Clinical Research and Public Health
Abstract
Background and aims: Pancreatic cancer is one of the deadliest cancers, still with low long term survival rates. Despite recent advances in treatment, it is extremely important to screen high-risk individuals in order to establish preventive and early detection measures and, in some cases, molecular driven therapeutic options. Familial pancreatic cancer (FPC) accounts for 4%-10% of pancreatic cancers. Several germline mutations are known to be related with an increased risk and might offer novel screening and therapy options. In this study, our goal was to discover the identity of a familial pancreatic cancer gene in two members of a family with FPC. Methods: Whole exome sequencing and PCR confirmation was performed on the surgical specimen and peripheral blood of an index patient and her sister in a family with high incidence of pancreatic cancer, to identify somatic and germline mutations associated with familial pancreatic cancer. Compartment-specific gene expression data and immunohistochemistry was used to characterize PALLD expression. Results: A germline mutation of the PALLD gene (NM_001166108.1:c.G154A:p.D52N) was detected in the index patient with pancreatic cancer. The identical PALLD mutation was identified in the tumor tissue of her sister. Whole genome sequencing showed similar somatic mutation patterns between the two sisters. Apart from the PALLD mutation, commonly mutated genes that characterize PDAC (KRAS and CDKN2A) were found in both tumor samples. However, the two patients harbored different somatic KRAS mutations (respectively G12D in the index patient and G12V in the index patient’s sister). Analysis for PALLD mutation in the healthy siblings of the two sisters was negative, indicating that the identified PALLD mutation might have a disease specific impact. Of note, compartment-specific gene expression data and IHC suggested a predominant role in cancer associated fibroblasts (CAFs). Conclusion: We identified a germline mutation of the palladin (PALLD) gene in two siblings in Europe, affected by familial pancreatic cancer, with a predominant function in the tumor stroma.
Authors
Lucia Liotta, Sebastian Lange, H. Carlo Maurer, Kenneth P. Olive, Rickmer Braren, Nicole Pfarr, Alexander Muckenhuber, Moritz Jesinghaus, Wilko Weichert, Katja Steiger, Sebastian Burger, Helmut Friess, Roland M. Schmid, Hana Alguel, Philipp Jost, Juliane Ramser, Christine Fischer, Anne S. Quante, Maximilian Reichert, Michael Quante
Abstract
Background: Estimates of seroprevalence to SARS-CoV-2 vary widely and may influence vaccination response. We ascertained IgG levels across a single US metropolitan site, Chicago, from June 2020 through December 2020. Methods: Participants (n=7935) were recruited through electronic advertising and received materials for a self-sampled dried blood spot assay through the mail or a minimal contact in person method. IgG to the receptor binding domain of SARS-CoV-2 was measured using an established highly sensitive and highly specific assay. Results: Overall seroprevalence was 17.9%, with no significant difference between method of contact. Only 2.5% of participants reported having had a diagnosis of COVID-19 based on virus detection, consistent with a 7-fold greater exposure to SARS-CoV-2 measured by serology than detected by viral testing. The range of IgG level observed in seropositive participants from this community survey overlapped with the range of IgG levels associated with COVID-19 cases having a documented positive PCR positive test. From a subset of those who participated in repeat testing, half of seropositive individuals retained detectable antibodies for 3-4 months. Conclusions: Quantitative IgG measurements with a highly specific and sensitive assay indicate more widespread exposure to SARS-CoV-2 than observed by viral testing. The range of IgG concentration produced from these asymptomatic exposures is similar to IgG levels occurring after documented non-hospitalized COVID-19, which is considerably lower than that produced from hospitalized COVID-19 cases. The differing ranges of IgG response, coupled with the rate of decay of antibodies, may influence response to subsequent viral exposure and vaccine.
Authors
Alexis R. Demonbreun, Thomas W. McDade, Lorenzo L. Pesce, Lauren A. Vaught, Nina L. Reiser, Elena Bogdanovic, Matthew P. Velez, Ryan R. Hsieh, Lacy M. Simons, Rana Saber, Daniel T. Ryan, Michael G. Ison, Judd F. Hultquist, John T. Wilkins, Richard T. D'Aquila, Brian Mustanski, Elizabeth M. McNally
Abstract
Introduction: Coronavirus 2019 (COVID-19) clinical course is heterogeneous, ranging from mild to severe multi-organ failure and death. In this study, we analyzed cell-free DNA (cfDNA) as a biomarker of injury to define the sources of tissue injury that contribute to such different trajectories. Methods: We conducted a multi-center prospective cohort study to enroll COVID-19 patients and collect plasma samples. Plasma cfDNA was subject to bisulfite sequencing. A library of tissue-specific DNA methylation signatures was used to analyze sequence reads to quantitate cfDNA from different tissue types. We then determined the correlation of tissue-specific cfDNA measures to COVID-19 outcomes. Similar analyses was performed for healthy controls and a comparator group of patients with respiratory syncytial virus and influenza. Results: We found markedly elevated levels and divergent tissue sources of cfDNA in COVID-19 patients compared to influenza and respiratory syncytial virus patients or healthy controls. The major sources of cfDNA in COVID-19 were hematopoietic cells, vascular endothelium, hepatocyte, adipocyte, kidney, heart and lung. cfDNA levels positively correlated with COVID-19 disease severity, c reactive protein, D-Dimer. cfDNA profile at admission identified patients who subsequently required intensive care or died during hospitalization. Furthermore, the increased cfDNA in COVID-19 patients generates excessive mitochondrial reactive oxygen species (mtROS) in renal tubular cells in a concentration-dependent manner. This mtROS production was inhibited by a toll-like receptor 9 (TLR-9)-specific antagonist. Conclusion cfDNA maps tissue injury that predict COVID-19 outcomes, and may mechanistically propagates COVID-19 induced tissue injury. Funding sources: Intramural Targeted Anti-COVID-19 grant, National Institutes of Health
Authors
Temesgen E. Andargie, Naoko Tsuji, Fayaz Seifuddin, Moon Kyoo Jang, Peter S.T. Yuen, Hyesik Kong, Ilker Tunc, Komudi Singh, Ananth Charya, Kenneth J. Wilkins, Steven D. Nathan, Andrea L. Cox, Mehdi Pirooznia, Robert A. Star, Sean Agbor-Enoh
Abstract
BACKGROUND Metabolic flexibility (MF) refers to the relative ability to utilize lipid and carbohydrate substrates and to transition between them. It is not clear whether MF is impaired in obese youth and what the determining factors are.METHODS We investigated the determinants of MF (increased respiratory exchange ratio [ΔRER] under insulin-stimulated conditions) in pubertal youth (n = 104; 15.6 ± 1.8 years) with obesity across the spectrum of glucose tolerance compared with normal weight (NW) controls, including body composition (fat-free mass [FFM], %body fat), visceral adipose fat (VAT) (MRI), glycemia, and insulin sensitivity (IS) [3-hour hyperinsulinemic-euglycemic clamp with measurement of lipolysis ([2H5] glycerol), free fatty acids (FFAs), and RER (indirect calorimetry)].RESULTS Youth with prediabetes and type 2 diabetes had lower ΔRER and oxidative and nonoxidative glucose disposal compared with NW, with no significant difference in ΔRER between NW and obese with normal glucose tolerance. In multiple regression analysis, ISFFM (β = 0.4, P = 0.004), percentage suppression of FFAs (r = 0.26, P = 0.007), and race/ethnicity (β = –0.23, P = 0.02) contributed to the variance in ΔRER (R2 = 0.30, P < 0.001) independent of percentage body fat (or VAT), sex, Tanner stage, and hemoglobin A1c.Conclusion MF is defective at the extreme of the metabolic phenotype in obese youth with dysglycemia related to a defect in IS limiting substrate utilization.FUNDING USDA/ARS Project Number 3092-51000-057.
Authors
Fida Bacha, Sara Klinepeter Bartz, Maurice Puyau, Anne Adolph, Susan Sharma
Abstract
BACKGROUND. Beige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3AR agonist mirabegron induced beige adipose tissue in obese insulin resistant subjects, and this was accompanied by improved glucose metabolism. Here, we evaluated whether pioglitazone treatment, or the combination pioglitazone and mirabegron treatment, was more effective at inducing beige adipose or BAT than mirabegron treatment alone. Both drugs were used at FDA-approved dosages. METHODS. We measured BAT by PET CT scans, beige adipose tissue by immunohistochemistry, and comprehensively characterized glucose and lipid homeostasis and insulin sensitivity by euglycemic clamp and oral glucose tolerance tests. Subcutaneous white adipose tissue, muscle fiber type composition and capillary density, lipotoxicity, and systemic inflammation were evaluated by immunohistochemistry, gene expression profiling, mass spectroscopy, and ELISAs. RESULTS. Treatment with pioglitazone or the combination of pioglitazone and mirabegron increased beige adipose tissue protein marker expression and improved insulin sensitivity and glucose homeostasis, but neither treatment induced BAT in these obese subjects. When the magnitude of the responses to the treatments were evaluated, mirabegron was found to be the most effective at inducing beige adipose tissue. Although monotherapy with either mirabegron or pioglitazone induced adipose beiging, combination treatment resulted in less beiging than either alone. The three treatments also had different effects on muscle fiber type switching and capillary density. CONCLUSION. The addition of pioglitazone to mirabegron treatment does not enhance beiging or increase BAT in obese, insulin-resistant research participants. TRIAL REGISTRATION. Clinicaltrials.gov NCT02919176. FUNDING. NIH: DK112282, P20GM103527, and CTSA grant UL1TR001998.
Authors
Brian S. Finlin, Hasiyet Memetimin, Beibei Zhu, Amy L. Confides, Hemendra J. Vekaria, Riham H. El Khouli, Zachary R. Johnson, Philip M. Westgate, Jianzhong Chen, Andrew J. Morris, Patrick G. Sullivan, Esther E. Dupont-Versteegden, Philip A. Kern
Abstract
BACKGROUND. Type 1 diabetes (T1D) is a risk factor for dementia and structural brain changes. It remains to be determined whether transient insulin deprivation that frequently occurs in insulin treated T1D individual alters brain function. METHODS. We therefore, performed functional and structural magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychological testing at baseline and following 5.4 ± 0.6 hours of insulin deprivation in 14 T1D and compared to 14 age-, sex-, and body mass index–matched, nondiabetic (ND) participants with no interventions. RESULTS. Insulin deprivation in T1D increased blood glucose, and β-hydroxybutyrate, while reducing bicarbonate levels. T1D participants showed lower baseline brain N-acetyl aspartate and myo-inositol levels but higher cortical fractional anisotropy, suggesting unhealthy neurons and brain microstructure. Although cognitive functions did not differ between T1D and ND at baseline, significant changes in fine motor speed as well as attention and short-term memory occurred following insulin deprivation in T1D participants. Insulin deprivation also reduced brain adenosine triphosphate levels and altered phosphocreatine/ adenosine triphosphate ratio. Baseline differences in functional connectivity in brain regions between T1D and ND were noted and on insulin deprivation further alterations in functional connectivity between regions especially cortical and hippocampus-caudate regions were observed. These alterations in functional connectivity correlated to brain metabolites and to changes in cognition. CONCLUSIONS. Transient insulin deprivation thus, caused alterations in executive aspects of cognitive function concurrent with functional connectivity between memory regions and the sensory cortex. These findings have important clinical implications as many patients with T1D inadvertently have periods of transient insulin deprivation. TRIAL REGISTRATION NUMBER. NCT03392441
Authors
Ana L. Creo, Tiffany M. Cortes, Hang Joon Jo, Andrea R.S. Huebner, Surendra Dasari, Jan-Mendelt Tillema, Aida N. Lteif, Katherine A. Klaus, Gregory N. Ruegsegger, Yogish C. Kudva, Ronald C. Petersen, John D. Port, K. Sreekumaran Nair
Abstract
BACKGROUND Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease that causes severe mucocutaneous fragility due to mutations in COL7A1 (encoding type VII collagen [C7]). In this phase I/IIa trial, we evaluated the safety and possible clinical efficacy of intravenous infusion of allogeneic human umbilical cord blood–derived mesenchymal stem cells (hUCB-MSCs) in patients with RDEB.METHODS Four adult and two pediatric patients with RDEB were treated with 3 intravenous injections of hUCB-MSCs (1 × 106 to 3 × 106 cells/kg) every 2 weeks and followed up for 8–24 months after treatment. The primary endpoint was safety. Secondary endpoints related to efficacy included clinical parameters, such as disease severity score, wound assessment, itch and pain score, and quality of life. C7 expression levels and inflammatory infiltrates in the skin, as well as serum levels of inflammatory markers and neuropeptides, were also assessed.RESULTS Intravenous hUCB-MSC infusions were well tolerated, without serious adverse events. Improvements in the Birmingham Epidermolysis Bullosa Severity Score, body surface area involvement, blister counts, pain, pruritus, and quality of life were observed with maximal effects at 56–112 days after treatment. hUCB-MSC administration induced M2 macrophage polarization and reduced mast cell infiltration in RDEB skin. Serum levels of substance P were decreased after therapy. Increased C7 expression was observed at the dermoepidermal junction in 1 of 6 patients at day 56.CONCLUSION To the best of our knowledge, this is the first clinical trial of systemic administration of allogeneic hUCB-MSCs in patients with RDEB, demonstrating safety and transient clinical benefits.TRIAL REGISTRATION ClinicalTrials.gov NCT04520022.FUNDING This work was supported by Daewoong Pharmaceutical Co. Ltd. and Kangstem Biotech Co. Ltd.
Authors
Sang Eun Lee, Seung-Ju Lee, Song-Ee Kim, Kinam Kim, Boyoung Cho, Kyounghwan Roh, Soo-Chan Kim
Abstract
Background: Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined. Methods: We measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. ICU admission, intubation, vasopressor and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristics and area under-the-curve assessment were used to compare MT-DNA levels to established and emerging inflammatory markers of COVID-19. Results: Circulating MT-DNA levels were highly elevated in patients who eventually died, required ICU admission, intubation, vasopressor use or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA is an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels have a similar or superior area-under-the curve when compared against clinically-established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy. Conclusions: These results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes. Funding: This project was supported by Washington University Institute of Clinical Translational Sciences COVID-19 Research Program. Sample procurement and patient outcome data collection was supported by the Washington University ICTS NIH grant UL1TR002345.
Authors
Davide Scozzi, Marlene Cano, Lina Ma, Dequan Zhou, Ji Hong Zhu, Jane A. O’Halloran, Charles W. Goss, Adriana M. Rauseo, Zhiyi Liu, Sanjaya Kumar Sahu, Valentina Peritore, Monica Rocco, Alberto Ricci, Rachele Amodeo, Laura Aimati, Mohsen Ibrahim, Ramsey R. Hachem, Daniel Kreisel, Philip A. Mudd, Hrishikesh S. Kulkarni, Andrew E. Gelman
Abstract
BACKGROUND Although CDK4/6 inhibitors are an established treatment for hormone receptor–positive, HER2-negative metastatic breast cancers, their benefit in other malignancies remains limited.METHODS We investigated factors associated with clinical outcomes from CDK4/6 inhibitor–based therapy among patients with G1/S phase cell-cycle alterations (CDK4/6 amplifications, CCND1/2/3 amplifications, or CDKN2A/B alterations).RESULTS Overall, 2457 patients with diverse solid tumors that underwent clinical-grade, next-generation sequencing (182–465 genes) and therapy outcome of (non–breast cancer) patients treated with matched CDK4/6 inhibitors were analyzed. G1/S phase cell-cycle alterations occurred in 20.6% (507 of 2457) of patients; 99% of those patients (n = 501) harbored ≥1 characterized co-alteration (median, 4; range, 0–24). In 40 patients with G1/S phase cell-cycle alterations given CDK4/6 inhibitors as part of their regimen, significantly longer median progression-free survival (PFS) was observed when CDK4/6 inhibitor–based therapies matched a larger proportion of tumor alterations, often because CDK4/6 inhibitors were administered together with other drugs that were matched to genomic co-alterations, hence achieving a high matching score (high vs. low [≥50% vs. <50%] matching score, PFS, 6.2 vs. 2.0 months, P < 0.001 [n = 40] [multivariate]) and higher rate of stable disease ≥6 months or an objective response (57% vs. 21%, P = 0.048).CONCLUSION In summary, in cell-cycle–altered cancers, matched CDK4/6 inhibitors, as part of an individualized regimen targeting a majority of genomic alterations, was independently associated with longer PFS.TRIAL REGISTRATION ClinicalTrials.gov NCT02478931.FUNDING Joan and Irwin Jacobs Fund, National Cancer Institute (P30 CA023100, R01 CA226803), and the FDA (R01 FD006334).
Authors
Shumei Kato, Ryosuke Okamura, Jacob J. Adashek, Noor Khalid, Suzanna Lee, Van Nguyen, Jason K. Sicklick, Razelle Kurzrock
Abstract
Background. Neuronal hyper-excitability characterizes the early stages of Alzheimer’s disease (AD). In animals, early misfolded tau and amyloid-beta (Aβ) protein accumulation, both central to AD neuropathology, promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and Aβ aggregates are first detected, respectively, in the brainstem and frontomedial and temporobasal cortices, decades prior to the onset of AD cognitive symptoms. Whether cortical excitability is related to early brainstem tau, and its associated neuroinflammation, and cortical Aβ aggregations remains unknown. Methods. We probed frontal cortex excitability, using transcranial magnetic stimulation combined with electroencephalography, in a sample of 64 healthy late middle-aged individuals (50-69 y; 45 women). We assessed whole-brain [18F]THK5351 positron emission tomography (PET) uptake as a proxy measure of tau/neuroinflammation, and whole-brain Aβ burden with [18F]Flutemetamol or [18F]Florbetapir radiotracers. Results. We find that higher [18F]THK5351 uptake in a brainstem monoaminergic compartment is associated with increased cortical excitability (r = .29, p = .02). By contrast, [18F]THK5351 PET signal in the hippocampal formation, although strongly correlated with brainstem signal in whole-brain voxel-based quantification analyses (pFWE-corrected < .001), was not significantly associated with cortical excitability (r = .14, p = .25). Importantly, no significant association was found between early Aβ cortical deposits and cortical excitability (r = -.20, p = .11). Conclusion. These findings reveal potential brain substrates for increased cortical excitability in preclinical AD and may constitute functional in vivo correlates of early brainstem tau accumulation and neuroinflammation in humans. Trial registration. EudraCT 2016-001436-35. Funding. F.R.S.-FNRS Belgium, Wallonie-Bruxelles International, ULiège, Fondation Simone et Pierre Clerdent, European Regional Development Fund.
Authors
Maxime Van Egroo, Daphne O. Chylinski, Justinas Narbutas, Gabriel Besson, Vincenzo Muto, Christina Schmidt, Davide Marzoli, Paolo Cardone, Nora Vandeleene, Martin Grignard, André Luxen, Eric Salmon, Christian Lambert, Christine Bastin, Fabienne Collette, Christophe Phillips, Pierre Maquet, Mohamed Ali Bahri, Evelyne Balteau, Gilles Vandewalle
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