BACKGROUND. Studies in cell cultures and rodents suggest that toll-like receptor (TLR)4 is involved in the pathogenesis of insulin resistance, but direct data in humans are limited. We tested the hypothesis that pharmacologic blockade of TLR4 with the competitive inhibitor eritoran would improve insulin resistance in humans. METHODS. In Protocol I, 10 lean, healthy subjects received the following 72-h intravenous (I.V.) infusions in a randomized crossover design: saline (30 ml/h)+vehicle; Intralipid® (30 ml/h)+vehicle; or Intralipid® (30 ml/h)+eritoran (12 mg I.V. every 12 h). In Protocol II, 9 obese, non-diabetic subjects received eritoran (12 mg I.V. every 12 h) or vehicle for 72 h, also in a randomized crossover design. The effects of eritoran were assessed with a euglycemic, hyperinsulinemic clamp. RESULTS. In Protocol I, lipid infusion significantly decreased peripheral insulin sensitivity (M value) by 14% and increased fasting plasma glucose (FPG), fasting plasma insulin (FPI) and HOMA insulin resistance index (HOMA-IR) by 7%, 22%, and 26%, respectively. Eritoran did not prevent lipid-induced alterations in these metabolic parameters. Eritoran also failed to improve any baseline metabolic parameters (M, FPG, FPI, HOMA-IR) in obese, insulin-resistant subjects (Protocol II). CONCLUSIONS. Acute TLR4 inhibition with eritoran did not protect against lipid-induced insulin resistance. Short-term eritoran administration also failed to improve obesity-associated insulin resistance. These data do not support a role for TLR4 in insulin resistance. Future studies with a different class of TLR4 inhibitors, longer drug exposure, and/or lipid-enhancing interventions richer in saturated fats may be needed to further clarify the role of TLR4 on metabolic dysfunction in humans. TRIAL REGISTRATIONS. ClinicalTrials.gov NCT02321111, NCT02267317 FUNDING. NIH grants R01DK080157, P30AG044271, P30AG013319 and UL1TR002645.
Hanyu Liang, Nattapol Sathavarodom, Claudia Colmenares, Jonathan Gelfond, Sara E. Espinoza, Vinutha Ganapathy, Nicolas Musi
BACKGROUND. Cognitive impairment is a common symptom of Parkinson’s Disease (PD), which increases in risk and severity as the disease progresses. The stage at which patients exhibit cognitive deficit on neuropsychological tests but daily social and occupational functioning is unaffected is termed mild cognitive impairment (MCI). Currently, an unmet clinical need is accurately predicting the risk of progression from the MCI stage to PDD which negatively affects the patients quality of life and incurs a greater cost on society and caregivers. METHODS. We investigated the use of a supervised learning algorithm called Support Vector Machine (SVM) to retrospectively stratify patients based on brain fluorodeoxyglucose (FDG) –PET. Of 43 PD-MCI patients scanned at baseline, 23 progressed to PDD within a 5 year follow-up period, whereas 20 remained stable MCI. The baseline FDG-PET scans were used to train an SVM model which optimally separated patients as PDD converters vs. stable MCI with 95% sensitivity and 91% specificity. RESULTS. The high classification performance was confirmed with 10-fold cross-validation (87% sensitivity and 85% specificity). The hyperplane of the resulting SVM model was topographically characterized by hypometabolism in the posterior temporal and parietal lobes and hypermetabolism in the anterior cingulum, putamen, insular gyrus, mesiotemporal lobe, postcentral gyrus and supplementary motor area. The statistical significance of the hyperplane topology was verified by a permutation test, suggesting that these brain metabolic signatures robustly predicted PDD conversions within 5 years from PD-MCI status. The performance of the SVM model was tested on an independent dataset from two brain imaging centers located in Seoul (South Korea) and Winnipeg (Canada) which confirmed that the model is also sensitive to later stage PDD (17 of 19; 89% sensitivity) and Dementia with Lewy Bodies (DLB; 16 of 17; 94% sensitivity). Only 12% of cognitively normal PD patients (2 of 17) were classified as PDD converters while none of the 18 normal control subjects were classified as such. Finally, anti-PD medication status did not change the SVM classification of the another set of 10 PD patients (3 of 10 patients were classified as PDD converters) who were scanned twice ON and OFF medication. CONCLUSIONS. These results potentially indicate that the proposed FDG-PET-based SVM classifier has high utility for providing accurate prognosis of dementia development in PD-MCI patients.
Samuel Booth, Kye Won Park, Chong Sik Lee, Ji Hyun Ko
BACKGROUND. Herpes simplex virus lymphadenitis (HSVL) is an unusual presentation of HSV reactivation in chronic lymphocytic leukemia (CLL) patients characterized by systemic symptoms and no herpetic lesions. The immune responses during HSVL have not been studied. METHODS. Peripheral blood and lymph node samples of a patient with HSVL were obtained. HSV-2 viral load, antibody levels, B and T cell responses, cytokine levels, and tumor burden were measured. RESULTS. This patient showed HSV-2 viremia for at least 6 weeks. During this period, she had a robust HSV-specific antibody response with neutralizing and antibody-dependent cellular phagocytosis activity. Activated (HLA-DR+, CD38+) CD4+ and CD8+ T cells increased 18-fold and HSV-specific CD8+ T cells were detected in the blood at higher numbers. HSV-specific B and T cell responses in the lymph node were also detected. Markedly elevated levels of pro-inflammatory cytokines in the blood were also observed. Surprisingly, a sustained decrease in CLL tumor burden without CLL-directed therapy was observed with this and also a prior episode of HSVL. CONCLUSION. HSVL should be considered as part of the differential diagnosis in CLL patients who present with signs and symptoms of aggressive lymphoma transformation. An interesting finding was the sustained tumor control after 2 episodes of HSVL in this patient. This tumor burden reduction may be due to the HSV-specific response serving as an adjuvant for activating tumor-specific or bystander T cells. Studies in additional CLL patients are needed to confirm and extend these findings. FUNDING. National Institutes of Health and Winship Cancer Institute.
Andres Chang, Anton M. Sholukh, Andreas Wieland, David L. Jaye, Mary Carrington, Meei-Li Huang, Hong Xie, Keith R. Jerome, Pavitra Roychoudhury, Alexander L. Greninger, Jean L. Koff, Jonathon B. Cohen, David M. Koelle, Lawrence Corey, Christopher R. Flowers, Rafi Ahmed
BACKGROUND. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here we explored the safety, feasibility and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous (auto)-TILs following concurrent chemoradiotherapy (CCRT) in CC patients with locally advanced disease. METHODS. Twenty-seven CC patients with stage III to IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practices (GMP) conditions and then infused after CCRT plus intramuscular interleukin (IL)-2 injections. RESTULTS. From 27 patients, TILs were successfully expanded from 20 patients, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there was no treatment-related mortality. Nine of 12 patients (75.0%) attained complete response, with a disease control duration of 9 to 22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of CC patients at baseline were correlated with the clinical response. CONCULSION. TIL-based ACT following CCRT was safe in an academic center setting, with potential effective responses in locally advanced CC patients. ‘Hot’ inflammatory immune environments are beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy. TRIAL REGISTRATION. ClinicalTrials.gov NCT04443296. FUNDING. Natinoal Key R&D Program: Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Provinve Sci-Tech International Key Program; the National Natural Science Foundation of China.
He Huang, Caiping Nie, Xiu-feng Liu, Bin Song, Jian-hui Yue, Jingxiao Xu, Jia He, Kui Li, Yan-ling Feng, Ting Wan, Min Zheng, Yanna Zhang, Wei-jun Ye, Jun-dong Li, Yan-fang Li, Jun-yun Li, Xin-Ping Cao, Zhi-min Liu, Xiao-Shi Zhang, Qing Liu, Xi Zhang, Ji-Hong Liu, Jiang Li
Background: Head and neck squamous cell carcinoma not associated with human papillomavirus (HPV-unrelated HNSCC) is associated with high rates of recurrence and poor survival. Methods: We conducted a clinical trial in 14 patients with newly diagnosed, HPV-unrelated HNSCC to evaluate the safety and efficacy of neoadjuvant bintrafusp alfa, a bifunctional fusion protein that blocks programmed death-ligand 1 (PD-L1) and neutralizes transforming growth factor-beta (TGF-). Results: Bintrafusp alfa was well tolerated, and no treatment-associated surgical delays or complications occurred. Objective pathologic responses were observed and 12 of 14 patients (86%) were alive and disease free at one year. Alterations in regulatory T cell infiltration and spatial distribution relative to proliferating CD8 T cells indicated reversal of Treg immunosuppression in the primary tumor. Detection of neoepitope-specific tumor T cell responses, but not viral-specific responses, correlated with development of a pathologic response. Detection of neoepitope-specific responses and pathologic responses in tumors was not correlated with genomic features or tumor antigenicity but was associated with reduced pre-treatment myeloid cell tumor infiltration. These results indicate that dual PD-L1 and TGF- blockade can safely enhance tumor antigen-specific immunity and highlight the feasibility of multi-mechanism neoadjuvant immunotherapy in patients with HPV-unrelated HNSCC. Conclusion: Our studies provide new insight into the ability of neoadjuvant immunotherapy to induce polyclonal neoadjuvant-specific T cell responses in tumors and suggest that features of the tumor microenvironment, such as myeloid cell infiltration, may be a major determinant of enhanced anti-tumor immunity following such treatment.
Jason M. Redman, Jay Friedman, Yvette Robbins, Cem Sievers, Xinping Yang, Wiem Lassoued, Andrew Sinkoe, Antonios Papanicolau-Sengos, Chyi-Chia R. Lee, Jennifer L. Marte, Evrim B. Turkbey, Wojciech Mydlarz, Arjun S. Joshi, Nyall R. London, Jr., Matthew Pierce, Rodney J. Taylor, Steven Hong, Andrew Nguyen, Patrick Soon-Shiong, Jeffrey Schlom, James L. Gulley, Clint T. Allen
BACKGROUND. Immune checkpoint inhibitors have modest activity in ovarian cancer (OC). To augment their activity, we used priming with a hypomethylating agent guadecitabine in a phase II study. METHODS. Eligible patients had platinum-resistant OC, normal organ function, measurable disease, and up to 5 prior regimens. Treatment was guadecitabine 30mg/m2 days 1-4, and pembrolizumab 200mg iv day 5, every 21 days. The primary endpoint was response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment. RESULTS. Among 35 evaluable patients, there were 3 partial responses (8.6%) and 8 (22.9%) patients with stable disease, resulting in clinical benefit rate (CBR) of 31.4% (95% CI: 16.9 – 49.3%). Median duration of clinical benefit was 6.8 months. Long-interspersed element-1 (LINE1) was hypomethylated in post-treatment PBMCs; methylomic and transcriptomic analyses showed activation of anti-tumor immunity in post-treatment biopsies. High dimensional immune profiling of PBMCs showed higher frequency of naive and/or central memory CD4+ T cells, and of classical monocytes in patients with durable CBR. Higher baseline density of CD8+ T and CD20+ B cells and presence of tertiary lymphoid structures in tumors were associated with durable CBR. CONCLUSION. Epigenetic priming using a hypomethylating agent with an immune check point inhibitor was feasible and induced durable clinical benefit associated to immune responses in selected patients with recurrent ovarian cancer. TRIAL REGISTRATION. ClinicalTrials.gov registration number: NCT02901899. FUNDING. USAMRMC/CDMRP W81XWH170141 (to DM and BZ), the Diana Princess of Wales endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center (to DM), the Walter S. and Lucienne Driskill Immunotherapy Research funds (to BZ), Astex Pharmaceutical, Inc., Merck & Co., Inc., NCI CCSG P30 CA060553 (to the Robert H. Lurie Comprehensive Cancer Center), NCI CCSG P30 CA060553 (to NUSeq Core facility), NCI CA060553 (to NU Flow Cytometry Core Facility).
Siqi Chen, Ping Xie, Matthew Cowan, Hao Huang, Horacio Cardenas, Russell Keathley, Edward J. Tanner, Gini F. Fleming, John W. Moroney, Alok Pant, Azza M. Akasha, Ramana V. Davuluri, Masha Kocherginsky, Bin Zhang, Daniela Matei
BACKGROUND Multiple islet autoantibodies (AAbs) predict the development of type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in only approximately 15% of individuals who are positive for single AAbs (generally against glutamic acid decarboxylase [GADA]); hence, the single GADA+ state may represent an early stage of T1D.METHODS Here, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic GADA+ and T1D donors.RESULTS Similar to the few remaining β cells in the T1D islets, GADA+ donor islets demonstrated a preserved insulin secretory response. By contrast, α cell glucagon secretion was dysregulated in both GADA+ and T1D islets, with impaired glucose suppression of glucagon secretion. Single-cell RNA-Seq of GADA+ α cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of cAMP-dependent protein kinase inhibitor β (PKIB), providing a molecular basis for the loss of glucose suppression and the increased effect of 3-isobutyl-1-methylxanthine (IBMX) observed in GADA+ donor islets.CONCLUSION We found that α cell dysfunction was present during the early stages of islet autoimmunity at a time when β cell mass was still normal, raising important questions about the role of early α cell dysfunction in the progression of T1D.FUNDING This work was supported by grants from the NIH (3UC4DK112217-01S1, U01DK123594-02, UC4DK112217, UC4DK112232, U01DK123716, and P30 DK019525) and the Vanderbilt Diabetes Research and Training Center (DK20593).
Nicolai M. Doliba, Andrea V. Rozo, Jeffrey Roman, Wei Qin, Daniel Traum, Long Gao, Jinping Liu, Elisabetta Manduchi, Chengyang Liu, Maria L. Golson, Golnaz Vahedi, Ali Naji, Franz M. Matschinsky, Mark A. Atkinson, Alvin C. Powers, Marcela Brissova, Klaus H. Kaestner, Doris A. Stoffers, for the HPAP Consortium
Background Deep learning has been widely used for glaucoma diagnosis. However, there is no clinically validated algorithm for glaucoma incidence and progression prediction. This study aims to develop a clinically feasible deep-learning system for predicting and stratifying the risk of glaucoma onset and progression based on color fundus photographs (CFPs), with clinical validation of performance in external population cohorts.Methods We established data sets of CFPs and visual fields collected from longitudinal cohorts. The mean follow-up duration was 3 to 5 years across the data sets. Artificial intelligence (AI) models were developed to predict future glaucoma incidence and progression based on the CFPs of 17,497 eyes in 9346 patients. The area under the receiver operating characteristic (AUROC) curve, sensitivity, and specificity of the AI models were calculated with reference to the labels provided by experienced ophthalmologists. Incidence and progression of glaucoma were determined based on longitudinal CFP images or visual fields, respectively.Results The AI model to predict glaucoma incidence achieved an AUROC of 0.90 (0.81–0.99) in the validation set and demonstrated good generalizability, with AUROCs of 0.89 (0.83–0.95) and 0.88 (0.79–0.97) in external test sets 1 and 2, respectively. The AI model to predict glaucoma progression achieved an AUROC of 0.91 (0.88–0.94) in the validation set, and also demonstrated outstanding predictive performance with AUROCs of 0.87 (0.81–0.92) and 0.88 (0.83–0.94) in external test sets 1 and 2, respectively.Conclusion Our study demonstrates the feasibility of deep-learning algorithms in the early detection and prediction of glaucoma progression.FUNDING National Natural Science Foundation of China (NSFC); the High-level Hospital Construction Project, Zhongshan Ophthalmic Center, Sun Yat-sen University; the Science and Technology Program of Guangzhou, China (2021), the Science and Technology Development Fund (FDCT) of Macau, and FDCT-NSFC.
Fei Li, Yuandong Su, Fengbin Lin, Zhihuan Li, Yunhe Song, Sheng Nie, Jie Xu, Linjiang Chen, Shiyan Chen, Hao Li, Kanmin Xue, Huixin Che, Zhengui Chen, Bin Yang, Huiying Zhang, Ming Ge, Weihui Zhong, Chunman Yang, Lina Chen, Fanyin Wang, Yunqin Jia, Wanlin Li, Yuqing Wu, Yingjie Li, Yuanxu Gao, Yong Zhou, Kang Zhang, Xiulan Zhang
BACKGROUND. In human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end-stage renal disease (ESRD). However, only about half of patients with moderate/severe TII develop ESRD. We hypothesized that this heterogeneity in outcome reflects different underlying inflammatory states. Therefore, we interrogated renal biopsies from LN longitudinal and cross-sectional cohorts. METHODS. Data was acquired using conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed computational pipelines by training and implementing several deep learning models and other computer vision techniques. RESULTS. High B cell densities were associated with protection from ESRD. In contrast, CD8, γδ and other CD4-CD8- T cells, were associated with both acute renal failure and progression to ESRD. B cells were often organized into large periglomerular neighborhoods with T follicular helper cells while CD4- T cells formed small neighborhoods in the tubulointerstitium whose frequency predicted progression to ESRD. CONCLUSIONS. These data reveal that specific in situ inflammatory states are associated with refractory and progressive renal disease. FUNDING. These studies were funded by the NIH Autoimmunity Centers of Excellence (AI082724), Department of Defense (LRI180083) and Alliance for Lupus Research, NIH S10-OD025081, S10-RR021039, and P30-CA14599 awards.
Rebecca Abraham, Madeleine S. Durkee, Junting Ai, Margaret Veselits, Gabriel Casella, Yuta Asano, Anthony Chang, Kichul Ko, Charles Oshinsky, Emily Peninger, Maryellen L. Giger, Marcus R. Clark
BACKGROUND. Patients undergoing immune-modifying therapies demonstrate a reduced humoral response after COVID-19 vaccination, but we lack a proper evaluation of the impact of such therapies on vaccine-induced T cell responses. METHODS. We longitudinally characterized humoral and Spike-specific T cell responses in inflammatory bowel disease (IBD) patients who are on antimetabolite therapy (azathioprine or methotrexate), TNF inhibitors and/or other biologic treatment (anti-integrin or anti-p40) for up to 6 months after completing two-dose COVID-19 mRNA vaccination. RESULTS. We demonstrated that a Spike-specific T cell response is not only induced in treated IBD patients at levels similar to healthy individuals, but also sustained at higher magnitude for up to 6 months after vaccination, particularly in those treated with TNF inhibitor therapy. Furthermore, the Spike-specific T cell response in these patients is mainly preserved against mutations present in SARS-CoV-2 B.1.1.529 (Omicron) and characterized by a Th1/IL-10 cytokine profile. CONCLUSION. Despite the humoral response defects, patients under immune-modifying therapies demonstrated a favorable profile of vaccine-induced T cell responses that might still provide a layer of COVID-19 protection. FUNDING. This study was funded by the National Centre for Infectious Diseases NCID Catalyst Grant (FY2021ES) and the National Research Fund Competitive Research Programme (NRF-CRP25-2020-0003). The funders played no role in the design, conduct, or reporting of this study.
Martin Qui, Nina Le Bert, Webber Pak Wo Chan, Malcolm Tan, Shou Kit Hang, Smrithi Hariharaputran, Jean Xiang Ying Sim, Jenny Guek Hong Low, Weiling Ng, Wei Yee Wan, Tiing Leong Ang, Antonio Bertoletti, Ennaliza Salazar
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