The characterization of the adaptive immune response to COVID-19 vaccination in individuals who recovered from SARS-CoV-2 infection may define current and future clinical practice. To determine the effect of two doses BNT162b2 mRNA COVID-19 vaccination schedule in individuals who recovered from COVID-19 (COVID-19 recovered) compared to naïve subjects, we evaluated SARS-CoV-2 Spike-specific T and B cell responses, as well as specific IgA, IgG, IgM and neutralizing antibodies titers in 22 individuals who received BNT162b2 mRNA COVID-19 vaccine, 11 of which had a previous history of SARS-CoV-2 infection. Evaluations were performed before vaccination and then weekly until 7 days post second injection. Data obtained clearly showed that one vaccine dose is sufficient to increase both cellular and humoral immune response in COVID-19 recovered subjects without any additional improvement after the second dose. On the contrary, the second dose is proved mandatory in naïve ones to further enhance the immune response. These findings were further confirmed at serological level in a larger cohort of naïve (68) and COVID-19 recovered (29) subjects, tested up to 50 days post vaccination. These results question whether a second vaccine injection in COVID-19 recovered subjects is required and indicate that millions of vaccine doses may be redirected to naïve individuals, thus shortening the time to reach herd immunity.
Alessio Mazzoni, Nicoletta Di Lauria, Laura Maggi, Lorenzo Salvati, Anna Vanni, Manuela Capone, Giulia Lamacchia, Elisabetta Mantengoli, Michele Spinicci, Lorenzo Zammarchi, Seble Tekle Kiros, Arianna Rocca, Filippo Lagi, Maria Grazia Colao, Paola Parronchi, Cristina Scaletti, Lucia Turco, Francesco Liotta, Gian Maria Rossolini, Lorenzo Cosmi, Alessandro Bartoloni, Francesco Annunziato
Myelofibrosis (MF) are a non-BCR-ABL myeloproliferative neoplasms (NMPs) associated with poor outcomes. Current treatment has little effect on the natural history of the disease. MF results from complex interactions between 1) the malignant clone, 2) an inflammatory context, and 3) remodeling of the bone marrow (BM) microenvironment. Each of these points is a potential target of PPAR-y activation. Here, we demonstrated the therapeutic potential of PPAR-y agonists in resolving MF in three mouse models. We showed that PPAR-y agonists reduce myeloproliferation, modulate inflammation, and protect the BM stroma in vitro and ex vivo. Activation of PPAR-y constitutes a relevant therapeutic target in MF and our data support the possibility of using PPAR-y agonists in clinical practice.
Juliette Lambert, Joseph Saliba, Carolina Calderon, Karine Sii-Felice, Mohammad Salma, Valérie Edmond, Jean-Claude Alvarez, Marc Delord, Caroline Marty, Isabelle Plo, Jean-Jacques Kiladjian, Eric Soler, William Vainchenker, Jean-Luc Villeval, Philippe Rousselot, Stephane Prost
Melanoma dedifferentiation has been reported as a state of cellular resistance to targeted therapies and immunotherapies as cancer cells revert to a more primitive cellular phenotype. Here we show that, counterintuitively, the biopsies of patient tumors that respond to anti-programmed cell death receptor 1 (PD-1) therapy decreased expression of melanocytic markers and increased neural crest markers, suggesting treatment-induced dedifferentiation. When modeling the effects in vitro, we documented that melanoma cell lines that were originally melanocytic differentiated underwent a process of neural crest dedifferentiation when continuously exposed to interferon gamma, through global chromatin landscape changes leading to enrichment in specific hyperaccessible chromatin regions. The interferon gamma-induced dedifferentiation signature corresponded with improved outcomes in patients with melanoma, challenging the notion that neural crest dedifferentiation is entirely an adverse phenotype.
Yeon Joo Kim, Katherine M. Sheu, Jennifer Tsoi, Gabriel Abril-Rodriguez, Egmidio Medina, Catherine S. Grasso, Davis Y. Torrejon, Ameya S. Champhekar, Kevin Litchfield, Charles Swanton, Daniel E. Speiser, Philip O. Scumpia, Alexander Hoffmann, Thomas G. Graeber, Cristina Puig-Saus, Antoni Ribas
Disrupting transmission of Borrelia burgdorferi (B. burgdorferi ) from infected ticks to humans is one strategy to prevent the significant morbidity from Lyme disease. We have previously shown that an anti-OspA human monoclonal antibody, 2217, prevents transmission of B. burgdorferi from infected ticks in animal models. Maintenance of a protective plasma concentration of a human monoclonal antibody for tick season presents a significant challenge for a pre-exposure prophylaxis strategy. Here, we describe the optimization of 2217 by amino acid substitutions (LS, M428L and N434S) into the Fc domain. The LS mutation led to a twofold-increase in half-life in cynomolgus monkeys. In a rhesus macaque model, 2217LS protected animals from tick transmission of spirochetes at a dose of 3 mg/kg. Crystallographic analysis of Fab in complex with OspA reveals that 2217 binds a novel epitope that is highly conserved among the B. burgdorferi, B. garinii, and B. afzelii species. Unlike most vaccines that may require boosters to achieve protection, our work supports the development of 2217LS as an effective pre-exposure prophylaxis in Lyme-endemic regions with a single dose at the beginning of tick season offering immediate protection that remains for the duration of exposure risk.
Zachary A. Schiller, Michael J. Rudolph, Jacqueline R. Toomey, Monir Ejemel, Alan LaRochelle, Simon A. Davis, Havard S. Lambert, Aurélie Kern, Amanda C. Tardo, Colby A. Souders, Eric Peterson, Rebecca D. Cannon, Chandrashekar Ganesa, Frank Fazio, Nicholas J. Mantis, Lisa A. Cavacini, John Sullivan-Bolyai, Linden T. Hu, Monica E. Embers, Mark S. Klempner, Yang Wang
Hypoxia is a hallmark of solid tumors that promotes cell growth, survival, metastasis and confers resistance to chemo and radiotherapies. Hypoxic responses are largely mediated by the transcription factor hypoxia-inducible factor (HIF)-1α and HIF-2α. Our work demonstrates that HIF-2α is essential for colorectal cancer (CRC) progression. However, targeting hypoxic cells is difficult and tumors rapidly acquire resistance to recently developed inhibitors of HIF-2α. To overcome this limitation, we performed a small molecule screen to identify HIF-2α dependent vulnerabilities. Several known ferroptosis activators and dimethyl fumarate (DMF), a cell permeable mitochondrial metabolite derivative, led to selective synthetic lethality in HIF-2α expressing tumor enteroids. Our work demonstrates that HIF-2α integrates two independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2α upreguated lipid and iron regulatory genes in colon cancer cells and colon tumors in mice and led to a ferroptosis-susceptible cell state. Secondly, via an iron dependent, lipid peroxidation-independent pathway, HIF-2α activation potentiated ROS, via irreversible cysteine oxidation and enhanced cell death. Inhibition or knockdown of HIF-2α decreased ROS and resistance to oxidative cell death in vitro and in vivo. Our results demonstrate a mechanistic vulnerability in cancer cells that were the dependent on HIF-2α that can be leveraged for colon cancer treatment.
Rashi Singhal, Sreedhar R. Mitta, Nupur K. Das, Samuel A. Kerk, Peter Sajjakulnukit, Sumeet Solanki, Anthony Andren, Roshan Kumar, Kenneth P. Olive, Ruma Banerjee, Costas A. Lyssiotis, Yatrik M. Shah
Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these potentially opposing functions by interrogating functional relationships between CAF subtypes, their mediators, desmoplasia and tumor growth in wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis, but not in non-desmoplastic metastatic tumors. Single cell RNA-sequencing in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell-depleted and HSC-selective knockout mice uncovered direct CAF-tumor interactions as tumor-promoting mechanism, mediated by myofibroblastic CAF (myCAF)-secreted hyaluronan and inflammatory CAF (iCAF)-secreted HGF. These effects were opposed by myCAF-expressed type-I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type-I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type-I collagen may convert CAF from tumor-promoting to tumor-restricting.
Sonakshi Bhattacharjee, Florian Hamberger, Aashreya Ravichandra, Maximilian Miller, Ajay Nair, Silvia Affo, Aveline Filliol, LiKang Chin, Thomas M. Savage, Deqi Yin, Naita Maren Wirsik, Adam Mehal, Nicholas Arpaia, Ekihiro Seki, Matthias Mack, Di Zhu, Peter A. Sims, Ben Z. Stanger, Kenneth P. Olive, Thomas Schmidt, Rebecca G. Wells, Ingmar Mederacke, Robert F. Schwabe
The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts; however, its regulation across PH subtypes is unknown. Since endothelial deficiency of iron-sulfur (Fe-S) clusters is pathogenic in PH, we hypothesized that a Fe-S biogenesis protein, frataxin (FXN), controls endothelial senescence. An endothelial subpopulation in rodent and patient lungs across PH subtypes exhibited reduced FXN and elevated senescence. In vitro, hypoxic and inflammatory FXN deficiency abrogated activity of endothelial Fe-S-containing polymerases, promoting replication stress, DNA damage response, and senescence. This was also observed in stem cell-derived endothelial cells from Friedreich’s ataxia (FRDA), a genetic disease of FXN deficiency, ataxia, and cardiomyopathy, often with PH. In vivo, FXN deficiency-dependent senescence drove vessel inflammation, remodeling, and PH, while pharmacologic removal of senescent cells in Fxn-deficient rodents ameliorated PH. These data offer a model of endothelial biology in PH, where FXN deficiency generates a senescent endothelial subpopulation, promoting vascular inflammatory and proliferative signals in other cells to drive disease. These findings also establish an endothelial etiology for PH in FRDA and left heart disease and support therapeutic development of senolytic drugs, reversing effects of Fe-S deficiency across PH subtypes.
Miranda K. Culley, Jingsi Zhao, Yi Yin Tai, Ying Tang, Dror Perk, Vinny Negi, Qiujun Yu, Chen-Shan C. Woodcock, Adam Handen, Gil Speyer, Seungchan Kim, Yen-Chun Lai, Taijyu Satoh, Annie M.M. Watson, Yassmin Al Aaraj, John Sembrat, Mauricio Rojas, Dmitry Goncharov, Elena A. Goncharova, Omar F. Khan, Daniel G. Anderson, James E. Dahlman, Aditi U. Gurkar, Robert Lafyatis, Ahmed U. Fayyaz, Margaret M. Redfield, Mark T. Gladwin, Marlene Rabinovitch, Mingxia Gu, Thomas Bertero, Stephen Y. Chan
BACKGROUND.The appearance of hyperglycemia is due to insulin resistance, functional deficits in the secretion of insulin and a reduction of β-cell mass. There is a long-standing debate as to the relative contribution of these factors to clinically manifest β-cell dysfunction. The aim of this study was to verify the effect of one of these factors, the reduction of β-cell mass, on the subsequent development of hyperglycemia. METHODS. To pursue this aim, non-diabetic patients, scheduled for identical pancreaticoduodenectomy surgery, underwent oral glucose tolerance tests (OGTT) and hyperglycaemic clamps (HC), followed by arginine stimulation before and after surgery. Based on post-surgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal (post-NGT), impaired (post-IGT) or diabetic (post-DM). RESULTS. At baseline the three groups showed similar fasting glucose and insulin levels, however, examining the various parameters, we found that reduced first-phase insulin secretion and reduced glucose sensitivity and rate sensitivity were predictors of eventual post-surgery development of impaired glucose tolerance and diabetes. CONCLUSION. Despite comparable functional mass and fasting glucose and insulin levels at baseline, and the very same 50% mass reduction, only reduced 1st phase insulin secretion and glucose sensitivity predicted the appearance of hyperglycemia. These functional alterations could be pivotal to the pathogenesis of type 2 diabetes (T2DM). TRIAL REGISTRATION. ClinicalTrials.gov Identifier: NCT02175459. FUNDING. Università Cattolica del Sacro Cuore; the Italian Ministry of Education, University and Research, European Foundation for the Study of Diabetes.
Teresa Mezza, Pietro Manuel Ferraro, Gianfranco Di Giuseppe, Simona Moffa, Chiara M.A. Cefalo, Francesca Cinti, Flavia Impronta, Umberto Capece, Giuseppe Quero, Alfredo Pontecorvi, Andrea Mari, Sergio Alfieri, Andrea Giaccari
Background. Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are highly comorbid and exhibit strong correlations with one another. We aimed to investigate mechanisms of underlying relationships between PTSD and three kinds of depressive phenotypes, namely, MDD, depressed affect (DAF), and depression (DEP, including both MDD and the broad definition of depression). METHODS. Genetic correlations between PTSD and the depressive phenotypes were tested using linkage disequilibrium score regression. Polygenic overlap analysis was used to estimate shared and trait-specific causal variants across a pair of traits. Causal relationships between PTSD and the depressive phenotypes were investigated using Mendelian randomization. Shared genomic loci between PTSD and MDD were identified using cross-trait meta-analysis. RESULTS. Genetic correlations of PTSD with the depressive phenotypes were in the range of 0.71~0.80. The estimated numbers of causal variants were 14,565, 12,965, 10,565, and 4,986 for MDD, DEP, DAF, and PTSD, respectively. In each case, causal variants contributing to PTSD were completely or largely covered by causal variants defining each of the depressive phenotypes. Mendelian randomization analysis indicates that the genetically determined depressive phenotypes confer a causal effect on PTSD (b = 0.21~0.31). Notably, genetically determined PTSD confers a causal effect on DEP (b = 0.14) and DAF (b = 0.15), but not MDD. Cross-trait meta-analysis of MDD and PTSD identifies 47 genomic loci, including 29 loci shared between PTSD and MDD. CONCLUSION. Evidence from shared genetics suggests that PTSD is a subtype of MDD. This study provides support to the efforts in reducing diagnostic heterogeneity in psychiatric nosology. FUNDING. The National Key Research and Development Program of China (2018YFC1314300) and the National Natural Science Foundation of China (81471364 and 81971255).
Fuquan Zhang, Shuquan Rao, Hongbao Cao, Xiangrong Zhang, Qiang Wang, Yong Xu, Jing Sun, Chun Wang, Jiu Chen, Xijia Xu, Ning Zhang, Lin Tian, Jianmin Yuan, Guoqiang Wang, Lei Cai, Mingqing Xu, Ancha Baranova
Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK-eIF2α-ATF4 signaling axis to drive fucosyltransferase-1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR and EPHA2 are glycoprotein targets of FUT1, where such fucosylation would consequently converge on deregulated AKT-mTOR-4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecular targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.
Jane H.C. Loong, Tin-Lok Wong, Man Tong, Rakesh Sharma, Lei Zhou, Kai-Yu Ng, Hua-Jian Yu, Chi Han Li, Kwan Man, Chung-Mau Lo, Xin-Yuan Guan, Terence K. Lee, Jing-Ping Yun, Stephanie Kwai Yee Ma
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