying new genotype-phenotype associations, enhancing the subclassification of diseases by widening the phenotypic spectrum of genetic variants, and understanding functional mechanisms of genetic variations
Harnessing Cancer Omics to Inform Precision Oncology
No full textThe development of high-throughput technologies greatly facilities precision oncology in the era of big data. With the growing size of pan-cancer genomic, transcriptomic and proteomic profiling data, there is imperative need for integrative analysis of molecular and clinical information in an efficient way. Here, we conducted omics analysis on three different cancer studies and developed an LLM-based bioinformatics chatbot, DrBioRight, that can perform cancer omics data mining based on natural language. We identified ultraconserved elements (UCE) that can be enhancers of tumor suppressor and silencers of oncogene in colon cancer via whole genome and targeted UCE sequencing from two cohorts. We characterized the tumor microenvironment of melanoma brain metastasis (MBM) during anti-PD1 therapy using single cell RNA sequencing (scRNA-seq) of patients’ cerebrospinal fluid (CSF) samples. We profiled functional proteomics from kidney tumor samples using reverse phase protein array (RPPA) and formulated an MTOR score that improves prognosis prediction of recurrent risk given Leibovich risk scoring. Finally, we selected high quality user queries to finetune the LLM modules of DrBioRight, evaluated its responses and improved its performances. Our results not only provide unique resources to the cancer research community, but also an online bioinformatics chatbot which helps users get access and conduct integrative analysis on cancer omics data efficiently
Variants in WASHC3, a Component of the WASH Complex, Cause Short Stature, Variable Neurodevelopmental Abnormalities, and Distinctive Facial Dysmorphism
No full textPurpose: Genetic defects that impair growth plate chondrogenesis cause a phenotype that varies from skeletal dysplasia to mild short stature with or without other syndromic features. In many individuals with impaired skeletal growth, the genetic causes remain unknown.
Method: Exome sequence was performed in 3 unrelated families with short stature, distinctive facies, and neurodevelopmental abnormalities. The impact of identified variants was studied in vitro.
Results: Exome sequencing identified variants in WASHC3, a component of the WASH complex. In the first family, a de-novo-dominant missense variant (p.L69F) impaired WASHC3 participation in the WASH complex, altered PTH1R endosomal trafficking, diminished PTH1R signaling, and affected growth plate chondrocyte hypertrophic differentiation, providing a likely explanation for the short stature. Knockdown of other WASH complex components also diminished PTH1R signaling. In the second and third families, a homozygous variant in the start codon (p.M1?) markedly reduced WASHC3 protein expression.
Conclusion: In combination with prior studies of WASH complex proteins, our findings provide evidence that the WASH complex is required for normal skeletal growth and that, consequently, genetic abnormalities impairing the function of the WASH complex (WASHopathy) cause short stature, as well as distinctive facies and variable neurodevelopmental abnormalities
Long-Read Sequencing of 945 Han Individuals Identifies Structural Variants Associated With Phenotypic Diversity and Disease Susceptibility
No full textGenomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations
Meeting Report: 1st International Conference on Polyploid Giant Cancer Cells-Biology, Clinical Applications, and the Birth of a New Field in Cancer Research
No full textIsolated Calvarial Lesion as the Initial Presentation of Metastatic Hepatocellular Carcinoma: A Case Report and Review of the Literature
No full textBackground: Hepatocellular carcinoma (HCC) contributes significantly to global cancer-related mortality, often because patients present at advanced stages of the disease. HCC commonly metastasizes to the lung, abdominal lymph nodes, and bone. However, even among bony metastases, calvarial lesions are exceptionally rare, especially in the initial presentation.
Case description: We describe a unique case of a 65-year-old African American woman who presented with a rapidly growing skull lesion as her first clinical sign of metastatic HCC. Imaging revealed an extensive soft-tissue mass involving the left calvaria and partially obstructing the superior sagittal sinus. We suspected that the lesion was a meningioma and offered surgery. Histological examination and further systemic workup later confirmed HCC. She was started on adjuvant therapy but unfortunately deteriorated from complications secondary to disease progression. We also reviewed the literature on cases of isolated calvarial metastases as the initial presentation of HCC. A total of 36 case reports were reviewed which included 38 patients. There were 32 males (84.2%), and the mean age was 58.97 ± 9.09 years old. The most common location of presentation was the parietal or occipital region (13, 34.2%), and 18 patients (47.4%) underwent neurosurgical treatment of the lesion. Among the 26 cases that had a follow-up, 84.6% (n = 22) did not survive treatment, and the mean survival time was 6.15 ± 5.94 months.
Conclusion: Isolated calvarial lesions are rarely the initial presenting sign of metastatic HCC. Often, these lesions may be misdiagnosed as benign tumors, such as meningiomas or hemangiopericytomas, given their appearance on imaging. However, early identification of HCC skull lesions is crucial to initiating treatment, including resection, radiation, and immunotherapy, which may help improve symptoms and extend survival. Our case report adds to the limited literature on this exceedingly rare entity
Traumatic Brain Injury in Pregnancy: A Single Level I Trauma Center Experience
No full textTraumatic brain injury (TBI) is less common in pregnancy than in the general population; however, it poses significant challenges in diagnosis and management. These include the potential teratogenicity of medications, radiation exposure from imaging modalities, physiological changes associated with pregnancy, and obstetric complications that may arise. Although there are general guidelines for trauma in the obstetric patient, they are not specific to TBI, and most recommendations are based on low-level evidence or institutional experiences.
We conducted a retrospective review of the hospital trauma registry over a 10-year period. We included all the patients admitted to our neurosurgical intensive care unit for TBI and confirmed pregnancy. The data was obtained through a chart review.
Among 2,027 TBI admissions, four patients were pregnant. Of these four patients, two underwent external ventricular drain placement; one required a decompressive craniectomy. Two patients delivered viable infants via cesarean section. Two patients were discharged home, and one to a personal care home. One patient was pronounced brain dead.
Our data confirmed the rarity of pregnancy in TBI. Even though this represents an infrequent clinical scenario, the complications and treatment can be challenging for clinicians. Therefore, pooled data from other level I trauma centers should be studied to formulate appropriate therapeutic directions, and the inclusion of this population in medical societies’ guidelines is necessary
N-Acetylaspartate From Fat Cells Regulates Postprandial Body Temperature
No full textN-acetylaspartate (NAA), the brain’s second most abundant metabolite, provides essential substrates for myelination through its hydrolysis1. However, the physiological roles of NAA in other tissues remain unknown. Here, we show that aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs blood NAA levels for postprandial body temperature regulation. Genetic ablation of Aspa in mice resulted in systemically elevated NAA levels, and the ensuing accumulation in WAT stimulated pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA levels positively correlated with the abundance of the pyrimidine intermediate orotidine 5′-monophosphate, and this relationship predicted lower body mass index in humans. Using whole-body and tissue-specific knockout mouse models, we observed that fat cells provided plasma NAA and suppressed postprandial body temperature elevation. Moreover, unopposed NAA from adipocytes greatly enhanced whole-body glucose disposal exclusively in WAT. Exogenous NAA also increased plasma pyrimidines and lowered body temperature. These data place WAT-derived NAA as an endocrine regulator of postprandial body temperature and define broader roles for metabolic homeostasis
Telehealth Is Effective in the Evaluation of Individuals With Undiagnosed Rare Disorders: An Undiagnosed Diseases Network Study
No full textPatients with undiagnosed and/or rare disorders frequently manifest dysmorphic and neurological features. There is a lack of information on the effectiveness of telehealth in the evaluation of these disorders. We thus compared an unassisted virtual physical examination (PE) with an in-person PE in undiagnosed individuals and also assessed participant telehealth satisfaction. Twenty-six individuals enrolled in the Undiagnosed Diseases Network study underwent an in-home synchronous virtual PE, and a subsequent in-person PE, by the same clinician. The participants completed surveys on telehealth usability and provider empathy. On PE, general appearance and craniofacial features showed near perfect agreement (κ = 0.81-1.00) between the telehealth and in-person evaluations. Specific components of the neurological examination demonstrated substantial agreement (speech, gait, coordination; κ \u3e 0.61), whereas others had moderate agreement (muscle tone, strength; κ = 0.41-0.60), and a few had none to slight agreement (skin; κ \u3c 0.20). Some systems could not be examined in the virtual PE. Importantly, features relevant to diagnosis or management were missed on the virtual PE in only 2/26 individuals. The participants were satisfied with the quality of the telehealth interaction, as well as empathy demonstrated by providers in the virtual interface. Telehealth is effective for PEs in undiagnosed diseases and is acceptable to affected individuals