Publications

BACKGROUND AND HYPOTHESIS: Cognitive impairment is a core disabling feature of schizophrenia (SZ). Changes in gut microbiota have been linked to cognitive dysfunction in SZ; however, changes in the oral microbiota in relation to immune dysregulation have only been recently reported, and their relevance to cognition remains unclear. The objective of this study was to explore the relationship between oral microbiota alterations and cognitive impairment in patients with SZ and to evaluate potential mediating mechanisms, including neuroinflammation and microbial functions.

STUDY DESIGN: In this cross-sectional study, we recruited 68 patients with SZ and 32 healthy controls (HC). Cognitive function was assessed using the Wechsler Adult Intelligence Scale-Fourth Edition. Oral microbiota composition was characterized by 16S rRNA gene sequencing, and microbial functions were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2) based on the 16S profiles. Neuroinflammation was assessed using peripheral kynurenine (KYN) pathway activity as a proxy.

STUDY RESULTS: The patients with SZ exhibited significantly lower oral microbiota alpha diversity (driven by reduced evenness) and showed greater cognitive impairment and differences in the KYN pathway markers (neuroinflammation proxies) compared to HC. They also showed shifts in specific bacterial genera and the PICRUSt2-predicted functional pathways. Importantly, the oral microbiota alterations were significantly associated with cognitive impairment. Exploratory mediation analysis suggested that several pathways, including glycan biosynthesis and metabolism, may play a role in this association. In contrast, KYN pathway markers showed no significant association.

CONCLUSIONS: Our findings show an association between the oral microbiota alpha diversity and cognitive impairment in SZ, with the PICRUSt2-predicted functional pathways potentially implicated.

The mTOR protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinositide-3 kinase (PI3K) and small guanosine triphosphate Ras signaling networks commonly deregulated in cancer and diabetes. Although mTOR phosphorylates many substrates in vitro, in cells, mTORC1 and mTORC2 have high specificity: mTORC2 phosphorylates the protein kinases Akt and PKC, but not closely related kinases that are mTORC1 substrates. To understand how mTORC2 recognizes substrates, we created semisynthetic probes to trap the mTORC2-Akt complex and determine its structure. Whereas most protein kinases recognize amino acids adjacent to the phosphorylation site, local sequence contributes little to substrate recognition by mTORC2. Instead, the specificity determinants were secondary and tertiary structural elements of Akt that bound the mTORC2 component mSin1 distal to the mTOR active site and were conserved amongst at least 18 related substrates. These results reveal how mTORC2 recognizes its canonical substrates and may enable the design of mTORC2-specific inhibitors.

BACKGROUND AND AIMS: Financial toxicity, the combined objective burden and subjective distress that affects patients' medical care, is not well described in patients with IBD. We aimed to characterize financial toxicity in patients with IBD.

METHODS: We designed and administered a de-identified survey to patients with IBD. The primary outcome, financial toxicity, was defined as a score <22 on the COST-FACIT scale, a validated measure. We constructed multivariable logistic regression models to evaluate associations adjusting for age, sex, race, type of IBD, IBD medications, household income and education level.

RESULTS: Respondents (n=669) had a median age of 49 years, were 62% female and 92% White. 52% were currently treated with advanced IBD-therapy and 58% reported IBD in remission/minimal activity. 53% were employed full-time. 61% had an annual household income ≥$100,000. 69% had private insurance and 31% had Medicare.21% reported trouble paying medical bills in the past year; 34% of working adults missed work in the past 7 days because of IBD. 39% experienced financial toxicity. Adjusting for confounders, adults <65 years were more likely to experience toxicity than older adults (aOR: 6.78, 95%CI: 2.60-17.65). Those with education less than a Bachelor's Degree (aOR: 2.73, 95%CI: 1.70-4.37), annual household income <$60,000 (aOR: 3.71, 95%CI: 2.14-6.42) and women were more likely to experience financial toxicity (aOR: 1.90; 95%CI: 1.28-2.81).

CONCLUSIONS: Financial toxicity was prevalent among patients with IBD, particularly among younger adults, those with lower income and education and women. Enquiring about financial toxicity should be incorporated into IBD clinical practice.

BackgroundBasilar artery occlusion (BAO) is a rare stroke type, with subtypes like vertebrobasilar tandem occlusion (VBTO), complicating treatment. Mechanical thrombectomy (MT) is increasingly used, but evidence on its safety and effectiveness in VBTO compared to isolated BAO (iBAO) remains limited.MethodsPubMed, Cochrane Central, Embase, Web of Science, and ScienceDirect were searched till May 2025. The risk ratios (RR) were pooled along with 95% Confidence intervals (CI) under the random effects model using Review Manager. The Newcastle Ottawa Scale and GRADE assessment were used to assess the quality of studies and certainty of evidence. Successful recanalization was defined as a Thrombolysis in Cerebral Infarction (TICI) score of ≥2b. The modified Rankin Scale (mRS) is a scale used to assess the severity of stroke, with functional independence defined as an mRS score of 0-2. Publication bias was assessed using funnel plots and Egger's regression test.ResultsNine studies, pooling a total of 737 patients, were included in this analysis. MT showed no significant difference in functional independence in the VBTO group compared to the iBAO group (RR = 1.25; 95% CI: 0.73, 2.12; p = .42). The successful recanalization was also comparable between the VBTO and iBAO arms when MT was performed (RR = 0.96; 95%CI 0.81, 1.13; p = .60). The risk of symptomatic intracerebral hemorrhage (sICH) was significantly increased when MT was performed in the VBTO arm compared to the iBAO group (RR = 2.20; 95%CI : 1.09, 4.46]; p = .03). The mortality rates were also comparable between the two groups (RR = 1.28; 95% CI 0.78, 2.10; p = .33). Also, in the VBTO patients, the successful recanalization rate showed no significant difference between the clean and dirty road techniques (RR = 1.04; 95% CI 0.90, 1.20; p = .63).ConclusionWhen MT was performed on VBTO and iBAO patients, the efficacy endpoints-such as functional independence and successful recanalization-and the safety endpoint of mortality were comparable. However, the risk of sICH was higher in the VBTO group.

BACKGROUND: Fimepinostat, an oral dual inhibitor of histone deacetylase (HDAC) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), has shown activity in preclinical models of Myc-driven pediatric malignancies. This Phase 1 trial aimed to determine the recommended pediatric Phase 2 dose (RPP2D), describe the toxicity profile, and evaluate the pharmacokinetics of fimepinostat in children with relapsed and refractory solid and central nervous system (CNS) tumors.

METHODS: This multicenter, Phase 1 study enrolled patients ages 1-21 years with relapsed or refractory solid tumors, CNS tumors, or lymphoma. The dose-escalation phase followed a 3 + 3 design, starting at 27.5 mg/m2 and escalating to 45 mg/m2. Following dose escalation, three expansion cohorts were opened including cohorts for patients with Myc(n)-driven neuroblastoma, Myc-driven extracranial solid tumors, and diffuse large B-cell lymphoma or Burkitt lymphoma. The pharmacokinetics of fimepinostat and its metabolites were studied after the first dose.

RESULTS: Twenty-six patients were enrolled, with 25 receiving treatment. The median age was 13.6 years (range: 4.1-20.9). In the dose-escalation phase, 12 patients were evaluable for DLT assessment. The RPP2D was initially determined to be 45 mg/m2 but was revised to 35 mg/m2 after observing DLTs in the dose-expansion phase. Treatment-related adverse events were primarily hematologic and gastrointestinal. No objective responses were observed in 23 evaluable patients. Three patients had stable disease for over four cycles, including a patient with MYCN amplified neuroblastoma with stable disease for 24 cycles. Pharmacokinetic analysis showed significant interpatient variability and rapid conversion of fimepinostat to its metabolites.

CONCLUSION: Fimepinostat was tolerable at a dose of 35 mg/m2 in children with relapsed and refractory solid and CNS tumors, but lacked significant clinical activity. Discovery of drugs to target Myc continues to be a high priority for childhood cancers.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02909777.

BACKGROUND AND AIMS: Diabetes is associated with increased risk of cardiovascular and renal disease. This study investigated the role of peptidylarginine deiminase 4 (PAD4), neutrophil extracellular traps (NETs), and inflammasome activation in diabetic cardiomyopathy (DCM) and kidney disease (DKD).

METHODS: Endomyocardial biopsies (EMB) from heart failure (HF) patients (n = 20) with or without diabetes were stained for NETs. Wild-type (WT) and PAD4⁻/⁻ mice were subjected to streptozotocin (STZ)-induced diabetes and cardiac function, blood glucose, body weight, and exercise tolerance were assessed longitudinally. NETosis and ASC specks were evaluated in mouse and human neutrophils. Cardiac and renal fibrosis was assessed by Sirius Red/Fast Green staining. Confocal microscopy, ELISA, and flow cytometry were used to quantify NETs, IL-1β, von Willebrand factor (VWF), cytokine transforming growth factor beta-1 (TGF-β1), and neutrophil infiltration.

RESULTS: Myocardial NET burden was increased in HF patients with diabetes. High glucose triggered inflammasome activation in human neutrophils. After STZ, PAD4⁻/⁻ and WT mice developed hyperglycaemia and weight loss, yet only WT neutrophils showed increased NETosis and ASC speck formation. Only diabetic WT mice exhibited elevated IL-1β and VWF levels, impaired cardiac function, reduced exercise tolerance, and pulmonary oedema; PAD4⁻/⁻ mice were protected. Wild-type diabetic hearts and kidneys showed greater fibrosis, neutrophil infiltration, NETs, and TGF-β1 levels. Kidney injury in WT mice was reflected by albuminuria and renal fibrosis, whereas PAD4⁻/⁻ mice preserved renal function.

CONCLUSIONS: Diabetes promotes neutrophil inflammasome activation and NETosis, driving cardiac and renal inflammation and fibrosis. Peptidylarginine deiminase 4 deficiency prevents heart failure and preserves kidney function in experimental diabetes.

BACKGROUND: The US Food and Drug Administration (FDA)-mandates Risk Evaluation and Mitigation Strategy (REMS) programs for certain drugs with serious side effects help ensure that the benefits of use outweigh the risks. REMS materials-including enrollment forms, fact sheets, and medication guides-inform patients and caregivers about drug risks and program requirements.

OBJECTIVE: To explore how effectively REMS materials communicate drug risk information and program requirements to patients and caregivers and to identify patients' and caregivers' preferences for risk communication.

METHODS: Interviews with patients and caregivers of patients prescribed REMS-covered drugs focused on REMS materials. Transcripts were coded manually, with answers to closed-ended questions tabulated in Excel.

RESULTS: The study included 43 patients and six caregivers across eight REMS-covered drugs: alemtuzumab, ambrisentan, clozapine, isotretinoin, lenalidomide, pegvaliase, pomalidomide, and sodium oxybate. Most participants were female (N = 42, 86%), white/non-Hispanic (N = 40, 82%), and college educated (N = 37, 76%). The average age was 40 years, with 27 (55%) having annual family incomes over $100,000. Most participants learned about REMS-covered drugs via printed information (N = 36, 73%), mostly REMS materials; conversations with providers about drug risks and benefits (N = 29, 59%); and websites found on their own (N = 42, 86%). Nearly all participants (N = 47, 96%) felt well-informed about drug risks and benefits, and most participants taking self-administered drugs (N = 28, 67%) reported understanding safe use "very well." However, knowledge gaps emerged around REMS-related risks and reasons for safe use measures; some participants misunderstood REMS enrollment forms as legal protections, not safety measures. Patients also widely varied in their valuations of REMS materials, with some feeling informed and empowered and others confused or intimidated. Preferences for risk communication varied; most participants (N = 36, 73%) wanted to receive information verbally from providers, with several wanting visual aids, summaries, and other resources.

DISCUSSION: Gaps in patients' and caregivers' understanding of REMS programs and drug risks highlight the merits of reviewing communication materials and strategies. Clear, concise, and comprehensive educational documents could promote understanding and adherence to REMS requirements.

BACKGROUND: The causes of individual headache attacks are commonly sought, yet the multiple potential influences make this task difficult. Information theory provides a framework for addressing this challenge by quantifying how unexpected an exposure is through surprisal. Prior research has shown that higher surprisal scores predict migraine onset, but the extent to which this relationship generalizes to tension-type headache remains unknown.

AIMS: This study aimed to determine whether surprisal is associated with incident tension-type headache attacks among individuals with episodic migraine.

METHODS: This secondary analysis proceeded from a prospective daily diary study in which 109 participants with migraine recorded potential triggers, headache activity, and symptoms twice daily for up to 28 days. Surprisal values were computed from person-specific probability distributions of diary responses, aggregated to yield average surprisal scores per diary entry. Associations between current surprisal and the onset of headache attacks within 12- and 24-hour intervals were evaluated. Analyses were conducted for all headaches combined and separately for migraine-only and tension-type headache-only attack sets.

RESULTS: Headache attacks occurred in 1,345 of 4,530 (29.7%) of 12-hour and 2,122 of 4,947 (42.9%) of 24-hour windows. Stratified analyses showed a strong association for migraine attacks, OR: 2.18 (95%CI: 1.15 - 4.14) at 12 hours and OR: 2.88 (95%CI: 1.77 - 4.69) at 24 hours. In contrast, associations with tension-type headache were weak and nonsignificant, OR: 1.01 (95%CI: 0.45 - 2.23) at 12 hours and OR: 1.40 (95%CI: 0.69 -2.86) at 24 hours. Exploratory nonlinear and contextual analyses within the tension-type headache subset revealed no consistent gradients or effect modification by prior-day surprisal.

CONCLUSIONS: Surprisal was associated with migraine but not tension-type headache attacks in this cohort. These findings suggest that migraine may be more sensitive to contextual unpredictability in the environment than tension-type headache. Future research should examine surprisal in populations with primary tension-type headache diagnoses to clarify whether the absence of association reflects true diagnostic differences or misclassification of attacks.

Dysregulated transcription is a defining hallmark of cancer. Recently, novel chemically induced proximity approaches have enabled the rewiring of transcriptional machinery to drive expression of pro-apoptotic genes using bivalent small molecules. In this work, we demonstrate that this strategy is amenable to relocalizing DNA bound transcriptional machinery, such as fusion transcription factors that commonly drive pediatric malignancies. Targeting fusion transcription factors, such as EWSR1::FLI1 in Ewing sarcoma, with these bivalent compounds may open new therapeutic avenues. Here, we develop a small molecule, EB-TCIP, that recruits FKBP12F36V-tagged EWSR1::FLI1 to DNA sites bound by the transcriptional regulator BCL6, leading to rapid chromatin remodeling and expression of BCL6 target genes. This proof-of-concept study demonstrates that DNA binding proteins with pioneering transcription factor activity, such as EWSR1::FLI1, can be relocalized on chromatin to induce expression of repressed genes. Insights herein will guide the development of future bivalent molecules that rewire DNA binding transcriptional machinery.