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Bone Marrow Transplantation Reverses Metabolic Alterations in Multiple Sulfatase Deficiency: A Case Series
Get PDFBACKGROUND: Multiple sulfatase deficiency (MSD) is an exceptionally rare neurodegenerative disorder due to the absence or deficiency of 17 known cellular sulfatases. The activation of all these cellular sulfatases is dependent on the presence of the formylglycine-generating enzyme, which is encoded by the SUMF1 gene. Disease-causing homozygous or compound heterozygous variants in SUMF1 result in MSD. Other than symptomatic treatment, no curative therapy exists as of yet for MSD. Eight out of these 17 sulfatases are primarily localized in the lysosome.
METHODS: Two siblings with attenuated MSD underwent hematopoietic cell transplantation (HCT), evaluating the possibility of lysosomal enzymatic cross-correction from the donor cells.
RESULTS: There is evidence of correction of currently available biomarkers within 3 months post-HCT. Untargeted metabolomics also shows continued correction of multiple biochemical abnormalities in the post-HCT period. Furthermore, this article also presents the neuropsychological outcomes of these children as well as the results of untargeted metabolomics analysis in this condition.
CONCLUSIONS: These data suggest biochemical benefits post-transplant along with slowing of disease progression. Long-term follow-up is necessary to fully evaluate the therapeutic benefit of HCT in MSD
GoldenBraid2.0 E. coli: A Comprehensive and Characterized Toolkit for Enterics
Get PDFModular cloning systems streamline laboratory workflows by consolidating genetic \u27parts\u27 into reusable and modular collections, enabling researchers to fast-track strain construction. The GoldenBraid 2.0 modular cloning system utilizes the cutting property of type IIS restriction enzymes to create defined genetic \u27grammars\u27, which facilitate the reuse of standardized genetic parts and assembly of genetic parts in the right order. Here, we present a GoldenBraid 2.0 toolkit of genetic parts designed to accelerate cloning in the model bacteriu
IGF-1 Impacts Neocortical Interneuron Connectivity in Epileptic Spasm Generation and Resolution
Get PDFLittle is known about the mechanisms that generate epileptic spasms following perinatal brain injury. Recent studies have implicated reduced levels of Insulin-like Growth Factor 1 (IGF-1) in these patients\u27 brains. Other studies have reported low levels of the inhibitory neurotransmitter, GABA. In the TTX brain injury model of epileptic spasms, we undertook experiments to evaluate the impact of IGF-1 deficiencies on neocortical interneurons and their role in spasms. Quantitative immunohistochemical analyses revealed that neocortical interneurons that express glutamic acid decarboxylase, parvalbumin, or synaptotagmin 2 co-express IGF-1. In epileptic rats, expression of these three interneuron markers were reduced in the neocortex. IGF-1 expression was also reduced, but surprisingly this loss was confined to interneurons. Interneuron connectivity was reduced in tandem with IGF-1 deficiencies. Similar changes were observed in surgically resected neocortex from infantile epileptic spasms syndrome (IESS) patients. To evaluate the impact of IGF-1 deficiencies on interneuron development, IGF-1R levels were reduced in the neocortex of neonatal conditional IGF-1R knock out mice by viral injections. Four weeks later, this experimental maneuver resulted in similar reductions in interneuron connectivity. Treatment with the IGF-1 derived tripeptide, (1-3)IGF-1, abolished epileptic spasms in most animals, rescued interneuron connectivity, and restored neocortical levels of IGF-1. Our results implicate interneuron IGF-1 deficiencies, possibly impaired autocrine IGF-1 signaling and a resultant interneuron dysmaturation in epileptic spasm generation. By restoring IGF-1 levels, (1-3)IGF-1 likely suppresses spasms by rescuing interneuron connectivity. Results point to (1-3)IGF-1 and its analogues as potential novel disease-modifying therapies for this neurodevelopmental disorder
Myeloid-Specific CAMKK2 Deficiency Protects Against Diet-Induced Obesity and Insulin Resistance by Rewiring Metabolic Gene Expression and Enhancing Energy Expenditure
No full textObjective: Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca2+-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic energy metabolism, and a coordinator of macrophage-mediated inflammatory responses. However, its role in obesity-associated metabolic dysfunction is not fully defined. The aim of this study was to determine the contribution of CAMKK2 to the regulation of inflammation and systemic metabolism during diet-induced obesity.
Methods: Mice with myeloid-specific deletion of Camkk2 were generated and challenged with a high-fat diet. Metabolic phenotyping, histological analyses, and transcriptomic profiling were used to assess whole-body metabolism, liver lipid accumulation, and gene expression in macrophages and adipose tissue.
Results: Myeloid-specific Camkk2 deficiency protected mice from high fat diet-induced obesity, insulin resistance and liver steatosis. These protective effects were associated with rewiring of metabolic and inflammatory gene expression in both macrophages and adipose tissue, along with enhanced whole-body energy expenditure.
Conclusions: Our data establish CAMKK2 as an important regulator of macrophage function and putative therapeutic target for treating obesity and related metabolic disorders
The Benefits of Exercise Training in Combination With Weight Loss Therapies
No full textThe primary treatment for obesity involves calorie restriction (CR) to promote dietary weight loss achieved through interventions including behavioral modification, bariatric surgery, and antiobesity medications. In adults with obesity, CR-induced weight loss enhances physical function and improves quality of life, while also reducing the burden of various obesity-related chronic conditions, including hypertension, diabetes, obstructive sleep apnea, and atherosclerotic heart disease. However, it is also associated with a decline in lean mass and bone mineral density, which increases the risk of sarcopenia and osteoporosis. When performed alongside CR, progressive resistance training (RT) attenuates this loss of lean mass and bone mass, while the addition of aerobic training (AT) further improves cardiorespiratory fitness. The individual benefits of RT and AT are complementary, and combining both exercise training modalities during CR provides the most optimal benefits for body composition and physical function. The World Health Organization recommends that adults engage in at least 150 min of moderate-intensity or 75 min of vigorous-intensity AT weekly and participate in RT activities involving major muscle groups at least 2 days per week. While this recommendation applies to the general adult population, regular exercise training that incorporates both RT and AT is particularly crucial for adults with obesity undergoing weight loss interventions. This clinical perspective highlights the benefits of exercise training alongside current weight loss strategies, such as lifestyle changes, bariatric surgery, and pharmacotherapy, with a focus on incretin-based therapies
Differences in Hepatocellular Carcinoma Incidence Trends Across US Census Divisions, 2001 to 2021
No full textBackground/Objectives: Hepatocellular carcinoma (HCC) is a leading cause of cancer diagnoses and deaths in the United States. This study serves as an update on secular trends in national HCC incidence rates while exploring potential geographic and racial/ethnic differences across all nine US census divisions.
Methods: We analyzed HCC incidence data reported to the United States Cancer Statistics (USCS) database from 2001 to 2021 (excluding 2020 data, based on the Centers for Disease Control and Prevention\u27s cautionary recommendations for COVID-19 pandemic data usage for trend analysis). We performed trend analyses of age-adjusted incidence rates in the US overall, by census divisions, and then stratified by race/ethnicity, using the National Cancer Institute\u27s Joinpoint Regression Program.
Results: Between 2001 and 2021, HCC incidence rates increased nationally, with an average annual percentage change (AAPC) of 2.51 (95% confidence interval (CI): 2.32-2.72); however, the rate decreased (annual percentage change (APC) -3.33 (95% CI: -4.78--1.96) in recent years from 2018 to 2021. Division 1 had the greatest decrease (APC -6.46 (95% CI: -9.62--3.96) from 2017 to 2021, while rates leveled in Division 6 (East South Central) and Division 7 (West South Central). HCC trends decreased substantially for non-Hispanic Black and Non-Hispanic Asian and Pacific Islander groups in almost all divisions in recent years, but trends were stable, decreased, or increased for other racial/ethnic populations.
Conclusions: Despite declining national HCC incidence rates, these trends were not uniform across racial/ethnic groups or US census divisions. Race-specific interventions are needed to reduce disparities in HCC incidence in all US census divisions
Racial and Ethnic Disparities in Human Papillomavirus Vaccination Among US-Born and Foreign-Born Adults Aged 18 to 26 Years in the United States
No full textBackground/objectives: Human papillomavirus (HPV) is linked to multiple cancers that can be prevented through vaccination. While the optimal age for vaccination is in childhood and adolescence, vaccination recommendations include adults through age 26 who missed childhood/adolescent vaccination. There are limited data about disparities among adults eligible for catch-up HPV vaccination. We conducted a comprehensive examination of HPV vaccination among US young adults, disaggregating the group by race/ethnicity and nativity status to identify subgroups that may require additional interventions.
Methods: We analyzed 2019 and 2022 data of individuals aged 18-26 years from the National Health Interview Survey. Generalized linear models using Poisson regression with log link were used to examine the receipt of 1+ dose of HPV vaccine, race/ethnicity, and nativity (i.e., US- versus foreign-born) status.
Results: The overall receipt of 1+ doses of HPV vaccine was 47.5%. The vaccination rate among the US-born group was 49.7% versus 31.9% among the foreign-born group with an adjusted prevalence ratio (APR) of 0.72; (95% CI, 0.62-0.82). Foreign-born non-Hispanic (NH) Black individuals (APR 0.31; 95% CI, 0.13-0.70) were less likely to be vaccinated against HPV than foreign-born NH White individuals, while US-born NH Asians (APR 1.27; 95% CI, 1.09-1.48) had a higher prevalence of the vaccination than the US-born NH White group. Additionally, foreign-born NH Asian (APR 0.60; 95% CI, 0.46-0.77), NH Black (APR 0.27; 95% CI, 0.12-0.61), and Hispanic (APR 0.76; 95% CI, 0.60-0.97) populations were less likely to be vaccinated than their respective US-born counterparts. Conclusion: Profound HPV vaccination inequalities exist among US young adults with particularly low vaccine coverage among racially and ethnically minoritized immigrant populations
Disentangling Hierarchical Chromatin Loops in Melanoma Metastasis
No full textFunctional states of the genome are dictated by chromosomal interactions through 3D genome folding. While its role in tumorigenesis is becoming clearer, its contribution to metastasis has yet to be explored. In this thesis, I investigate how chromatin architecture influences melanoma progression, given its aggressive metastatic behavior. The transition to metastasis requires cellular plasticity, including changes in cell state such as epithelial-to-mesenchymal transition, suggesting a role for epigenomic remodeling. However, whether chromosome looping directly influences metastatic cell fate decisions is unclear. Mammalian genomes are organized into Topologically Associating Domains (TADs), insulated regions maintained by CTCF and cohesin that regulate enhancer-promoter (E-P) interactions. Disruption of these domains and loops alters gene expression and contributes to cancer progression. Here, I identify significant alterations in chromatin looping between primary and metastatic melanoma, implicating 3D genome remodeling in metastatic potential.
One of the central discoveries of this thesis is the role of super-enhancer looping in mediating inflammatory signaling and immune evasion in disseminated tumor cells. The mechanisms underlying organotropic colonization during metastasis remain poorly understood. I demonstrate that reprogrammed three-dimensional chromatin structure of metastatic melanoma cells contributes to this process. Using a newly developed aggressive melanoma model, I establish that chromatin reorganization facilitates survival and growth of disseminated tumor cells within the lung metastatic niche, in part by promoting immune evasion. These adaptations involve chromatin hyperacetylation, AP-1 transcription factor enrichment, and promiscuous intrachromosomal interactions. Specifically, I identify two de novo long-range super-enhancer loops of clinical relevance that establish regulatory hubs encompassing interferon response and pro-survival genes. Epigenetic editing of a single super-enhancer anchor silences the metastatic-specific hub, resulting in coordinated downregulation of genes within the loop, increased susceptibility to CD8⁺ T cell cytotoxicity, attenuated lung metastasis, and improved host survival. While these findings support a role for these loops in immune modulation, they may also contribute to metastatic fitness through additional mechanisms such as survival and metabolic reprogramming. Collectively, this study reveals that tumor-intrinsic chromatin loop function via a novel action-at-a-distance super-enhancer model contributes to melanoma lung colonization, positioning 3D genome reorganization as a potential therapeutic vulnerability that may extend to other metastatic cancers.
To further define higher order chromatin organization in the context of melanoma progression, I performed an unbiased comparative analysis of loop domains across a cohort of patient-matched primary and metastatic melanomas. This resulted in identification of conserved metastatic TAD disruptions (splits) that epigenetically misregulated the expression of clustered protocadherins (cPCDH) via CTCF rewiring. Epigenetic silencing of these CTCF sites resulted in alterations in adhesion-migration dynamics of melanoma cells.
This thesis is the first to describe the contribution of chromosomal looping in the context of melanoma metastasis. By integrating chromatin conformation capture techniques with functional epigenetic perturbation studies, I show that spatial genome reorganization supports metastatic fitness through features such as immune evasion and transcriptional control. These findings provide a framework for understanding how chromatin architecture influences metastasis and illuminate alternative therapeutic modalities for metastatic melanoma
Congestion and Sinonasal Illness in Outer Space: A Study on the International Space Station
No full textObjectives: This study aims to characterize quantitative data pertaining to sinonasal symptoms and their related medication use aboard the International Space Station (ISS). A secondary focus involves correlating these findings with mission parameters such as extravehicular activity (EVA) participation and mission duration.
Methods: This retrospective cohort study was conducted utilizing data requested from the National Aeronautics and Space Administration (NASA) Lifetime Surveillance of Astronaut Health (LSAH) program.
Results: Of 71 de-identified ISS astronauts beginning with Expedition 1 in the year 2000 through 62 in 2019, there were 754 logged medical events; 60 astronauts reported any type of sinonasal medical event (85%), the most common being general nasal congestion in 53 astronauts (75%). Symptoms were attributed to microgravity-induced fluid shifts in 34 astronauts (57%) while 17 (28%) attributed symptoms to ear clearing and barotrauma. Pseudoephedrine was the most used medication, with 95 recorded uses, followed by oxymetazoline spray at 51. Among the 60 astronauts with sinonasal medical events, the 24 with references to extravehicular activity (EVA) participation in their records had on average, 9.19 more records than those without (95% CI: 2.29-17.06).
Conclusion: Sinonasal symptoms are a prevalent medical concern among astronauts aboard the ISS. The findings suggest that early spaceflight-associated fluid shifts contribute significantly to these symptoms, often requiring medication use. A correlation between EVA participation and a higher number of medical events highlights an occupational risk factor.
Level of evidence: 3
Clerkship Students\u27 Use of Clinical Reasoning Concepts After a Pre-clinical Reasoning Course
No full textBackground: Many medical schools have incorporated clinical reasoning (CR) courses into their pre-clinical curricula to address the quality and safety issue of diagnostic error. It is unknown how students use concepts and practices from pre-clinical CR courses once in clerkships.
Objective: We sought to understand how students utilize CR concepts from a pre-clinical course during clerkships and to identify facilitators and barriers to the use of reasoning concepts.
Design: We used structured interviews to gain insight into medical students\u27 experiences with CR concepts in clerkships.
Participants: We interviewed 16 students who had completed a pre-clinical CR course and subsequently completed a neurology, internal medicine, or pediatrics clerkship.
Approach: We used constructivist grounded theory to perform a qualitative analysis and to develop a theoretical model to describe findings.
Key results: Insights fell into three main areas: (1) CR concept carryover, representing concepts taught in the CR course, such as problem representation, illness scripts, schema, and prioritized differential diagnosis, which were utilized in clerkships; (2) CR concept reinforcers, which included the clerkship setting and supervising physicians who emphasized and provided feedback on CR; and (3) CR concept diminishers, which included time constraints and supervisors who were unfamiliar with or did not reinforce CR concepts.
Conclusions: Concepts taught in a pre-clinical CR course influenced how students prepared for and navigated clinical encounters. Contextual factors both enhanced and inhibited the utilization of CR concepts. Our findings align with social learning theories including social cognitive theory and ecological psychology. This contextual view-taking into account interactions between personal, social, and environmental factors-can help educators integrate CR education from the classroom to the clinical setting