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SARS-CoV-2 causes a wide spectrum of clinical manifestations and significant mortality. Studies investigating underlying immune characteristics are needed to understand disease pathogenesis and inform vaccine design. In this study, we examined immune cell subsets in hospitalized and nonhospitalized individuals. In hospitalized patients, many adaptive and innate immune cells were decreased in frequency compared with those of healthy and convalescent individuals, with the exception of an increase in B lymphocytes. Our findings show increased frequencies of T cell activation markers (CD69, OX40, HLA-DR, and CD154) in hospitalized patients, with other T cell activation/exhaustion markers (PD-L1 and TIGIT) remaining elevated in hospitalized and nonhospitalized individuals. B cells had a similar pattern of activation/exhaustion, with increased frequency of CD69 and CD95 during hospitalization followed by an increase in PD1 frequencies in nonhospitalized individuals. Interestingly, many of these changes were found to increase over time in nonhospitalized longitudinal samples, suggesting a prolonged period of immune dysregulation after SARS-CoV-2 infection. Changes in T cell activation/exhaustion in nonhospitalized patients were found to positively correlate with age. Severely infected individuals had increased expression of activation and exhaustion markers. These data suggest a prolonged period of immune dysregulation after SARS-CoV-2 infection, highlighting the need for additional studies investigating immune dysregulation in convalescent individuals.
Jacob K. Files, Sushma Boppana, Mildred D. Perez, Sanghita Sarkar, Kelsey E. Lowman, Kai Qin, Sarah Sterrett, Eric Carlin, Anju Bansal, Steffanie Sabbaj, Dustin M. Long, Olaf Kutsch, James Kobie, Paul A. Goepfert, Nathan Erdmann
Total views: 3604
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 1 million deaths worldwide; thus, there is an urgent need to develop preventive and therapeutic strategies. The antituberculosis vaccine bacillus Calmette-Guérin (BCG) demonstrates nonspecific, protective innate immune–boosting effects. Here, we determined whether a history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a longitudinal, retrospective observational study of a diverse cohort of health care workers (HCWs).METHODS We assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, which included information on BCG vaccination status and preexisting demographic and clinical characteristics, from an observational cohort of HCWs in a multisite Los Angeles health care organization. We used multivariate analysis to determine whether a history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion.RESULTS Of the 6201 HCWs, 29.6% reported a history of BCG vaccination, whereas 68.9% had not received BCG vaccination. Seroprevalence of anti–SARS-CoV-2 IgG as well as the incidence of self-reported clinical symptoms associated with coronavirus disease 2019 (COVID-19) were markedly decreased among HCWs with a history of BCG vaccination compared with those without BCG vaccination. After adjusting for age and sex, we found that a history of BCG vaccination, but not meningococcal, pneumococcal, or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion.CONCLUSIONS A history of BCG vaccination was associated with a decrease in the seroprevalence of anti–SARS-CoV-2 IgG and a lower number of participants who self-reported experiencing COVID-19–related clinical symptoms in this cohort of HCWs. Therefore, large randomized, prospective clinical trials of BCG vaccination are urgently needed to confirm whether BCG vaccination can confer a protective effect against SARS-CoV-2 infection.
Magali Noval Rivas, Joseph E. Ebinger, Min Wu, Nancy Sun, Jonathan Braun, Kimia Sobhani, Jennifer E. Van Eyk, Susan Cheng, Moshe Arditi
Total views: 3345
Four different endemic coronaviruses (eCoVs) are etiologic agents for the seasonal common cold, and these eCoVs share extensive sequence homology with human SARS coronavirus 2 (SARS-CoV-2). Here, we show that individuals with, as compared with those without, a recent documented infection with eCoV were tested at greater frequency for respiratory infections but had a similar rate of SARS-CoV-2 acquisition. Importantly, the patients with a previously detected eCoV had less-severe coronavirus disease 2019 (COVID-19) illness. Our observations suggest that preexisting immune responses against endemic human coronaviruses can mitigate disease manifestations from SARS-CoV-2 infection.
Manish Sagar, Katherine Reifler, Michael Rossi, Nancy S. Miller, Pranay Sinha, Laura F. White, Joseph P. Mizgerd
Total views: 3070
FOXP3+ Tregs rely on fatty acid β-oxidation–driven (FAO-driven) oxidative phosphorylation (OXPHOS) for differentiation and function. Recent data demonstrate a role for Tregs in the maintenance of tissue homeostasis, with tissue-resident Tregs possessing tissue-specific transcriptomes. However, specific signals that establish tissue-resident Treg programs remain largely unknown. Tregs metabolically rely on FAO, and considering the lipid-rich environments of tissues, we hypothesized that environmental lipids drive Treg homeostasis. First, using human adipose tissue to model tissue residency, we identified oleic acid as the most prevalent free fatty acid. Mechanistically, oleic acid amplified Treg FAO–driven OXPHOS metabolism, creating a positive feedback mechanism that increased the expression of FOXP3 and phosphorylation of STAT5, which enhanced Treg-suppressive function. Comparing the transcriptomic program induced by oleic acid with proinflammatory arachidonic acid, we found that Tregs sorted from peripheral blood and adipose tissue of healthy donors transcriptomically resembled the Tregs treated in vitro with oleic acid, whereas Tregs from patients with multiple sclerosis (MS) more closely resembled an arachidonic acid transcriptomic profile. Finally, we found that oleic acid concentrations were reduced in patients with MS and that exposure of MS Tregs to oleic acid restored defects in their suppressive function. These data demonstrate the importance of fatty acids in regulating tissue inflammatory signals.
Saige L. Pompura, Allon Wagner, Alexandra Kitz, Jacob LaPerche, Nir Yosef, Margarita Dominguez-Villar, David A. Hafler
Total views: 2575
Mitochondrial disorders represent a large collection of rare syndromes that are difficult to manage both because we do not fully understand biochemical pathogenesis and because we currently lack facile markers of severity. The m.3243A>G variant is the most common heteroplasmic mitochondrial DNA mutation and underlies a spectrum of diseases, notably mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). To identify robust circulating markers of m.3243A>G disease, we first performed discovery proteomics, targeted metabolomics, and untargeted metabolomics on plasma from a deeply phenotyped cohort (102 patients, 32 controls). In a validation phase, we measured concentrations of prioritized metabolites in an independent cohort using distinct methods. We validated 20 analytes (1 protein, 19 metabolites) that distinguish patients with MELAS from controls. The collection includes classic (lactate, alanine) and more recently identified (GDF-15, α-hydroxybutyrate) mitochondrial markers. By mining untargeted mass-spectra we uncovered 3 less well-studied metabolite families: N-lactoyl-amino acids, β-hydroxy acylcarnitines, and β-hydroxy fatty acids. Many of these 20 analytes correlate strongly with established measures of severity, including Karnofsky status, and mechanistically, nearly all markers are attributable to an elevated NADH/NAD+ ratio, or NADH-reductive stress. Our work defines a panel of organelle function tests related to NADH-reductive stress that should enable classification and monitoring of mitochondrial disease.
Rohit Sharma, Bryn Reinstadler, Kristin Engelstad, Owen S. Skinner, Erin Stackowitz, Ronald G. Haller, Clary B. Clish, Kerry Pierce, Melissa A. Walker, Robert Fryer, Devin Oglesbee, Xiangling Mao, Dikoma C. Shungu, Ashok Khatri, Michio Hirano, Darryl C. De Vivo, Vamsi K. Mootha
Total views: 2415
BACKGROUND Therapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODS We recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients’ tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTS The vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSION This vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATION Phase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDING Center for Clinical Research, NCI, NIH.
Gal Cafri, Jared J. Gartner, Tal Zaks, Kristen Hopson, Noam Levin, Biman C. Paria, Maria R. Parkhurst, Rami Yossef, Frank J. Lowery, Mohammad S. Jafferji, Todd D. Prickett, Stephanie L. Goff, Christine T. McGowan, Samantha Seitter, Mackenzie L. Shindorf, Anup Parikh, Praveen D. Chatani, Paul F. Robbins, Steven A. Rosenberg
Total views: 2059
BACKGROUND Since December 2019, an outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, and is now becoming a global threat. We aimed to delineate and compare the immunological features of severe and moderate COVID-19.METHODS In this retrospective study, the clinical and immunological characteristics of 21 patients (17 male and 4 female) with COVID-19 were analyzed. These patients were classified as severe (11 cases) and moderate (10 cases) according to the guidelines released by the National Health Commission of China.RESULTS The median age of severe and moderate cases was 61.0 and 52.0 years, respectively. Common clinical manifestations included fever, cough, and fatigue. Compared with moderate cases, severe cases more frequently had dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer as well as markedly higher levels of IL-2R, IL-6, IL-10, and TNF-α. Absolute numbers of T lymphocytes, CD4+ T cells, and CD8+ T cells decreased in nearly all the patients, and were markedly lower in severe cases (294.0, 177.5, and 89.0 × 106/L, respectively) than moderate cases (640.5, 381.5, and 254.0 × 106/L, respectively). The expression of IFN-γ by CD4+ T cells tended to be lower in severe cases (14.1%) than in moderate cases (22.8%).CONCLUSION The SARS-CoV-2 infection may affect primarily T lymphocytes, particularly CD4+ and CD8+ T cells, resulting in a decrease in numbers as well as IFN-γ production by CD4+ T cells. These potential immunological markers may be of importance because of their correlation with disease severity in COVID-19.TRIAL REGISTRATION This is a retrospective observational study without a trial registration number.FUNDING This work is funded by grants from Tongji Hospital for the Pilot Scheme Project, and partly supported by the Chinese National Thirteenth Five Years Project in Science and Technology for Infectious Disease (2017ZX10202201).
Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, Xiaoping Zhang, Minxia Zhang, Shiji Wu, Jianxin Song, Tao Chen, Meifang Han, Shusheng Li, Xiaoping Luo, Jianping Zhao, Qin Ning
Total views: 1828
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus 2019 (COVID-19) pneumonia. Little is known about the kinetics, tissue distribution, cross-reactivity, and neutralization antibody response in patients with COVID-19. Two groups of patients with RT-PCR–confirmed COVID-19 were enrolled in this study: 12 severely ill patients in intensive care units who needed mechanical ventilation and 11 mildly ill patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severely ill patients had viral shedding in a variety of tissues for 20–40 days after onset of disease (8/12, 66.7%), while the majority of mildly ill patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA 10 days after onset (9/11, 81.8%). Mildly ill patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both the severe and mild groups at 9 days after onset, and remained at a high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in patients with COVID-19 but not in patients with MERS. High levels of neutralizing antibodies were induced after about 10 days after onset in both severely and mildly ill patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from patients with COVID-19 inhibited SARS-CoV-2 entry. Sera from convalescent patients with SARS or Middle East respiratory syndrome (MERS) did not. Anti–SARS-CoV-2 S and N IgG levels exhibited a moderate correlation with neutralization titers in patients’ plasma. This study improves our understanding of immune response in humans after SARS-CoV-2 infection.
Yanqun Wang, Lu Zhang, Ling Sang, Feng Ye, Shicong Ruan, Bei Zhong, Tie Song, Abeer N. Alshukairi, Rongchang Chen, Zhaoyong Zhang, Mian Gan, Airu Zhu, Yongbo Huang, Ling Luo, Chris Ka Pun Mok, Manal M. Al Gethamy, Haitao Tan, Zhengtu Li, Xiaofang Huang, Fang Li, Jing Sun, Yanjun Zhang, Liyan Wen, Yuming Li, Zhao Chen, Zhen Zhuang, Jianfen Zhuo, Chunke Chen, Lijun Kuang, Junxiang Wang, Huibin Lv, Yongliang Jiang, Min Li, Yimin Lin, Ying Deng, Lan Tang, Jieling Liang, Jicheng Huang, Stanley Perlman, Nanshan Zhong, Jingxian Zhao, J.S. Malik Peiris, Yimin Li, Jincun Zhao
Total views: 1719
Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1–expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1’s receptor, deleted in colorectal carcinoma; and therapeutic α1 adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1+ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1–driven adrenergic processes and introduced α1 blockers as a potentially new fibrotic therapy.
Ruijuan Gao, Xueyan Peng, Carrighan Perry, Huanxing Sun, Aglaia Ntokou, Changwan Ryu, Jose L. Gomez, Benjamin C. Reeves, Anjali Walia, Naftali Kaminski, Nir Neumark, Genta Ishikawa, Katharine E. Black, Lida P. Hariri, Meagan W. Moore, Mridu Gulati, Robert J. Homer, Daniel M. Greif, Holger K. Eltzschig, Erica L. Herzog
Total views: 1630
Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell–mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell–like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α–induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti–PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.
Kartik Sehgal, Andrew Portell, Elena V. Ivanova, Patrick H. Lizotte, Navin R. Mahadevan, Jonathan R. Greene, Amir Vajdi, Carino Gurjao, Tyler Teceno, Luke J. Taus, Tran C. Thai, Shunsuke Kitajima, Derek Liu, Tetsuo Tani, Moataz Noureddine, Christie J. Lau, Paul T. Kirschmeier, David Liu, Marios Giannakis, Russell W. Jenkins, Prafulla C. Gokhale, Silvia Goldoni, Maria Pinzon-Ortiz, William D. Hastings, Peter S. Hammerman, Juan J. Miret, Cloud P. Paweletz, David A. Barbie
Total views: 1500
Carbohydrate restriction, used since the 1700s to prolong survival in people with diabetes, fell out of favor after the discovery of insulin. Despite costly pharmacological and technological developments in the last few decades, current therapies do not achieve optimal outcomes, and most people with diabetes remain at high risk for micro- and macrovascular complications. Recently, low-carbohydrate diets have regained popularity, with preliminary evidence of benefit for body weight, postprandial hyperglycemia, hyperinsulinemia, and other cardiometabolic risk factors in type 2 diabetes and, with more limited data, in type 1 diabetes. High-quality, long-term trials are needed to assess safety concerns and determine whether this old dietary approach might help people with diabetes attain clinical targets more effectively, and at a lower cost, than conventional treatment.
Belinda S. Lennerz, Andrew P. Koutnik, Svetlana Azova, Joseph I. Wolfsdorf, David S. Ludwig
Total views: 7940
The molecular mechanisms of cellular insulin action have been the focus of much investigation since the discovery of the hormone 100 years ago. Insulin action is impaired in metabolic syndrome, a condition known as insulin resistance. The actions of the hormone are initiated by binding to its receptor on the surface of target cells. The receptor is an α2β2 heterodimer that binds to insulin with high affinity, resulting in the activation of its tyrosine kinase activity. Once activated, the receptor can phosphorylate a number of intracellular substrates that initiate discrete signaling pathways. The tyrosine phosphorylation of some substrates activates phosphatidylinositol-3-kinase (PI3K), which produces polyphosphoinositides that interact with protein kinases, leading to activation of the kinase Akt. Phosphorylation of Shc leads to activation of the Ras/MAP kinase pathway. Phosphorylation of SH2B2 and of Cbl initiates activation of G proteins such as TC10. Activation of Akt and other protein kinases produces phosphorylation of a variety of substrates, including transcription factors, GTPase-activating proteins, and other kinases that control key metabolic events. Among the cellular processes controlled by insulin are vesicle trafficking, activities of metabolic enzymes, transcriptional factors, and degradation of insulin itself. Together these complex processes are coordinated to ensure glucose homeostasis.
Alan R. Saltiel
Total views: 2520
The field of gene therapy has made considerable progress over the past several years. Adeno-associated virus (AAV) vectors have emerged as promising and attractive tools for in vivo gene therapy. Despite the recent clinical successes achieved with recombinant AAVs (rAAVs) for therapeutics, host immune responses against the vector and transgene product have been observed in numerous preclinical and clinical studies. These outcomes have hampered the advancement of AAV gene therapies, preventing them from becoming fully viable and safe medicines. The human immune system is multidimensional and complex. Both the innate and adaptive arms of the immune system seem to play a concerted role in the response against rAAVs. While most efforts have been focused on the role of adaptive immunity and developing ways to overcome it, the innate immune system has also been found to have a critical function. Innate immunity not only mediates the initial response to the vector, but also primes the adaptive immune system to launch a more deleterious attack against the foreign vector. This Review highlights what is known about innate immune responses against rAAVs and discusses potential strategies to circumvent these pathways.
Manish Muhuri, Yukiko Maeda, Hong Ma, Sanjay Ram, Katherine A. Fitzgerald, Phillip W.L. Tai, Guangping Gao
Total views: 2267
Interferons (IFNs) are pleiotropic cytokines critical for regulation of epithelial cell functions and for immune system regulation. In cancer, IFNs contribute to tumor-intrinsic and -extrinsic mechanisms that determine the quality of antitumor immunity and response to immunotherapy. In this Review, we focus on the different types of tumor IFN sensitivity that determine dynamic tumor-immune interactions and their coevolution during cancer progression and metastasis. We extend the discussion to new evidence supporting immunotherapy-mediated immunoediting and the dual opposing roles of IFNs that lead to immune checkpoint blockade response or resistance. Understanding the intricate dynamic responses to IFN will lead to novel immunotherapeutic strategies to circumvent protumorigenic effects of IFN while exploiting IFN-mediated antitumor immunity.
Michelle von Locquenghien, Catalina Rozalén, Toni Celià-Terrassa
Total views: 1968
Dietary modification is central to obesity treatment. Weight loss diets are available that include various permutations of energy restriction, macronutrients, foods, and dietary intake patterns. Caloric restriction is the common pathway for weight reduction, but different diets may induce weight loss by varied additional mechanisms, including by facilitating dietary adherence. This narrative Review of meta-analyses and select clinical trials found that lower-calorie diets, compared with higher-calorie regimens, reliably induced larger short-term (<6 months) weight losses, with deterioration of this benefit over the long term (>12 months). Few significant long-term differences in weight loss were observed for diets of varying macronutrient composition, although some regimens were found to have short-term advantages (e.g., low carbohydrate versus low fat). Progress in improving dietary adherence, which is critical to both short- and long-term weight loss, could result from greater efforts to identify behavioral and metabolic phenotypes among dieters.
Ariana M. Chao, Kerry M. Quigley, Thomas A. Wadden
Total views: 1913
Chimeric antigen receptor (CAR) T cell therapy has shown considerable promise for hematologic malignancies, leading to the US Food and Drug Administration approval of two CAR T cell–based therapies for the treatment of B cell acute lymphoblastic leukemia and large B cell lymphoma. Despite success in hematologic malignancies, the treatment landscape of CAR T cell therapy for solid tumors has been limited. There are unique challenges in the development of novel CAR T cell therapies to improve both safety and efficacy. Improved understanding of the immunosuppressive tumor microenvironment and resistance mechanisms has led to encouraging approaches to mitigating these obstacles. This Review will characterize challenges with current CAR T designs for hematologic malignancies and solid tumors and emphasize preclinical and clinical strategies to overcome them with novel CAR T cell therapies.
Emiliano Roselli, Rawan Faramand, Marco L. Davila
Total views: 1721
2021 to 2022 marks the one hundredth anniversary of ground-breaking research in Toronto that changed the course of what was, then, a universally fatal disease: type 1 diabetes. Some would argue that insulin’s discovery by Banting, Best, Macleod, and Collip was the greatest scientific advance of the 20th century, being one of the first instances in which modern medical science was able to provide lifesaving therapy. As with all scientific discoveries, the work in Toronto built upon important advances of many researchers over the preceding decades. Furthermore, the Toronto work ushered in a century of discovery of the purification, isolation, structural characterization, and genetic sequencing of insulin, all of which influenced ongoing improvements in therapeutic insulin formulations. Here we discuss the body of knowledge prior to 1921 localizing insulin to the pancreas and establishing insulin’s role in glucoregulation, and provide our views as to why researchers in Toronto ultimately achieved the purification of pancreatic extracts as a therapy. We discuss the pharmaceutical industry’s role in the early days of insulin production and distribution and provide insights into why the discoverers chose not to profit financially from the discovery. This fascinating story of bench-to-beside discovery provides useful considerations for scientists now and in the future.
Gary F. Lewis, Patricia L. Brubaker
Total views: 1638
Diabetes mellitus is a major public health problem, affecting about 10% of the population. Pharmacotherapy aims to protect against microvascular complications, including blindness, end-stage kidney disease, and amputations. Landmark clinical trials have demonstrated that intensive glycemic control slows progression of microvascular complications (retinopathy, nephropathy, and neuropathy). Long-term follow-up has demonstrated that intensive glycemic control also decreases risk of macrovascular disease, albeit rigorous evidence of macrovascular benefit did not emerge for over a decade. The US FDA’s recent requirement for dedicated cardiovascular outcome trials ushered in a golden age for understanding the clinical profiles of new type 2 diabetes drugs. Some clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) receptor agonists reported data demonstrating cardiovascular benefit (decreased risk of major adverse cardiovascular events and hospitalization for heart failure) and slower progression of diabetic kidney disease. This Review discusses current guidelines for use of the 12 classes of drugs approved to promote glycemic control in patients with type 2 diabetes. The Review also anticipates future developments with potential to improve the standard of care: availability of generic dipeptidylpeptidase-4 (DPP4) inhibitors and SGLT2 inhibitors; precision medicine to identify the best drugs for individual patients; and new therapies to protect against chronic complications of diabetes.
Simeon I. Taylor, Zhinous Shahidzadeh Yazdi, Amber L. Beitelshees
Total views: 1516
IL-36 is a member of the IL-1 superfamily and consists of three agonists and one receptor antagonist (IL-36Ra). The three endogenous agonists, IL-36α, –β, and –γ, act primarily as proinflammatory cytokines, and their signaling through the IL-36 receptor (IL-36R) promotes immune cell infiltration and secretion of inflammatory and chemotactic molecules. However, IL-36 signaling also fosters secretion of profibrotic soluble mediators, suggesting a role in fibrotic disorders. IL-36 isoforms and IL-36 have been implicated in inflammatory diseases including psoriasis, arthritis, inflammatory bowel diseases, and allergic rhinitis. Moreover, IL-36 has been connected to fibrotic disorders affecting the kidney, lung, and intestines. This review summarizes the expression, cellular source, and function of IL-36 in inflammation and fibrosis in various organs, and proposes that IL-36 modulation may prove valuable in preventing or treating inflammatory and fibrotic diseases and may reveal a mechanistic link between inflammation and fibrosis.
Michael Elias, Shuai Zhao, Hongnga T. Le, Jie Wang, Markus F. Neurath, Clemens Neufert, Claudio Fiocchi, Florian Rieder
Total views: 1361
Idiopathic pulmonary fibrosis (IPF) affects hundreds of thousands of people worldwide, reducing their quality of life and leading to death from respiratory failure within years of diagnosis. Treatment options remain limited, with only two FDA-approved drugs available in the United States, neither of which reverse the lung damage caused by the disease or prolong the life of individuals with IPF. The only cure for IPF is lung transplantation. In this review, we discuss recent major advances in our understanding of the role of the immune system in IPF that have revealed immune dysregulation as a critical driver of disease pathophysiology. We also highlight ways in which an improved understanding of the immune system’s role in IPF may enable the development of targeted immunomodulatory therapies that successfully halt or potentially even reverse lung fibrosis.
Kevin Shenderov, Samuel L. Collins, Jonathan D. Powell, Maureen R. Horton
Total views: 1264