Stage Of Disease Research Articles

DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response.

The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. DNL343 is an investigational CNS-penetrant small-molecule ISR inhibitor designed to activate the eukaryotic initiation factor 2B (eIF2B) and suppress aberrant ISR activation. DNL343 reduced CNS ISR activity and neurodegeneration in a dose-dependent manner in two established in vivo models - the optic nerve crush injury and an eIF2B loss of function (LOF) mutant - demonstrating neuroprotection in both and preventing motor dysfunction in the LOF mutant mouse. Treatment with DNL343 at a late stage of disease in the LOF model reversed elevation in plasma biomarkers of neuroinflammation and neurodegeneration and prevented premature mortality. Several proteins and metabolites that are dysregulated in the LOF mouse brains were normalized by DNL343 treatment, and this response is detectable in human biofluids. Several of these biomarkers show differential levels in CSF and plasma from patients with vanishing white matter disease (VWMD), a neurodegenerative disease that is driven by eIF2B LOF and chronic ISR activation, supporting their potential translational relevance. This study demonstrates that DNL343 is a brain-penetrant ISR inhibitor capable of attenuating neurodegeneration in mouse models and identifies several biomarker candidates that may be used to assess treatment responses in the clinic.

Chest wall muscle area, ventilatory efficiency and exercise capacity in systemic sclerosis.

To investigate the potential contribution of chest wall muscle area (CWMA) to the ventilatory efficiency and exercise capacity in patients with Systemic Sclerosis (SSc) without interstitial lung disease (ILD). Forty-four consecutive SSc patients [F = 37, median age 53.5years (IQR 43.5-58)] were examined using chest high-resolution computed tomography (HRCT), pulmonary function tests and cardiopulmonary exercise testing (CPET). The CWMA was evaluated at the level of the ninth thoracic vertebra on CT images by two independent evaluators blinded to the patient information. CPET parameters analyzed were maximum oxygen uptake (VO2 max) and VO2 at anaerobic threshold (VO2@AT); minute ventilation (VE); maximum tidal volume (VT). A statistically significant positive correlation was found between CWMA and maximum workload (r = 0.470, p < 0.01), VO2 max ml/min (r = 0.380, p < 0.01), VO2@AT (r = 0.343, p < 0.05), VE (r = 0.308, p < 0.05), VT (r = 0.410, p < 0.01) and VO2/heart rate (r = 0.399, p < 0.01). In multiple regression analysis, VO2 max (ml/min) was significantly associated with CWMA [β coefficient = 5.226 (95% CI 2.824, 7.628); p < 0.001], diffusing capacity for carbon monoxide (DLco) [β coefficient = 6.749 (95% CI 1.460, 12.039); p < 0.05] and body mass index (BMI) [β coefficient = 41.481 (95% CI 8.802, 74.161); p < 0.05]. In multiple regression analysis, maximum workload was significantly associated with CWMA [β coefficient = 0.490 (95% CI 0.289, 0.691); p < 0.001], DLco [β coefficient = 0.645 (95% CI 0.202, 1.088); p < 0.01] and BMI [β coefficient = 3.747 (95% CI 1.013, 6.842); p < 0.01]. In SSc-patients without ILD, CWMA represents an important variable in exercise capacity and can be evaluated by the mediastinal window available in the HRCT images required for lung disease staging.

The relationship between endolymphatic hydrops features and hearing loss in Bilateral Meniere's disease

BackgroundThis study aimed to investigate the relationship between the features of endolymphatic hydrops and hearing loss in patients with Bilateral Meniere's Disease.MethodsA retrospective analysis was conducted on 77 patients diagnosed with Bilateral Meniere's Disease. The features of endolymphatic hydrops in the affected ear were evaluated through gadolinium-enhanced inner ear Magnetic resonance imaging. The Spearman correlation coefficient, paired t-tests, and Wilcoxon signed-rank tests were employed for data analysis.ResultsThe analysis revealed a significant correlation between the degree of endolymphatic hydrops and hearing loss across all frequencies(0.125–8 kHz), including the cochlear, vestibular, and overall degree of endolymphatic hydrops. The strongest correlation between the overall degree of endolymphatic hydrops and hearing loss was observed at low frequencies (r = 0.571, p < 0.05), followed by mid-frequencies (r = 0.508, p < 0.05), and high-frequencies (r = 0.351, p < 0.05), with a correlation of r = 0.463, p < 0.05 for the staging of Meniere's disease. Affected Ears with endolymphatic hydrops both in the cochlea and vestibule exhibited more severe hearing loss and Meniere's disease staging compared to those with isolated endolymphatic hydrops within the same patient.ConclusionsThe features of endolymphatic hydrops in patients with Bilateral Meniere's Disease were found to correlate with the severity of hearing loss and the staging of Meniere's disease.

Morphometry of medial temporal lobe subregions using high-resolution T2-weighted MRI in ADNI3: Why, how, and what's next?

This paper for the 20th anniversary of the Alzheimer's Disease Neuroimaging Initiative (ADNI) provides an overview of magnetic resonance imaging (MRI) of medial temporal lobe (MTL) subregions in ADNI using a dedicated high-resolution T2-weighted sequence. A review of the work that supported the inclusion of this imaging modality into ADNI Phase 3 is followed by a brief description of the ADNI MTL imaging and analysis protocols and a summary of studies that have used these data. This review is supplemented by a new study that uses novel surface-based tools to characterize MTL neurodegeneration across biomarker-defined AD stages. This analysis reveals a pattern of spreading cortical thinning associated with increasing levels of tau pathology in the presence of elevated amyloid beta, with apparent epicenters in the transentorhinal region and inferior hippocampal subfields. The paper concludes with an outlook for high-resolution imaging of the MTL in ADNI Phase 4. HIGHLIGHTS: As of Phase 3, the Alzheimer's Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) protocol includes a high-resolution T2-weighted MRI scan optimized for imaging hippocampal subfields and medial temporal lobe (MTL) subregions. These scans are processed by the ADNI core to obtain automatic segmentations of MTL subregions and to derive morphologic measurements. More detailed granular examination of MTL neurodegeneration in response to disease progression is achieved by applying surface-based modeling techniques. Surface-based analysis of gray matter loss in MTL subregions reveals increasing and spatially expanding patterns of neurodegeneration with advancing stages of Alzheimer's disease (AD), as defined based on amyloid and tau positron emission tomography biomarkers in accordance with recently proposed criteria. These patterns closely align with post mortem literature on spread of pathological tau in AD, supporting the role of tau pathology in the presence of elevated levels of amyloid beta as the driver of neurodegeneration.

Higher Prevalence of Hepatitis B and C Infections among Indian Patients with Von Willebrand Disease

Background: The use of recombinant coagulation factors has reduced the incidence of hepatitis B and C infections in hemophilia patients. As recombinant von Willebrand factor is not easily available, patients with von Willebrand disease (VWD) may be at higher risk for acquiring hepatitis B and C infections. The prevalence of hepatitis B and C infections in the Indian population is ~0.95% and ~0.3%, respectively. Aims: This single tertiary center study aimed to assess the prevalence of hepatitis B and C infections and the profile of liver disease caused by these viruses among patients with VWD. Methodology: We retrospectively enrolled VWD patients treated in our center from January 2012 to December 2022 and analyzed the prevalence of hepatitis B and C infection and stage of liver disease. Results: Among 189 patients with VWD during the study period, 5 of 61 (8.1%) VWD patients screened were hepatitis B surface antigen positive (age: 34 [24–42] years; median (range); plasma VWF antigen: 10.1, [0–40] IU/dL). One patient had cholangiohepatoma at presentation, whereas none had chronic liver disease. Four of five patients received multiple bloodproduct transfusions before coming to our institution, with 10 (7–18) years interval between 1st transfusion and to detection of hepatitis B infection. Four of the 47 VWD patients (8.5%) screened were positive for hepatitis C virus antibody (48 [43–59] years, plasma VWF antigen: 20 [0–21.5] IU/dL). One patient had chronic liver disease. All four patients received multiple blood product transfusions before coming to our institution, with 15.5 (2–39) years interval between 1st transfusion and to the detection of hepatitis C infection. Conclusions: The prevalence of hepatitis B infection (8.1%) and hepatitis C infection (8.5%) was 8-fold and 28-fold higher, respectively, in VWD patients than the general population in India. VWD patients remain at high risk for acquiring transfusion-transmitted viral infections and appropriate interventions are needed to address this.

Associations between cuprotosis-related genes and the spectrum of metabolic dysfunction-associated fatty liver disease: An exploratory study.

To explore the associations between cuprotosis-related genes (CRGs) across different stages of liver disease in metabolic dysfunction-associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC). We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD-related HCC (n = 271) and two MAFLD single-cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome-wide association study (GWAS). GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD-related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction-associated fatty liver to metabolic-associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD. GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T-cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis.

Cluster analysis of 100 Marfan patients based on aortic 4D flow MRI and Z-score: insights into disease heterogeneity and stratification of subgroups.

4D flow MRI-derived variables from Marfan patients are highly heterogeneous. Our aim was to identify distinct Marfan patient subgroups based on aortic 4D flow MRI and Z-score for stratification of distinct hemodynamic profiles and clinical features by means of hierarchical cluster analysis. One hundred Marfan patients underwent baseline aortic 4D flow MRI at 3 T. Z-scores, degree of helical and vortical flow, wall shear stress, flow displacement, and peak velocity were determined in the ascending aorta. Sex, age, BMI, antihypertensive medication, and dural ectasia were recorded. Hierarchical cluster analysis was performed using 4D flow MRI variables and Z-scores as input. Cluster analysis resulted in three distinct clusters characterized by different Z-scores (mean ± SD); cluster 1: 0.4 ± 1.1 vs. cluster 2: 3.1 ± 1.1 vs. cluster 3: 3.6 ± 1.9. The three clusters delivered differences in helical and vortical flow patterns (global p = 0.003 and p < 0.001, respectively), wall shear stress (0.49 ± 0.11 vs. 0.44 ± 0.12 vs. 0.37 ± 0.09 N/m2, global p < 0.001), flow displacement (0.11 ± 0.05 vs. 0.16 ± 0.08 vs. 0.15 ± 0.07, global p = 0.006), and peak velocity (76.3 ± 9.0 vs. 60.1 ± 7.3 vs. 56.0 ± 7.8 cm/s, global p < 0.001). Patients in cluster 1 and 2 were relevantly younger than in cluster 3 (32.3 ± 13.8 vs. 32.8 ± 12.6 vs. 40.2 ± 15.0 years, all pairwise ∆p < 0.0297). Hierarchical cluster analysis based on aortic 4D flow MRI and Z-score revealed three distinct subgroups of Marfan patients, each characterized by specific hemodynamic profiles and clinical features. Follow-up of our patients is warranted to assess if 4D flow MRI- and Z-score-based stratification can predict future aortic diameter growth and ultimately improve outcomes. A combination of Z-score and 4D flow MRI-derived parameters may help identify subgroups of Marfan patients representing different stages or phenotypes of aortic disease, which require specific management strategies. Four-dimensional (4D) flow MRI-derived variables of Marfan patients are highly heterogeneous across varying Z-scores. Cluster analysis based on 4D flow MRI and Z-score revealed three distinct subgroups of Marfan patients. A combination of Z-score and 4D flow MRI-derived parameters may identify different stages of aortic disease in Marfan patients.

The association between social vulnerability and geriatric assessment impairments among older adults with gastrointestinal cancers-The CARE Registry.

Older adults comprise the majority of patients with gastrointestinal (GI) cancer. Geriatric assessments (GAs) are recommended for older adults with cancer in part to detect aging-related impairments (e.g., frailty) associated with early mortality. Social factors like social vulnerability may also influence aging-related impairments. However, the association between social vulnerability and aging outcomes among older adults with cancer is understudied. The authors included 908 older adults aged 60 years and older who were recently diagnosed with GI cancer undergoing GA at their first prechemotherapy visit to the University of Alabama at Birmingham oncology clinic. The primary exposure of interest was the social vulnerability index (SVI). Outcomes were frailty (frail vs. robust/prefrail) and total number of GA impairments (range, 0-13). The authors examined the association between SVI and outcomes using Poisson regression with robust variance estimation and generalized estimating equations. The median age at GA was 69 years (interquartile range, 64-75 years), 58.2% of patients were male, 22.6% were non-Hispanic Black, 29.1% had colorectal cancer, 28.2% had pancreatic cancer, and 70.3% had stage III/IV disease. Adjusting for age, sex, cancer type, and disease stage, each decile increase in the SVI was associated with an 8% higher prevalence of frailty (prevalence ratio, 1.08; 95% confidence interval, 1.05-1.11) and a 4% higher average count of total GA impairments (risk ratio, 1.04; 95% confidence interval, 1.02-1.06). The results were attenuated after further adjustment for race and education. Greater social vulnerability was associated with a higher prevalence of frailty and an increasing average number of GA impairments among older adults with GI cancers before systemic treatment. Intervening on social vulnerability may be a target for improving the risk of frailty and GA impairments, but associations of race and education should be further evaluated.

Abstract C054: Clinicogenomic determinants of response to FOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line systemic therapy for pancreatic cancer

Abstract Background: FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GA) are two recommended first-line systemic options for pancreatic cancer; however, there is limited evidence to support a particular regimen or provide guidance for treatment selection. We sought to compare outcomes for FFX versus GA across disease stages, and test whether there was an association between clinicogenomic features, treatment response, and survival. Methods: For this retrospective analysis, we utilized AACR’s GENIE PANC v1.2 database, the first large-scale pancreatic cancer dataset that combines genomic data with clinical annotations. The clinicogenomic profiles of patients were stratified and compared by stage: resectable/borderline resectable (R/BR), locally advanced (LA), or metastatic (MET). Patients who received FFX or GA as first-line therapy were compared across stages, with a focus on MET patients. We evaluated OS and PFS as survival outcomes and performed an adjusted analysis using Cox proportional hazards modeling. Treatment responses were further evaluated by change in serum CA 19-9. To test for features associated with treatment response, the genomic profiles of best and worst responders were compared. Results: Of 987 patients with complete genomic data, there were 452 R/BR, 82 LA, and 453 MET. While there was no difference in KRAS status, patients with later-stage disease accumulated greater common co-alterations: CDKN2A (19%, 23%, 35%), SMAD4 (26%, 29%, 30%), TP53 (72%, 73%, 77%), and ARID1A (6%, 6%, 11). Within MET patients, there was no significant difference in PFS between those treated with FFX (n=239) and GA (n=82), but patients treated with FFX had significantly longer OS, even after multivariable adjustment (median 1.14 vs. 0.854 years, p &amp;lt; 0.01; HR: 0.66, 95% CI: 0.49- 0.89, p &amp;lt; 0.01). Despite improved OS in FFX patients, GA patients had a greater reduction in CA 19-9 (median 50.0 vs. 69.0 U/mL). In addition, when comparing the genomic profiles of best/worst responders for MET patients treated with FFX and GA, there was no clear signal that one regimen should be favored over another in a specific context. Exploratory analyses in the R/BR and LA groups indicated no significant survival differences between first-line FFX vs. GA patients, nor in first-line treatment among patients who developed metastases post- diagnosis. Conclusion: Common co-alterations appear to accumulate in later-stage disease, and outcomes in patients undergoing systemic therapy is worse generally in patients with more complex genomic profiles. However, we did not observe any specific genomic features suggestive of a particular response to FFX vs. GA. Of note, we found that Met GA patients had a larger magnitude in CA 19-9 response, even though Met FFX was associated with improved OS. This provokes important questions regarding how biochemical response should be gauged in patients treated with these regimens. Citation Format: Kunling Tong, Elishama Kanu, Ethan Agritelley, Jiayin Bao, Peter J Allen, Daniel P Nussbaum. Clinicogenomic determinants of response to FOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line systemic therapy for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C054.

Determination of hepatitis B virus (HBV) DNA in serum by nucleic acid screening

The determination of serum hepatitis B Virus (HBV) DNA is of paramount significance in the comprehensive management of HBV infection. It aids in diagnosis, disease staging, and treatment monitoring, ultimately improving patient outcomes and reducing the burden of HBV-related morbidity and mortality. In this work, serum HBV DNA detection was performed using a novel nucleic acid screening system. The sensitivity, selectivity, repeatability, cross reactivity, and HBV DNA stability were evaluated and compared with published data. The detection limit of 95% was 29.12 IU/mL and the 95% confidence interval was from 23.71 to 34.55 IU/mL. Blood samples that contain free hemoglobin (1 g/L, 2 g/L, 4 g/L) and triglycerides (3 mmol/L, 6 mmol/L and 9 mmol/L) were also analyzed. The results demonstrated that the system can also be used in the presence of free hemoglobin and triglycerides. The mean of the cycle threshold (Ct) in 5-day replicates was 35.71 ± 0.35 with a coefficient of variation (CV) of 0.97%. The results of negative samples in the anti-cross contamination experiment showed no response. The coincidence rate for 3001 samples over 20 days of real-time stability measurements and external quality assessment samples was 100%. The results demonstrate the effectiveness of the nucleic acid system for HBV-DNA, providing a theoretical basis for other small and medium-sized blood stations or hospitals to these devices.

The application of cell products for the treatment of critical limb ischemia in patients with diabetes mellitus: a review of the literature

The number of patients with diabetes mellitus (DM) has been progressively increasing worldwide over the past decades, and many international organizations consider DM as a public health emergency of the 21st century.Critical limb ischemia (CLI) is the most severe stage of peripheral arterial disease (PAD) in DM and is characterized by a high risk of limb loss without revascularization. Traditional treatment tactics include open and endovascular revascularization surgical techniques. However, in patients not eligible for revascularization and in cases where performed surgical treatment performed has been ineffective, there are almost no therapeutic alternatives, often leading to amputations and death. As of today, one of the newest non-surgical treatment options is cell therapy. Among different cells, mesenchymal stromal cells (MSCs) are potentially one of the most prospective for use in this patient population.This article provides an overview of clinical trials using cell therapy in patients with CLI.To analyze publications, electronic databases PubMed, SCOPUS, ClinicalTrials, and ScienceDirect were searched to identify published data from clinical trials, research studies, and review articles on cell therapy for critical lower extremity ischemia. After the search, 489 results were received.As a result of systematic selection, 22 clinical trials were analyzed.According to the analyzed literature data, the use of cell products in this category of patients is effective and safe. Cell therapy can stimulate the formation of new vessels and enhances collateral circulation; it is also reported improved distal perfusion, increased pain-free walking distance, decreased amputation rates, and increased survival rates.Nevertheless, further study of the potential use of this category of drugs is needed.

Abstract B024: Multiplexed 3D atlas of state transitions and potential prognostic role of poly- ADP ribose glycohydrolase (PARG) in chronic pancreatitis and PDAC

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC), a disease predominantly associated with chronic inflammation, ranks as the third-leading cause of cancer-related mortality. The limited efficacy of current PDAC therapies is, in part, attributed to the challenges posed by late- stage diagnosis, highlighting the urgent need for early detection techniques to improve treatment outcomes. Sustained pancreatic inflammation induces the production of reactive oxygen species, leading to the activation of the DNA damage repair network, including enzymes such as poly-ADP ribose glycohydrolase (PARG). PARG is crucial for degrading poly-ADP ribose (PAR) chains catalyzed by PARP and, thus, regulating key cellular responses to DNA damage. However, the role of PARG in the molecular etiology of pancreatic diseases remains unclear. As a first step, we conducted a single-cell spatial analysis on a multiplex immunofluorescence cyclic dataset focusing on pathways involved in: immune and stromal alterations influencing cell-state transitions; differentiation; and critical cellular signaling pathways. Specifically, we evaluated the expression patterns of DNA damage enzymes (i.e., PARG), to elucidate their potential roles in the transformation from chronic inflammation to malignancy. Method: The human pancreatitis tissue microarray (TMA), consisting of 6 normal, 36 pancreatitis, 36 pancreatic intraepithelial neoplasia (PanINs), and 6 PDAC samples in duplicate, obtained from patients with pancreatitis or pancreatic cancer diagnosed at Oregon Health and Science University. We generated a comprehensive 48-plex image dataset that was processed through unsupervised clustering and manual gating to identify common cell types across different stages of pancreatic disease, including epithelial, stromal, immune, and endothelial. Result and conclusion: We observed moderate to strong cytoplasmic PARG expression in pancreatitis samples compared to normal tissue (p &amp;lt; 0.001), which significantly decreased in PanINs (p &amp;lt; 0.001) and PDAC samples (p &amp;lt; 0.001). Notably, the PARG expression was primarily in CK19-positive epithelial cells. Further evaluation showed that DNA damage markers, such as pRPA and γH2AX, increased as the disease progressed from pancreatitis to PanINs to PDAC. Therefore, there was an inverse correlation between PARG expression and DNA damage marker expression in cells exhibiting DNA damage. Additionally, PARG expression was inversely correlated with proliferating cells, marked by Ki67 and PCNA, at the single-cell level. In conclusion, our single-cell spatial analysis supports the notion that PARG expression correlates with resolution of DNA damage and that its reduced expression associates with disease progression and cellular proliferation. Overall, these findings support early phase clinical trials using PARG inhibitors in the oncologic space, and as a potential target for early detection of PDAC and treatment of other pancreatic diseases. Mechanistically, PARG loss may provide a setting for faulty DNA repair and thus, an accumulation of driver mutations. Citation Format: Vidhi M Shah, Jennifer Eng, Koei Chin, Brett C. Sheppard, Jonathan R. Brody, Rosalie C. Sears. Multiplexed 3D atlas of state transitions and potential prognostic role of poly- ADP ribose glycohydrolase (PARG) in chronic pancreatitis and PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B024.

Abstract IA-01: Targeting autophagy in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most vexing problems in cancer with 5-year overall survival rates of 13%, thus there is a need for new therapeutic targets. PDAC have a distinct dependence on autophagy, a conserved eukaryotic catabolic pathway that serves to degrade proteins, other macromolecules, and organelles via the lysosome as part of a recycling process to maintain cellular homeostasis during basal and stress conditions. The unique importance of autophagy in PDAC suggests that there may be a subset of proteins that are specifically targeted by autophagy for degradation, which would promote proliferation and survival, and that these may represent new targets for therapy. Using a quantitative PDAC cellular autophagosomal proteomics approach, we identified NCOA4 as the autophagy receptor for ferritin, the cellular iron storage complex, and demonstrated that ferritin autophagy (ferritinophagy) is a highly regulated process and plays a central role in the larger context of cellular and organismal iron homeostasis. Given the reliance of PDAC, on both high levels of autophagy as well as iron, we studied the role of NCOA4 and ferritinophagy in PDAC thereby identifying NCOA4-mediated ferritinophagy and more broadly lysosomal iron metabolism as a PDAC dependency and therapeutic target. We recently determined the cryo-EM structure of the NCOA4-Ferritin complex for future drug design. To identify the role of autophagy and the lysosome in PDAC metastatic progression, we co-developed an in vivo capable lysosomal enrichment that enables capture and proteomic profiling of lysosomes at different stages of tumor evolution, including early stage, late stage, and metastatic disease. Employing this strategy, we successfully captured lysosomal proteins from primary tumors (pancreas), as well as lung and liver metastases. Our preliminary analysis revealed an enrichment of resident lysosomal membrane and luminal proteins in the datasets, confirming successful isolation of intact lysosomes from these complex tissues. Additionally, we identified non-resident lysosomal proteins (termed cargo) that are enriched and co-evolve with advancing tumor stages. Notably, our results reveal distinct differences in the lysosomal proteome of tumor cells across different tissues. These findings emphasize the critical role of lysosomal function in tumor progression and suggest that targeting lysosomal components could be a promising therapeutic strategy for treating metastatic PDAC. Finally, given the challenging pharmacokinetic and pharmacodynamic properties and limited clinical efficacy of hydroxychloroquine as an autophagy/lysosomal inhibition strategy, we are now exploring novel autophagy inhibition strategies in PDAC to effectively target this pathway for clinical benefit. Citation Format: Joseph D. Mancias. Targeting autophagy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr IA-01.

Long-term outcomes in antibody-negative autoimmune encephalitis: a retrospective study.

Despite constituting one-third of suspected autoimmune encephalitis (AE) patients, antibody-negative cases without typical AE features are understudied. We aim to characterize the clinical phenotypes and long-term outcomes of "possible only" and "probable" AE cases. We conducted a retrospective analysis of adult patients evaluated at Mayo Clinic's Autoimmune Neurology Clinic (01/01/2006-12/31/2020), meeting diagnostic criteria for "possible only" or "probable but antibody-negative" AE, with ≥ 1year of follow-up. All patients underwent neural antibody testing. Among fifty-one patients, six had a change in diagnosis (non-autoimmune, 2) and were excluded from further analysis. Forty-five patients were analyzed [median age, 61years (range 20-88); female, 21 (47%); median follow-up, 36months (range 12-174)]. A nadir modified Rankin Scale (mRS) ≥ 3 was recorded in 41/45 (91%). CSF was inflammatory in 20/44 (45%) and MRI had encephalitic changes in 21/45 (47%). Unclassified neural-specific IgG staining on tissue-based assay was detected in five (11%). Two patients (4%) had paraneoplastic causation. Relapses (> 3months from onset) were noted in 14 (31%). Memory dysfunction (69%), attention deficits (38%), and gait instability (29%) were the most frequent at the last follow-up. Most patients (76%) were independent at the last follow-up and only two required an assistive device to ambulate; 11 patients (24%) had poor neurological outcome (mRS ≥ 3). Higher mRS score and gait assistance requirement at 3months were predictive of poor outcome (P ≤ 0.01). Despite significant disability at initial disease stages, most antibody-negative AE patients regain independent functioning. Early functional status and gait assistance requirements may predict long-term prognosis.

Characterization of fission and fusion mitochondrial dynamics in HD fibroblasts according to patient's severity status

Huntington's Disease (HD) is an inheritable neurodegenerative condition caused by an expanded CAG trinucleotide repeat in the HTT gene with a direct correlation between CAG repeats expansion and disease severity with earlier onset-of- disease. Previously we have shown that primary skin fibroblasts from HD patients exhibit unique phenotype disease features, including distinct nuclear morphology and perturbed actin cap linked with cell motility, that are correlated with the HD patient disease severity. Here we provide further evidence that mitochondrial fission-fusion morphology balance dynamics, classified using a custom image-based high-content analysis (HCA) machine learning tool, that improved correlation with HD severity status. This mitochondrial phenotype is supported by appropriate changes in fission-fusion biomarkers (Drp1, MFN1, MFN2, VAT1) levels in the HD patients' fibroblasts. These findings collectively point towards a dysregulation in mitochondrial dynamics, where both fission and fusion processes may be disrupted in HD cells compared to healthy controls. This study shows for the first time a methodology that enables identification of HD phenotype before patient's disease onset (Premanifest). Therefore, we believe that this tool holds a potential for improving precision in HD patient's diagnostics bearing the potential to evaluate alterations in mitochondrial dynamics throughout the progression of HD, offering valuable insights into the molecular mechanisms and drug therapy evaluation underlying biological differences in any disease stage.

Late Cancer Presentation and Increase Palliative Care Burden on Healthcare Delivery in Makurdi Benue State: A Need for Strategic Intervention

The study employed a narrative review design for the purpose of identifying statistical findings on late-stage cancer diagnosis from previously published studies to use as evidence to describe the prevailing incidence of patients’ presenting with late-stage cancer disease in Benue State. The data were searched from journals indexed in Google scholar, Semantic scholar, ResearchGate, Cross-references, PubMed, DOAJ, and Abstract journals. The statistical results obtained from the review shows that, late-stage cancer presentation among people who develop the disease is a common situation in Nigeria. Specifically, to Benue State one among the few published studies reported that patients who had presented with advanced clinical diseases as evidenced by fungating masses, palpable axillary nodes, are indications of histologically established metastatic disease. Another study applying the FIGO Staging method revealed that (81.8%) presented with advanced stage disease ranging from stage IIb–IV and stage III disease was the commonest with (42.9%) of cases. A recent study revealed that (46.7%) of patients were diagnosed with stage II disease. Whereas (49.1%) presented with advanced stage III and (1.3%) stage IV disease respectively. Based on these evidences, is the pertinent need to solicit for a strategic intervention by various stakeholders in the health system to establish a specialized palliative care service facility in Benue State. Late cancer presentation is an eligible condition for palliative care; early and routine referral of cancer patients for palliative care will accord patients the benefits of enjoying improved QOL and delay of early death from the disease.

Pro-efferocytic nanotherapies reduce vascular inflammation without inducing anemia in a large animal model of atherosclerosis

Atherosclerosis is an inflammatory disorder responsible for cardiovascular disease. Reactivation of efferocytosis, the phagocytic removal of cells by macrophages, has emerged as a translational target for atherosclerosis. Systemic blockade of the key ‘don’t-eat-me’ molecule, CD47, triggers the engulfment of apoptotic vascular tissue and potently reduces plaque burden. However, it also induces red blood cell clearance, leading to anemia. To overcome this, we previously developed a macrophage-specific nanotherapy loaded with a chemical inhibitor that promotes efferocytosis. Because it was found to be safe and effective in murine studies, we aimed to advance our nanoparticle into a porcine model of atherosclerosis. Here, we demonstrate that production can be scaled without impairing nanoparticle function. At an early stage of disease, we find our nanotherapy reduces apoptotic cell accumulation and inflammation in the atherosclerotic lesion. Notably, this therapy does not induce anemia, highlighting the translational potential of targeted macrophage checkpoint inhibitors.

The Azygos Esophageal Recess Is Not to Be Missed in Screening Lung Cancer With LDCT.

Lesion overlooking and late diagnostic workup can compromise the efficacy of low-dose CT (LDCT) screening of lung cancer (LC), implying more advanced and less curable disease stages. We hypothesized that the azygos esophageal recess (AER) of the right lower lobe (RLL) might be an area prone to lesion overlooking in LC screening. Two radiologists reviewed the LDCT examinations of all the screen-detected incident LCs observed in the active arm of 2 randomized clinical trials: ITALUNG and national lung screening trial. Those in the AER were compared with those in the remainder of the RLL for possible differences in diagnostic lag according to the Lung-RADS 1.1 recommendations, size, stage, and mortality. Six (11.7%) of 51 screen-detected incident LCs of the RLL were located in the AER. The diagnostic lag time was significantly longer (P=0.046) in the AER LC (mean 14±9mo) than in the LC in the remaining RLL (mean 7.3±1mo). Size and stage at diagnosis were not significantly different. All 6 subjects with LC in the AER and 16 (35.5%) of 45 subjects with LC in the remaining RLL (P=0.004) died of LC after a median follow-up of 12 years. Our retrospective study indicates that AER might represent a lung region of the RLL prone to have early LC overlooked due to detection or interpretation errors with possible detrimental consequences for the subject undergoing LC screening.

Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer.

Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy. In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded. A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = 0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = 0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group. Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.).

AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer.

Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.