Faculty Bibliography

BACKGROUND/UNASSIGNED:Discovery and incorporation of predictive and prognostic biomarkers enhance outcomes for patients with cancer. Clinico-genomic datasets, which retrospectively link real-world clinical data to tumor sequencing data, are important resources for biomarker research, which has historically relied on robust research infrastructures exclusive to large academic centers. The objective was to evaluate the feasibility of a pragmatic, technology-enabled platform at community-based research sites for development of a prospective clinico-genomic database supported by centralized electronic health record (EHR)-based patient ascertainment and data processing. METHODS/UNASSIGNED:Adults with stage IV or recurrent metastatic non-small cell lung cancer or extensive-stage small-cell lung cancer were enrolled at 23 US sites upon initiating a standard line of therapy. Enrollment rates were estimated from eligible populations at individual centers. Clinical data from routinely collected EHR documentation were centrally processed and normalized for quality control. Serial blood samples at pre-specified timepoints (baseline, during treatment and at disease progression/end of therapy) were used for circulating tumor DNA (ctDNA) genomic profiling. RESULTS/UNASSIGNED:Between December 2019 and May 2021, 944 patients enrolled, representing ≈25 % of eligible patients. Eight-hundred seventeen of 944 (87 %), 406 of 606 (67 %) and 398 of 852 (47 %) participants provided qualifying samples for ctDNA testing at baseline, during treatment and at disease progression/end of therapy, respectively. Samples were provided at all three timepoints by 35 % of participants. CONCLUSION/UNASSIGNED:A community-based oncology patient cohort was rapidly enrolled, creating a real-world clinico-genomic dataset. This pragmatic study platform has potential research applications where prospective real-world data may contribute to evidence generation.

PURPOSE/OBJECTIVE:Cryotherapy is an effective mucositis intervention for selected chemotherapy regimens, but reliance on ice chips has limited its applicability. Our objective was to assess the efficacy and tolerability of a reusable, self-contained, device as an alternative delivery mode. METHODS:A total of 164 patients randomized 2:1 received the device (Chemo Mouthpiece; CMP]) + best supportive care (BSC) (arm A) or BSC only (control, arm B), across 16 study sites. Inclusion criteria allowed broad tumor diagnosis and chemotherapy regimens. During the first two cycles of treatment, patients completed daily questionnaires in which they graded oral pain (OP) and analgesic use (AU) to control mouth pain. A questionnaire assessed device tolerability at the trial's end. RESULTS:The majority of patients received chemotherapy for breast cancer (arm A 52.7%, arm B 61.1%). Colorectal cancers were the next most common diagnosis. The percentage of visits in which any OP (> 0) in cycles 1 and 2 was reported was less among device-using individuals (CMP 17.8% vs Control 24.6%; p < 0.001). Whereas 26% of controls (arm B) required analgesics during their two cycles of treatment, the frequency was 11.3% among arm A (p = 0.01). Arm B AU was reported in 7.7% of visits compared to 1.8% of arm A visits (p < 0.001). End-of-study assessments of device tolerability were favorable. CONCLUSIONS:CMP use for 14 days following chemotherapy infusion mitigated chemotherapy-associated OP and AU. The effect was seen over two cycles of treatment with known stomatotoxic agents having both short and long half-lives. The device was well tolerated. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov (NCT04595838) Posted August 31, 2020.

Guideline-recommended screening programs exist for only a few single-cancer types, and these cancers represent less than one-half of all new cancer cases diagnosed each year in the U.S. In addition, these "single-cancer" standard of care (SoC) screening tests vary in accuracy, adherence, and effectiveness, though all are generally understood to lead to reductions in cancer-related mortality. Recent advances in high-throughput technologies and machine learning have facilitated the development of blood-based multi-cancer early detection (MCED) tests. The opportunity for early detection of multiple cancers with a single blood test holds promise in addressing the current unmet need in cancer screening. By complementing existing SoC screening, MCED tests have the potential to detect a wide range of cancers at earlier stages when patients are asymptomatic, enabling more effective treatment options and improved cancer outcomes. MCED tests are positioned to be utilized as a complementary screening tool to improve screening adherence at the population level, to broaden screening availability for individuals who are not adherent with SoC screening programs, as well as for those who may harbor cancers that do not have SoC testing available. Published work to date has primarily focused on test performance relating to sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). MCED tests will require approval through the pre-market approval pathway from the United States Food and Drug Administration. Additional studies will be needed to demonstrate clinical utility (i.e., improvements in health outcomes) and establish optimal implementation strategies, (i.e., testing intervals), follow-up and logistics of shared decision making. Here, we propose core attributes of MCED testing for which clinical data are needed to ideally position MCED testing for widespread use in clinical practice.

BACKGROUND:Next-generation sequencing (NGS) testing in patients with metastatic non-small cell lung cancer (mNSCLC) identifies actionable driver oncogenes (ADO) and targeted treatment (TT). Potential inequities were evaluated in NGS testing and TT in patients with mNSCLC. PATIENTS AND METHODS/METHODS:This retrospective study used a nationwide electronic health record-derived deidentified database for patients ≥18 years diagnosed with mNSCLC between 4/2018 and 4/2024, ≥2 recorded visits, and follow-up ≥90 days post diagnosis. For TT, patients must have received NGS testing before first-line (1L) treatment and harbored ≥1 1L ADO. RESULTS:A total of 15 392 patients with mNSCLC were included: 66% with commercial insurance, 16% with Medicare, 12% with other, 4% with Medicaid, and 3% with other government insurance. Patients with commercial insurance had significantly higher odds of receiving NGS testing vs Medicare, Medicaid, or other insurance. While patient characteristics varied across insurances, the effect of insurance type on NGS testing did not differ by race/ethnicity, age, or socioeconomic status (SES). Site of care was a significant effect modifier, with increased odds of NGS testing for community vs academic settings for commercial, Medicare, and other insurance and decreased odds for Medicaid. When all patients received NGS testing, significantly lower odds of receiving TT occurred for patients with SES 2 vs SES 1 (lowest); higher odds occurred for Asian vs white patients. CONCLUSION/CONCLUSIONS:Insurance is a key contributor to inequity in NGS testing. When all patients received NGS testing, equity was achieved in patients receiving TT, except those with lower SES, who potentially did not qualify for Medicaid.

BACKGROUND:To progress adolescent mental health research beyond our present achievements-a complex account of brain and environmental risk factors without understanding neurobiological embedding in the environment-we need methods to uncover relationships between the developing brain and real-world environmental experiences. METHODS:We investigated associations between brain function, environments, and emotional and behavioral problems using participants from the Adolescent Brain Cognitive Development (ABCD) Study (n = 2401 female). We applied manifold learning, a promising technique for uncovering latent structure from high-dimensional biomedical data such as functional magnetic resonance imaging. Specifically, we developed exogenous PHATE (potential of heat-diffusion for affinity-based trajectory embedding) (E-PHATE) to model brain-environment interactions. We used E-PHATE embeddings of participants' brain activation during emotional and cognitive processing tasks to predict individual differences in cognition and emotional and behavioral problems both cross-sectionally and longitudinally. RESULTS:E-PHATE embeddings of participants' brain activation and environments at baseline showed moderate-to-large associations with total, externalizing, and internalizing problems at baseline, across several subcortical regions and large-scale cortical networks, compared with the zero-to-small effects achieved by voxelwise data or common low-dimensional embedding methods. E-PHATE embeddings of the brain and environment at baseline were also related to emotional and behavioral problems 2 years later. These longitudinal predictions showed a consistent moderate effect in the frontoparietal and attention networks. CONCLUSIONS:The embedding of the adolescent brain in the environment yields enriched insight into emotional and behavioral problems. Using E-PHATE, we demonstrated how the harmonization of cutting-edge computational methods with longstanding developmental theories advances the detection and prediction of adolescent emotional and behavioral problems.

BACKGROUND:Freezing of gait (FOG) is a common gait disorder that often accompanies Parkinson's disease (PD). The current understanding of brain functional organization in FOG was built on the assumption that the functional connectivity (FC) of networks is static, but FC changes dynamically over time. We aimed to characterize the dynamic functional connectivity (DFC) in patients with FOG based on high temporal-resolution functional MRI (fMRI). METHODS:Eighty-seven PD patients, including 29 with FOG and 58 without FOG, and 32 healthy controls underwent resting-state fMRI. Spatial independent component analysis and a sliding-window approach were used to estimate DFC. RESULTS:Four patterns of structured FC 'states' were identified: a frequent and sparsely connected network (State I), a less frequent but highly synchronized network (State IV), and two states with opposite connecting directions between the visual network and the sensorimotor network (positively connected in State II, negatively connected in State III). Compared with the non-FOG group, patients with FOG spent significantly less time in State II and more time in State III. The longer dwell time in State III was correlated with more severe FOG symptoms. The fractional window of State III tended to correlate to visual-spatial and executive dysfunction in FOG. Moreover, fewer transitions between brain states and lower variability in local efficiency were observed in FOG, suggesting a relatively 'rigid' brain. CONCLUSIONS:This study highlights how visuomotor network dynamics are related to the presence and severity of FOG in PD patients, which provides new insights into understanding the pathophysiological mechanisms that underly FOG. © 2025 International Parkinson and Movement Disorder Society.

X-ray absorption spectroscopy (XAS) of 3d transition metals provides important electronic structure information for many fields. However, X-ray-induced radiation damage under physiological temperature has prevented using this method to study dilute aqueous systems, such as metalloenzymes, as the catalytic reaction proceeds. Here we present a new approach to enable operando XAS of dilute biological samples and demonstrate its feasibility with K-edge XAS spectra from the Mn cluster in photosystem II and the Fe-S centers in photosystem I. This approach combines highly efficient sample delivery strategies and a robust signal normalization method with high-transmission Bragg diffraction-based spectrometers at X-ray free-electron lasers (XFELs) in a damage-free, shot-by-shot mode. These photon-out spectrometers have been optimized for discriminating the metal Mn/Fe Kα fluorescence signals from the overwhelming scattering background present on currently available detectors for XFELs that lack suitable energy discrimination. We quantify the enhanced performance metrics of the spectrometer and discuss its potential applications for acquiring time-resolved XAS spectra of biological samples during their reactions at XFELs.

Mitochondrial Ca²⁺ transport regulates many neuronal functions including synaptic transmission, ATP production, gene expression and neuronal survival. The mitochondrial Ca²⁺ uniporter (MCU) is the core molecular component of the mitochondrial Ca²⁺ uptake complex in the inner mitochondrial membrane. MCUb is a paralog of MCU that negatively regulates mitochondrial Ca²⁺ uptake in the heart and the cells of the immune system. However, the function of MCUb in the brain is largely unknown. Here, we report that MCUb knockout (KO) led to enhanced mitochondrial Ca²⁺ uptake in cortical neurons. By simultaneously monitoring changes in cytosolic and mitochondrial Ca²⁺ concentrations, [Ca²⁺]_cyt and [Ca²⁺]_mt, respectively, we also found that MCUb KO reduced the [Ca²⁺]_cyt threshold required to induce mitochondrial uptake in cortical neurons during electrical stimulation. Exposure of cortical neurons to toxic concentrations of glutamate led to a collapse of mitochondrial membrane potential (ΔΨ_mt) and [Ca²⁺]_cyt deregulation, and MCUb deletion accelerated the development of both events. Furthermore, using the middle cerebral artery occlusion (MCAO) as a model of transient ischemic stroke in mice, we found that MCUb KO significantly increased MCAO-induced brain damage in male, but not female mice. These results suggest that MCUb regulates neuronal Ca²⁺ dynamics and excitotoxicity and reveal a sex-dependent role of MCUb in controlling resistance to brain damage following ischemic stroke.

Respiratory tract infections (RTIs) caused by bacteria or viruses are associated with stroke severity. Recent studies have revealed an imbalance in the von Willebrand factor (VWF)-ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) axis in patients with RTIs, including coronavirus disease 2019. We examined whether this imbalance contributes to RTI-mediated stroke severity. Wild-type (WT), Vwf-/-, or Adamts13-/- mice with respective littermate controls (Vwf+/+ or Adamts13+/+) were infected intranasally with sublethal doses of Staphylococcus aureus (on days 0, 2, and 5) or mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; on day 0) and subjected to transient (30 or 45 minutes) cerebral ischemia followed by reperfusion. In S aureus-infected mice, infarct volumes were assessed on day 2 and functional outcomes on weeks 1 and 4 after reperfusion. In SARS-CoV-2-infected mice, infarct volumes and functional outcomes (Bederson score) were assessed on day 1 after reperfusion. We demonstrated that S aureus or SARS-CoV-2 RTI was accompanied by an imbalance in the VWF-ADAMTS13 axis and an increase in plasma levels of interleukin-6, C-X-C motif chemokine ligand 1, and monocyte chemoattractant protein-1, which was associated with larger infarcts and worse functional outcomes (P < .05 vs mock infection). S aureus- or SARS-CoV-2-infected Vwf-/- mice exhibited reduced infarcts and improved functional outcomes, whereas infected Adamts13-/- mice displayed greater stroke severity (P < .05 vs control). In the models of RTI preceding stroke, VWF contributes to stroke severity, whereas ADAMTS13 is protective.