Clinical Medicine
Abstract
Background: Innate immune activation impacts lung transplant outcomes. Dectin-1 is an innate receptor important for pathogen recognition. We hypothesized that genotypes reducing dectin-1 activity would be associated with infection, graft dysfunction, and death in lung transplant recipients. Methods: We assessed the rs16910526 CLEC7A gene polymorphism Y238X, which results in dectin-1 truncation, in 321 lung allograft recipients at a single institution and in 1,129 lung allograft recipients in the multi-center lung transplant outcomes group (LTOG) cohort. Differences in dectin-1 mRNA, cytokines, protein levels, immunophenotypes, and clinical factors were assessed. Results: Y238X carriers had decreased dectin-1 mRNA expression (P = 0.0001), decreased soluble dectin-1 protein concentrations in BAL (P = 0.008) and plasma (P = 0.04), and decreased monocyte surface dectin-1 (P = 0.01) compared to wild type subjects. Y238X carriers had an increased risk of fungal pathogens (HR 1.17, CI 1.0 – 1.4), an increased risk of graft dysfunction or death (HR 1.6, CI 1.0 – 2.6), as well increased mortality in the UCSF cohort (HR 1.8, CI 1.1 – 3.8) and in the LTOG cohort (HR 1.3, CI 1.1 – 1.6), compared to CLEC7A wildtype subjects. Conclusion: Increased rates of graft dysfunction and death associated with this dectin-1 polymorphism may be amplified by immunosuppression that drives higher fungal burden from compromised pathogen recognition. Funding: Project funding came from the UCSF Nina Ireland Program for Lung Health (NIPLH) Innovative Grant program, award number IK2CX001034 from the Clinical Sciences Research & Development Service of the VA Office of Research and Development, and the Joel D. Cooper Career Development Award from the International Society for Heart and Lung Transplantation.
Authors
Daniel R. Calabrese, Ping Wang, Tiffany Chong, Jonathan Hoover, Jonathan P. Singer, Dara Torgerson, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel Dugger, Jason D. Christie, LTOG investigators, John R. Greenland
Abstract
Background: Myeloid-derived suppressor cells (MDSCs) are elevated in glioblastoma (GBM) patient circulation, present in tumor tissue, and associated with poor prognosis. While low-dose chemotherapy reduces MDSCs in preclinical models, the use of this strategy to reduce MDSCs in GBM patients has yet to be evaluated. Methods: A phase 0/1 dose-escalation clinical trial was conducted in recurrent glioblastoma patients treated 5-7 days prior to surgery with low-dose chemotherapy via capecitabine followed by concomitant low-dose capecitabine and bevacizumab. Clinical outcomes, including progression-free and overall survival, were measured, along with safety and toxicity profiles. Over the treatment time course, circulating MDSC levels were measured by multi-parameter flow cytometry, and tumor tissue immune profiles were assessed via mass cytometry time-of-flight. Results: A total of 11 patients were enrolled across escalating dose cohorts of 150, 300, and 450 mg bid. No serious adverse events related to the drug combination were observed. Compared to pre-treatment baseline, circulating MDSCs were found to be higher after surgery in the 150 mg treatment arm and lower in the 300 mg and 450 mg treatment arms. Increased cytotoxic immune infiltration was observed after low-dose capecitabine compared to untreated GBM patients in the 300 mg and 450 mg treatment arms. Conclusions: Low-dose, metronomic capecitabine in combination with bevacizumab is well tolerated in GBM patients and was associated with a reduction in circulating MDSC levels and an increase in cytotoxic immune infiltration into the tumor microenvironment. Trial registration: NCT02669173
Authors
David M. Peereboom, Tyler J. Alban, Mathew M. Grabowski, Alvaro G. Alvarado, Balint Otvos, Defne Bayik, Gustavo Roversi, Mary McGraw, Pengjing Huang, Alireza M. Mohammadi, Harley I. Kornblum, Tomas Radivoyevitch, Manmeet S. Ahluwalia, Michael A. Vogelbaum, Justin D. Lathia
Abstract
Background. The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. Methods. To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry. Results. We identified a genome-wide significant (p<5E-8) locus in the KCND3 (potassium voltage gated channel subfamily D member 3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, p=7.7E-12), but did not reveal additional loci. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery. Conclusions. In this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies. Funding. For detailed information per study, see Acknowledgments.
Authors
Alexander Teumer, Teresa Trenkwalder, Thorsten Kessler, Yalda Jamshidi, Marten E. van den Berg, Bernhard Kaess, Christopher P. Nelson, Rachel Bastiaenen, Marzia De Bortoli, Alessandra Rossini, Isabel Deisenhofer, Klaus Stark, Solmaz Assa, Peter S. Braund, Claudia Cabrera, Anna F. Dominiczak, Martin Gögele, Leanne M. Hall, M. Arfan Ikram, Maryam Kavousi, Karl J. Lackner, Christian Müller, Thomas Münzel, Matthias Nauck, Sandosh Padmanabhan, Norbert Pfeiffer, Tim D. Spector, Andre G. Uitterlinden, Niek Verweij, Uwe Völker, Helen R. Warren, Mobeen Zafar, Stephan B. Felix, Jan A. Kors, Harold Snieder, Patricia B. Munroe, Cristian Pattaro, Christian Fuchsberger, Georg Schmidt, Ilja M. Nolte, Heribert Schunkert, Peter Pramstaller, Philipp S. Wild, Pim van der Harst, Bruno H. Stricker, Renate B. Schnabel, Nilesh J. Samani, Christian Hengstenberg, Marcus Dörr, Elijah R. Behr, Wibke Reinhard
Abstract
BACKGROUND Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridioides difficile infection (rCDI) in adults and children, but donor stool samples are currently screened for only a limited number of potential pathogens. We sought to determine whether putative procarcinogenic bacteria (enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, and Escherichia coli harboring the colibactin toxin) could be durably transmitted from donors to patients during FMT.METHODS Stool samples were collected from 11 pediatric rCDI patients and their respective FMT donors prior to FMT as well as from the patients at 2–10 weeks, 10–20 weeks, and 6 months after FMT. Bacterial virulence factors in stool DNA extracts and stool cultures were measured by quantitative PCR: Bacteroides fragilis toxin (bft), Fusobacterium adhesin A (fadA), and Escherichia coli colibactin (clbB).RESULTS Four of 11 patients demonstrated sustained acquisition of a procarcinogenic bacteria. Whole genome sequencing was performed on colony isolates from one of these donor/recipient pairs and demonstrated that clbB+ E. coli strains present in the recipient after FMT were identical to a strain present in the donor, confirming strain transmission. Conversely, 2 patients exhibited clearance of procarcinogenic bacteria following FMT from a negative donor.CONCLUSION Both durable transmission and clearance of procarcinogenic bacteria occurred following FMT, suggesting that additional studies on appropriate screening measures for FMT donors and the long-term consequences and/or benefits of FMT are warranted.FUNDING Crohn’s & Colitis Foundation, the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University School of Medicine, the National Cancer Institute, and the Canadian Institutes of Health Research.
Authors
Julia L. Drewes, Alina Corona, Uriel Sanchez, Yunfan Fan, Suchitra K. Hourigan, Melissa Weidner, Sarah D. Sidhu, Patricia J. Simner, Hao Wang, Winston Timp, Maria Oliva-Hemker, Cynthia L. Sears
Abstract
BACKGROUND Recessive dystrophic epidermolysis bullosa (RDEB) patients have mutations in the COL7A1 gene and thus lack functional type VII collagen (C7) protein; they have marked skin fragility and blistering. This single-center phase 1/2a open-label study evaluated the long-term efficacy, safety, and patient-reported outcomes in RDEB patients treated with gene-corrected autologous cell therapy.METHODS Autologous keratinocytes were isolated from participant skin biopsies. Epidermal sheets were prepared from cells transduced with a retrovirus carrying the full-length human COL7A1 gene. These gene-corrected autologous epidermal sheets measured 5 × 7 cm (35 cm2) and were transplanted onto 6 wound sites in each of 7 adult participants (n = 42 sites total) from 2013 to 2017. Participants were followed for 2 to 5 years.RESULTS No participants experienced any serious related adverse events. Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001). At year 1, 68% (26 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.025). At year 2, 71% (27 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.019).CONCLUSION C7 expression persisted up to 2 years after treatment in 2 participants. Treated wounds with 50% or greater healing demonstrated improvement in patient-reported pain, itch, and wound durability. This study provides additional data to support the clinically meaningful benefit of treating chronic RDEB wounds with ex vivo, C7 gene–corrected autologous cell therapy. This approach was safe and promoted wound healing that was associated with improved patient-reported outcomes.TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT01263379.FUNDING Epidermolysis Bullosa Research Partnership, Epidermolysis Bullosa Medical Research Foundation, NIH R01 AR055914, Office of Research and Development at the Palo Alto Veteran’s Affairs Medical Center, and the Dermatology Foundation.
Authors
Shaundra Eichstadt, Melissa Barriga, Anusha Ponakala, Claudia Teng, Ngon T. Nguyen, Zurab Siprashvili, Jaron Nazaroff, Emily S. Gorell, Albert S. Chiou, Lisa Taylor, Phuong Khuu, Douglas R. Keene, Kerri Rieger, Rohit K. Khosla, Louise K. Furukawa, H. Peter Lorenz, M. Peter Marinkovich, Jean Y. Tang
Abstract
Background: Hydroxymethyl-glutaryl-coenzyme A reductase inhibitors (‘statins’) are prescribed to millions of people. Statins are anti-inflammatory independent of their cholesterol-reducing effects. To date, most reports on the immune effects of statins have assayed a narrow array of variables and have focused on cell lines, rodent models, or patient cohorts. We sought to define the effect of rosuvastatin on the ‘immunome’ of healthy, normocholesterolemic subjects. Methods: Prospective study of rosuvastatin (20 mg/day x 28 days) in 18 statin-naïve adults with low density lipoprotein-cholesterol <130 mg/dL. A panel of >180 immune/biochemical/endocrinologic variables was measured at baseline, and days 14, 28, and 42 (14 days after drug withdrawal). Drug effect was evaluated using linear mixed effects models. Potential interactions between drug and baseline high-sensitivity C-reactive protein (hsCRP) were evaluated. Results: A wide array of immune measures changed (nominal p<0.05) during rosuvastatin treatment, although the changes were modest in magnitude and few met a false discovery rate of 0.05. Among changes noted were a concordant increase in pro-inflammatory cytokines (IFNγ, IL-1β, IL-5, IL-6, TNFα) and peripheral blood neutrophil frequency, and a decline in activated T regulatory cell frequency. Several drug effects were significantly modified by baseline hsCRP, and some did not resolve after drug withdrawal. Among other unexpected rosuvastatin effects were changes in erythrocyte indices, glucose-regulatory hormones, CD8+ T cells, and haptoglobin. Conclusion: Rosuvastatin induces modest changes in immunologic and metabolic measures in normocholesterolemic subjects, with several effects dependent upon baseline CRP. Future, larger studies are warranted to validate these changes and their physiological significance.
Authors
Peer W. F. Karmaus, Min Shi, Shira Perl, Angélique Biancotto, Julián Candia, Foo Cheung, Yuri Kotliarov, Neal Young, Michael B. Fessler
Abstract
Background: In this study, we aimed to identify the lipidomic predictors of early type-2 diabetic kidney disease (DKD) progression which are currently undefined DKD progression. Methods: This longitudinal study included 92 American Indians with type-2 diabetes. Serum lipids (406 from 18 classes) were quantified using mass spectrometry from baseline samples when iothalamate glomerular filtration rate (GFR) was ≥90 mL/min. Affymetrix GeneChip Array was used to measure renal transcript expression. DKD Progression was defined as ≥40% decline in GFR during follow up. Results: Participants had a mean age of 45±9 years and median urine albumin-creatinine ratio of 43 (interquartile range 11 to 144). The 32 progressors had significantly higher relative abundance of polyunsaturated triacylglycerols (TAG)s and a lower abundance of C16-20 acylcarnitines (AC)s (p<0.001). In a Cox regression model the main effect terms of unsaturated free fatty acids and phosphatidylethanolamines and the interaction terms of C16-20 ACs and short, low-double-bond TAGs by categories of albuminuria independently predicted progression of DKD. Renal expression of acetyl-CoA carboxylase encoding gene (ACACA) correlated with serum diacylglycerols in the glomerular compartment (r=0.36, p=0.006), and with low-double-bond TAGs in the tubulointerstitial compartment (r=0.52, p<0.001). Conclusion: Collectively, the findings reveal a previously unrecognized link between lipid markers of impaired mitochondrial β-oxidation and enhanced lipogenesis, with DKD progression, in individuals with preserved GFR. Renal acetyl-CoA carboxylase activation accompanies these lipidomic changes and suggests that it may be the underlying mechanism linking lipid abnormalities to DKD progression. Funding: R24DK082841, K08DK106523, R03DK121941, P30DK089503, P30DK081943, P30DK020572
Authors
Farsad Afshinnia, Viji Nair, Jiahe Lin, Thekkelnaycke M. Rajendiran, Tanu Soni, Jaeman Byun, Kumar Sharma, Patrice E. Fort, Thomas W. Gardner, Helen C. Looker, Robert G. Nelson, Frank C. Brosius, Eva L. Feldman, George Michailidis, Matthias Kretzler, Subramaniam Pennathur
Abstract
BACKGROUND Cytokine biomarkers have already been used to predict acute graft-versus-host disease (aGVHD) onset, nonrelapse mortality, and overall survival in human and mouse models, but the consistency of the consequences between patients and mice has not been evaluated. Furthermore, no study about any biomarker or biomarker panel for aGVHD grading or steroid sensitivity of aGVHD patients simultaneously has been reported.METHODS Here we established an aGVHD mouse model and explored the relation between aGVHD onset and variations of some cytokines. Based on the results and latest progress, we selected 16 cytokines and compared their serum variations in aGVHD patients and non-aGVHD patients after allogeneic hematopoietic stem cell transplantation. Using protein microarray, we explored the relation between the cytokine levels and aGVHD-related events (onset, grading, and steroid sensitivity).RESULTS The increase of chemokine levels in murine aGVHD was very consistent with that of patients. We found obviously higher levels of IL-2, IL-4, Elafin, sST2, TLR4, and TNF-α, and lower levels of TGF-β in both aGVHD mouse models and aGVHD patients. In addition, patients with severe aGVHD showed increased IL-6, TLR4, TNF receptor 1 (TNFR1), and Elafin and decreased TGF-β. TLR4 and TNFR1 were significantly increased in steroid-refractory aGVHD patients compared with steroid-effective patients (P < 0.05).CONCLUSION A combination of TLR4, TNFR1, TGF-β, and Elafin could be a new 4-biomarker panel to assist aGVHD diagnosis, grading, and evaluation of steroid sensitivity for clinical aGVHD patients.TRIAL REGISTRATION ChiCTR1900022292 “Clinical Research of Umbilical Cord–Derived Mesenchymal Stromal Cells in the Prophylaxis of Graft-Versus-Host Disease After HLA-Haploidentical Stem-Cell Transplantation.”FUNDING National Key Research Program, National Natural Science Foundation of China, Chongqing Social Career and People’s Livelihood Security Science and Technology Innovation Project, Fundamental and Frontier Research Program of Chongqing, and Foundation of Xinqiao Hospital.
Authors
Xiaoping Li, Ting Chen, Qiangguo Gao, Wei Zhang, Yunshuo Xiao, Wen Zhu, Lingyu Zeng, Zhenyu Li, Shijie Yang, Rui Wang, Xiaoqi Wang, Yimei Feng, Xi Zhang
Abstract
Background: Circadian timing of treatments can largely improve tolerability and efficacy in patients. Thus, drug metabolism and cell cycle are controlled by molecular clocks in each cell, and coordinated by the core body temperature 24-hour rhythm, which is generated by the hypothalamic pacemaker. Individual circadian phase is currently estimated with questionnaire-based chronotype, center-of-rest time, dim light melatonin onset (DLMO), or timing of CBT maximum (acrophase) or minimum (bathyphase). Methods: We aimed at circadian phase determination and read-out during daily routine in volunteers stratified by sex and age. We measured (i) chronotype; (ii) q1min CBT using two electronic pills swallowed 24-hours apart; (iii) DLMO through hourly salivary samples from 18:00 to bedtime; (iv) q1min accelerations and surface temperature at anterior chest level for seven days, using a tele-transmitting sensor. Circadian phases were computed using cosinor and Hidden-Markov modelling. Multivariate regression identified the combination of biomarkers that best predicted core temperature circadian bathyphase. Results: Amongst the 33 participants, individual circadian phases were spread over 5h10min (DLMO), 7h (CBT bathyphase) and 9h10 min (surface temperature acrophase). CBT bathyphase was accurately predicted, i.e. with an error <1h for 78.8% of the subjects, using a new digital health algorithm (INTime), combining time-invariant sex and chronotype score, with computed center-of-rest time and surface temperature bathyphase (adjusted R-squared = 0.637). Conclusion: INTime provided a continuous and reliable circadian phase estimate in real time. This model helps integrate circadian clocks into precision medicine and will enable treatment timing personalisation following further validation.
Authors
Sandra Komarzynski, Matei Bolborea, Qi Huang, Bärbel Finkenstädt, Francis Lévi
Abstract
Background. HIV-infected patients with poor virologic control and multi-drug resistant virus have limited therapeutic options. The current study was undertaken to evaluate the safety, immunologic effects, and antiviral activity of peripheral lymphocytes transferred from an elite controller, whose immune system is able to control viral replication without antiretroviral medications, to an HLA-B*2705-matched progressor. Methods. Approximately 22 billion cells were collected from an elite controller by lymphaphersis and infused within 6 hours into a recipient with a pre-infusion CD4+ T cell count of 10 cells/μL (1%) and HIV plasma viral load of 114,993 copies/mL. Results. Donor cells were cleared from the recipient's peripheral blood by day 8. A transient decrease in viral load to 58,421 (day 3) was followed by a rebound to 702,972 (day 6) before returning to baseline values by day 8. The decreased viral load was temporally associated with peak levels of donor T cells, including CD8+ T cells that had high levels of expression of Ki67, perforin, and granzyme B. Notably, recipient CD8+ T cells also expressed increased expression of these markers, especially in HIV-specific tetramer positive cells. Conclusions. These results suggest that the adoptive transfer of lymphocytes from an HIV-infected elite controller to an HIV-infected patient with progressive disease may be able to perturb the immune system of the recipient in both positive and negative ways.
Authors
Stephen A. Migueles, Cheryl Chairez, Siying Lin, Noah V. Gavil, Danielle M. Rosenthal, Milad Pooran, Ven Natarajan, Adam Rupert, Robin Dewar, Tauseef Rehman, Brad T. Sherman, Joseph Adelsberger, Susan Leitman, David Stroncek, Caryn G. Morse, Mark Connors, H. Clifford Lane, Joseph A. Kovacs
No posts were found with this tag.
