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Genetic and Epigenetic Mechanisms of Endocrine Resistance in ER+ Breast Cancer: Response to SERDs and RTK-Mediated Transcriptional Rewiring
No full textBreast cancer is the most common cancer affecting women, of which 70% is estrogen receptor-positive (ER+). ER+ breast cancer is typically treated with endocrine therapy, but in ~40% of cases, resistance to these therapies develops. The largest known mechanism of resistance is alterations in ER (ERmuts) accounting for ~18% of cases. Our lab previously identified the second major mechanism of clinical endocrine resistance - alterations in the MAPK pathway. While studies have shown that novel oral selective ER degraders (SERDs) - a class of endocrine therapy, effectively target ERmuts, their efficacy against other mechanisms has not been reported. This study aims to evaluate whether four of the novel oral SERDs under active clinical development can overcome other common endocrine resistance mechanisms, compare their efficacies, and characterize mechanisms of adaptive resistance to these drugs prospectively. We engineered ER+ breast cancer cell lines to express resistance-conferring alterations and tested their response to SERDs in monotherapy and standard-of-care (SOC) combinations. To study adaptive resistance, we developed resistant cell lines by culturing ER+ cell lines in increasing concentrations of SERDs over the course of months and characterized them with epigenomic and transcriptomic profiling. Additionally, we looked at the transcriptional basis of endocrine resistance conferred by common MAPK alterations via transcriptomic and epigenomic assays. Our results show the limited clinical scope of novel oral SERDs against MAPK-driven resistance, although SERD combination therapies represent a promising avenue deserving further exploration. Additionally, novel SERDs are not interchangeable, and clinical resistance is likely. Adaptive resistance to SERDs appears to involve compensatory MAPK signaling, highlighting the need to investigate this mechanism of resistance. Epigenomic profiling of MAPK alterations indicates a switch to non-canonical ER activity and AP-1 driven transcription. Further investigation into identifying vulnerabilities in MAPK-driven adaptive resistance will aid in designing SERD treatment regimens and navigating a post-SERD therapeutic landscape to improve patient outcomes
COST-EFFECTIVENESS EVALUATION OF CHLORHEXIDINE-COATED VERSUS STANDARD PERIPHERALLY INSERTED CENTRAL CATHETERS (PICCS)
No full textPeripherally inserted central catheters (PICCs) play a crucial role in providing long-term intravenous therapy for patients requiring extended vascular access. With multiple PICC types available, understanding their cost-effectiveness is essential for healthcare decisions that balance clinical benefits with economic considerations. This study assesses the economic and clinical outcomes of chlorhexidine-coated PICCs (AGBA PICCs) versus standard PICCs, aiming to guide best practices in vascular access by addressing the gap in comprehensive cost-effectiveness comparisons. Using a decision-analytic model, costs and quality-adjusted life years (QALYs) between the two types were compared. Primary data from five Chinese university-affiliated medical centers were gathered from 2020 to 2023, with a Delphi panel validating the model inputs. The base case incremental cost-effectiveness ratio (ICER) was assessed against established willingness-to-pay (WTP) thresholds. One-way sensitivity analyses were conducted to address the assumptions and uncertainties.
The analysis revealed that while AGBA PICCs offer lower initial placement costs, they incur higher complication rates compared to standard PICCs, which influences long-term cost-effectiveness. After adjusting for complication rates and QALYs, standard PICCs emerged as more cost-effective over a one-year period, with an incremental cost-effectiveness ratio (ICER) of ¥-40,043.78 (100) per QALY gained. The mean healthcare cost per patient of standard PICCs was RMB 21,987.32 (USD 3,242.82), affecting 0.68 QALYs in 90 days. The mean healthcare cost per patient of AGBA PICCs was RMB 19,696.23 (USD 2,904.92), affecting 0.73 QALYs in 90 days, thus resulting in incremental costs of RMB 2,291.10 (USD 428.44). After the model simulation, standard PICCs gained -0.05 QALYs. The ICER for AGBA PICCs compared with standard PICCs was
ABSTRACT
consistently centered at RMB 4,271.31 (USD 629.96).
Although standard PICCs have higher initial costs, their lower complication rates make them a more valuable option for long-term vascular access, offering better overall cost-efficiency. One-way sensitivity analyses of effectiveness and cost versus WTP confirmed the robustness of the model across various parameter changes, indicating that AGBA PICCs could provide significant healthcare savings over a 1-year period when adopted in routine chemotherapy treatment for patients with hematologic disease
Inside Newsrooms & Beyond: A Qualitative Study of the Experiences of Palestinian Journalists in the United States During the Ongoing Gaza Genocide
No full textThis exploratory study examines the personal and professional experiences of Palestinian journalists and media workers in the United States. Using Muted Group Theory as a foundation, the study employed a qualitative survey and interviews to investigate the experiences of this population to understand their connections and reactions to the ongoing genocide in Gaza, resulting changes to their relationships in their professional environment, and reflections on the current political climate in the United States and how that relates to their reporting experiences.
The results show that Palestinians in the United States are deeply impacted by the ongoing genocide and staggering death toll of journalists in Gaza. Palestinian journalists described maintaining neutral relationships to their employers but hold somewhat unfavorable attitudes towards the larger industry, a politicization of their Palestinian identity, and an increase in activity by watchdog groups to suppress the Palestinian perspectives in reporting. Participants shared their verbal and nonverbal communication tactics as they navigate their identity and professional expectations within newsrooms. Overall, participants said they feel media coverage has shifted slightly to sympathize more with the Palestinian cause since October 2023.
The tactics described by Muted Group Theory that appeared in the experiences of participants include self-censorship, avoidance, increased visibility, utilization of liaisons, and confrontational tactics. The findings of this study demonstrate the impact of the political environment and U.S. foreign policy on newsrooms, the impact of the genocide on Palestinian identity in the U.S., and heightened feelings of responsibility amongst Palestinian journalists in the U.S. The findings underscore the dangers of attacks on Palestinian voices in journalism and media, and the heightened importance of amplifying Palestinian stories and sources in media coverage. This study was limited by the timing and political environment, as security was a consistent concern for participants. Future research is required to analyze a deeper understanding of the Palestinian experience during the Gaza genocide globally, investigate the role of news organizations in the U.S. in manufacturing consent for the genocide, and the experiences of Palestinians belonging to various critical industries
UNRAVELING THE ROLE OF HMGA1 CHROMATIN REGULATORS IN TUMOR DEVELOPMENT AND IMMUNOSUPPRESSION: INSIGHTS FROM PANCREATIC DUCTAL ADENOCARCINOMA
Get PDFPancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause
of cancer-related mortality in the United States by 2030. Despite recent advances in targeted
therapies and immunotherapy, PDAC remains a highly lethal disease, largely due to its latestage
diagnosis, immunosuppressive tumor microenvironment, and the emergence of drug
resistance. Thus, there is a dire need to identify novel therapeutic targets for this highly
refractory tumor. Prior studies from our group reveal that the High Mobility Group A1 (HMGA1)
chromatin regulator plays a key role in pancreatic tumor progression; however, the
downstream pathways are only beginning to emerge. In this study, we uncover a novel
downstream effector of HMGA1, Nima-related kinase 2 (NEK2). While NEK2 is known to
promote chromosomal instability, cellular proliferation, immunosuppression, and therapy
resistance in other malignancies, its role in PDAC is incompletely understood. We hypothesize
that NEK2 is an important HMGA1 effector in PDAC, and, further, disruption of the HMGA1-
NEK2 axis will sensitize PDAC tumors to therapy. To investigate this, we integrated
sequencing analyses from public databases (patient datasets, immune-cell infiltration
prediction algorithms,) and performed preliminary in vitro studies. Our preliminary findings
suggest that HMGA1 and NEK2 are co-regulated in PDAC and other tumor types. Moreover,
computational analyses suggest that HMGA1 regulates NEK2-driven cell cycle and immune
pathways in PDAC. Finally, preliminary drug studies identify NEK2 as a promising therapeutic
target. Future studies will leverage single-cell RNA sequencing and imaging mass cytometry
to further elucidate molecular mechanisms underlying HMGA1-mediated regulation of the
tumor immune microenvironment
Targeting dysregulation of NAAG and glutamate in cognitive disorders
No full textGlutamatergic dysregulation is linked to cognitive deficits in a range of disorders. A novel approach to normalizing glutamatergic signaling is inhibition of glutamate carboxypeptidase II (GCPII). GCPII cleaves glutamate from N-acetylaspartyl glutamate (NAAG). Upregulation of GCPII in disease exacerbates excitotoxicity by increasing glutamate levels and decreasing the amount of NAAG available to bind at the metabotropic glutamate receptor 3 where it increases pro-cognitive firing and modulates signaling.
Prior GCPII inhibitors, while potent and selective, have poor pharmacokinetics and brain penetration. In this work, we utilized two high-throughput screening approaches to identify novel scaffolds. We conducted a DNA encoded library screen with saturating concentrations of an active site binder allowing us to identify compounds which likely bind allosteric pockets. A nanoDSF assay confirmed interaction between the compounds and GCPII despite no functional enzymatic inhibition being observed. We also conducted a screen of a known drug library with a new, sensitive LC-MS/MS method. Cefsulodin and amaranth were identified in this effort and shown to be dose dependent, competitive and noncompetitive inhibitors, with IC50 values of 2 ± 0.1 and 0.3 ± 0.01 µM respectively
Clinically, we wanted to understand which patient populations would benefit from treatment with GCPII inhibitors. With the Johns Hopkins Center for the Advancement of HIV Neurotherapeutics, we conducted a retrospective analysis of neuroimaging data in older people with HIV (PWH) and found several positive relationships between higher brain NAAG and better cognition.
We also conducted a prospective study in young adults with ADHD. For the first time, we combined functional MRI with magnetic resonance spectroscopy to examine brain activity and brain chemistry in regions related to memory. The stimulant methylphenidate altered relationships between glutamate and brain activity and increased task-relevant network connectivity. Glutamate levels and brain activity during working memory also correlated with cognition. We found that NAAG acted antagonistically to glutamate in task-activated regions, suggesting the relationship between NAAG and cognition in ADHD is distinct from that in PWH.
This body of work provides novel chemical scaffolds which can be developed as GCPII inhibitors and broadens our understanding of the role of NAAG and glutamate in cognition
Structural Vestibular Neuroimaging in an Aging Population
Get PDFAlthough emerging evidence links impairments in vestibular function with balance and cognitive deficits in aging and neurodegenerative diseases like Alzheimer's, the precise neural mechanisms underlying these relationships remain unclear. Vestibular sensory information about head motion and orientation is transmitted from the inner ear to neural circuits targeting the hippocampus, sensorimotor cortex, and prefrontal cortex—regions involved in spatial cognitive, self-motion perception and motor control, and executive abilities. Structural alterations in these regions may modulate the relationship between age-related declines in vestibular, sensorimotor, and cognitive functioning. Advances in structural neuroimaging analysis now enable sensitive quantification of alterations in brain volume, shape, and microstructural integrity. This work aims to characterize how age-related vestibular function is associated with structural brain alterations in these three, targeted circuits. First, we review structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI) studies involving vestibular conditions to characterize the human vestibular brain network. Next, we investigate gray matter atrophy rates over time in a hippocampal network in older adults with intact versus bilaterally impaired vestibular function based on longitudinal sMRI. We then identify gray matter regions in sensorimotor and prefrontal cortices associated to vestibular function through combined volume and high-spatial-resolution shape analyses based on sMRI. Finally, we examine the associations between vestibular function and white matter microstructural integrity within these targeted circuits based on DTI
SHARP AMPLIFICATION OF CHALLENGING NUCLEIC ACID TEMPLATES
Get PDFPolymerase Chain Reaction (PCR) established the foundation for modern genomic analysis by enabling DNA amplification at an unprecedented scale. However, this essential technique remains constrained by fundamental limitations in amplifying challenging DNA sequences, particularly those with extreme base composition or repetitive elements. To overcome these limitations, we developed SHARP (SSB-Helicase Assisted Rapid PCR), an isothermal amplification method that reimagines nucleic acid amplification through enzymatic mechanisms. This system integrates an engineered PcrA M6 superhelicase of enhanced processivity with single-stranded DNA binding proteins (SSB) and optimized reaction components to achieve efficient strand separation without thermal cycling.
The SHARP demonstrates versatility across challenging template configurations, successfully amplifying sequences with up to 91% AT-content and complex repetitive elements, including 35 consecutive ankyrin repeats and multiple Widom 601 nucleosome positioning sequences. Through mathematical modeling using coupled ordinary differential equations, we examined the system's underlying kinetics and identified key parameters as optimization targets. The system exhibits environmental adaptability, maintaining amplification efficiency across a broad pH range (6.0-9.0) and diverse buffer compositions, suggesting robust performance in varied experimental conditions.
Integration of reverse transcriptase enables direct RNA amplification, with demonstrated sensitivity down to 20 pg input template under simplified thermal control conditions. SHARP's compatibility with diverse buffer conditions provides advantages for RNA amplification in scenarios where thorough sample purification is not feasible. The platform's isothermal operation eliminates traditional thermal cycling constraints, enabling simplified instrumentation requirements particularly valuable for resource-limited settings. These capabilities establish SHARP as a versatile platform for molecular diagnostics, research applications, and potential industrial-scale nucleic acid amplification
Streamlining Account Reconciliation: Improving Efficiency and Accuracy in Health Policy and Management’s Monthly Financial Procedures
Get PDFThe following report explores the challenges and inefficiencies within the current account reconciliation process for sponsored projects in a university department. Prompted by findings from a 2023 audit, the study identifies weaknesses in the existing reconciliation protocol, which was developed as a temporary solution to meet compliance standards. The research aims to assess the effectiveness of this procedure, propose improvements, and implement changes to optimize efficiency and accuracy.
The project leverages comparative analysis of reconciliation practices at other research-driven institutions, including the University of Florida and Johns Hopkins University School of Medicine, to identify best practices. Key themes include compliance with federal guidelines (OMB Uniform Guidance), streamlining reconciliation steps, utilizing SAP tools for financial reporting, and adopting risk-based approaches to prioritize high-risk areas. The study also emphasizes the importance of collaboration and feedback in developing standardized procedures that align with departmental needs.
Through a combination of needs assessment, process evaluation, and implementation of recommended changes, this thesis seeks to enhance the
department’s monthly reconciliation process. The goal is to establish a sustainable protocol that ensures compliance, improves efficiency, reduces errors, and supports the department’s broader financial management objectives
Ratbot - A Surgical Robotic Solution To Enable Brain-wide Recording In Rodents
No full textAccurate and repeatable implantation of high-density neural probes in rodents is essential for obtaining reliable electrophysiological data, yet manual procedures are typically laborious, error-prone, and impacted by operator fatigue. This thesis present an integrated robotic solution named Ratbot that streamlines preoperative implantation planning and intraoperative slot-drilling with real-time force-feedback control. In the planning module, users interact with a Unity-based interface to visualize a 3D reconstruction of multiple probes and skull plate, define target locations, and generate collision-free probe trajectories via a hybrid sample-based and potential-field optimization. The planned craniotomy slots are then executed by a compact six-joint robot arm equipped with a force-torque sensor. During drilling, vertical projections of net force and smoothed gradient estimates guide completion detection, preventing over-penetration and ensuring consistent slot depth. Preliminary real-skull experiments demonstrate that force-feedback control significantly improves drilling precision and repeatability, with reliable detection of bone breakthrough and minimal variation in slot geometry. RatBot's modular hardware fixtures and software architecture support rapid adaptation to new probe designs and skull-plate configurations. By automating critical steps in rodent neural probe implantation and integrating intuitive visualization, RatBot reduces the cognitive and physical burden on surgeons and lays the groundwork for future extensions in robotic craniotomy and probe insertion
CHARACTERIZATION OF METAL EXPOSURE FROM ELECTRONIC CIGARETTE USE (VAPING) VIA URINE BIOMARKERS
No full textSignificance: The use of electronic cigarettes (e-cigarettes) has raised concerns about toxic metal exposure from device components. We compared differences in urinary biomarkers of metal exposure between e-cigarette users and non-users. We also investigated, among e-cigarette users, the associations of metal concentrations in e-cigarette aerosol as well as urinary cotinine with users’ urinary metal concentrations, use behaviors and device characteristics.
Methods: We conducted a three-wave cross-sectional study (2015-2020) recruiting 143 exclusive e-cigarette users and 80 non-users, matched on sex, age and race. E-cigarette aerosol and urine samples were analyzed for 11 metals using inductively coupled plasma mass spectrometry (ICP-MS); urine was also analyzed for cotinine (a nicotine metabolite used as a proxy measure for intensity of use) via ELISA. We used geometric mean regression and generated geometric mean ratio (GMR) to compare concentrations of each metal in urine between users and non-users. Among e-cigarette users, urine cotinine concentrations and e-cigarette aerosol concentrations were classified into tertiles. We estimated associations between urine cotinine and e-cigarette aerosol with urinary metal concentrations using GMR. All models were adjusted for age, sex, race, education, recruitment wave, and previous smoking status. Correlation and network visualization were used for mixture characterization.
Results: After adjustment, chromium (GMR: 2.46, [1.24, 3.14]) and lead (GMR: 1.95, [1.15, 2.83]) were significantly higher in users than non-users. As cotinine concentration increases in the urine, there is a significant increasing linear trend across tertiles in urinary aluminum (p-trend=0.005 ppb had 69% higher urinary arsenic than those with <0.005 ppb (p<0.05). Urinary nickel increased monotonically across aerosol exposure tertiles by 22% (tertile 2) and 72% (tertile 3) (p-trend<0.01).
Conclusion: This matched-control study provides compelling evidence of elevated toxic metal exposure among e-cigarette users. Increased use of e-cigarettes as reflected by urine cotinine, as well as use of devices that produce higher metal aerosol concentrations, was associated with higher urinary metals among e-cigarette users. These findings support the need for Public Health interventions, regulations and safety practices that limit user exposure to metals from e-cigarette use