Insulin-secreting β cell loss or dysfunction is a feature of both type 1 and type 2 diabetes. Strategies to restore β cell mass are limited, as sources of healthy islets are scarce and mature β cells are not readily expanded in vitro. In this issue of the JCI, Ou et al. report that mature β cell expansion can be induced in situ through epigenetic editing of regulatory elements in pancreatic tissue. Specifically, hypomethylation at imprinting control region 2 (ICR2) in human islets promoted β cell expansion. Importantly, transplantation of these epigenetically edited islets into diabetic mice reduced blood glucose levels. Together, these results support further evaluation of this strategy for restoring β cell mass in patients with diabetes.
Tao Wang, Duanqing Pei
Interactions between IgG Fc and its receptors (FcγRs) have been shown to augment broadly neutralizing Ab–mediated (BnAb-mediated) protection from simian-human immunodeficiency virus (SHIV) challenge. In the current issue of the JCI, Parsons and collaborators compared the BnAb PGT121 with a version engineered to have impaired FcγR binding for their ability to protect macaques from an intravenous challenge with SHIV-infected cells as well as to treat already infected animals. Unexpectedly, and in contrast to previous studies, both versions of the Ab were equally able to prevent infection and decrease viral loads in infected animals. Thus, FcγR engagement does not always improve the in vivo antiviral activity of BnAbs.
Donald Forthal, Andrés Finzi
Graft-versus-tumor (GVT) effects have been thought to mostly result from allogeneic transplants; however, there is a growing body of research that supports a possible autologous GVT effect. In early clinical studies, a positive correlation between lymphocyte count recovery after autologous transplantation and overall survival has been observed. However, mechanistic studies to identify the mediators of autologous GVT responses have been lacking. In this issue of the JCI, Vuckovic et al. observed a T cell–dependent autologous GVT effect in the Vk*MYC myeloma model. Moreover, the authors showed that CD8+ T cells mediate myeloma control through IFN-γ secretion, which could be further augmented with a CD137 agonist, suggesting a therapeutic approach for enhancing autologous GVT.
Shuai Dong, Irene M. Ghobrial
βIV-Spectrin, along with ankyrin and Ca2+/calmodulin-dependent kinase II (CaMKII), has been shown to form local signaling domains at the intercalated disc, while playing a key role in the regulation of Na+ and K+ channels in cardiomyocytes. In this issue of the JCI, Unudurthi et al. show that under chronic pressure overload conditions, CaMKII activation leads to βIV-spectrin degradation, resulting in the release of sequestered STAT3 from the intercalated discs. This in turn leads to dysregulation of STAT3-mediated gene transcription, maladaptive remodeling, fibrosis, and decreased cardiac function. Overall, this study presents interesting findings regarding the role of CaMKII and βIV-spectrin under physiological as well as pathological conditions.
Mohit Hulsurkar, Ann P. Quick, Xander H.T. Wehrens
Ischemia-reperfusion (I/R) sets off a devastating cascade of events, leading to cell death and possible organ failure. Treatments to limit I/R-associated damage are lacking, and the pathways that drive injury are poorly understood. In this issue of the JCI, Wei and colleagues identify microRNA-668 (miR-668) as a protective factor in acute kidney injury (AKI). miR-668 was shown to repress mitochondrial fission–associated protein MTP18, thereby inhibiting pathogenic mitochondrial fragmentation. In murine models of I/R-induced AKI, treatment with a miR-668 mimetic reduced mitochondrial fragmentation and improved renal function. Moreover, HIF-1α was shown to be required for miR-688 expression in response to I/R. Importantly, Wei et al. show miR-668 upregulation in a cohort of human patients with AKI. Together, these results identify a HIF-1α/miR-668/MTP18 axis that may have potential as a therapeutic target for AKI.
Nicholas Chun, Steven G. Coca, John Cijiang He
People with diabetes mellitus are at higher risk of developing serious ascending infections of the urinary tract. The traditional explanation has focused on the role of glycosuria in promoting bacterial growth. Using mouse models, Murtha et al. demonstrate that when the intracellular insulin signaling pathway is compromised, antimicrobial defenses are compromised too, and the mice are unable to effectively handle uropathogenic E. coli introduced experimentally into the urinary tract. These observations strongly support the hypothesis that the antimicrobial defenses of the kidney are dependent on insulin, and the urinary tract infections associated with diabetes occur due to reduced expression of these key effectors of innate immunity.
Cancer cells evade the immune system through a variety of different mechanisms, including the inhibition of antitumor effector T cells via checkpoint ligand–receptor interaction. Moreover, studies have shown that blocking these checkpoint pathways can reinvigorate the antitumor immunity, thereby prompting the development of numerous checkpoint immunotherapies, several of which are now being approved to treat multiple types of cancer. However, only a fraction of patients achieves promising long-term outcomes in response to checkpoint inhibition, suggesting the existence of additional unknown tumor-induced immunosuppressive pathways. In this issue of the JCI, Klement and colleagues describe an additional pathway of T cell inhibition in cancer. Specifically, the authors demonstrate that downregulation of IRF8, a molecular determinant of apoptotic resistance, in tumor cells aborts repression of osteopontin, which in turn binds to its physiological receptor CD44 on activated T cells and suppresses their activation. These results suggest that osteopontin may act as another immune checkpoint and may serve as a target to expand the number of patients who respond to immune checkpoint inhibitor therapy.
Michael R. Shurin
Inhibitors that target specific kinases or oncoproteins have become popular additions to or replacements for cytotoxic chemotherapies to treat many different types of cancer. However, many tumors lack a discernable target kinase and an amplified oncoprotein and/or rely on several cooperating mechanisms for progression. Thus, combinations of targeted therapies are essential for treating many cancers to avoid the rapid emergence of resistance. In this issue of the JCI, Ren et al. use an elegant kinase activity–profiling method and identify activity of the oncogene polo-like kinase-1 (PLK1) as an important driver of double-hit lymphoma (DHL), an aggressive subgroup of B cell lymphoma characterized by chromosomal translocations involving c-MYC and BCL2 or BCL6. Moreover, PLK1 activity was associated with MYC expression and poor prognosis in DHL patients. PLK1 inhibition with volasertib, alone and in combination with the BCL-2 inhibitor venetoclax, was efficacious in multiple DHL models, including mice harboring DHL patient–derived xenografts. Together, these data support PLK1 as a promising prognostic marker and therapeutic target for DHL.
Quais N. Hassan II, Lapo Alinari, John C. Byrd
Chronic obstructive pulmonary disease (COPD) is extremely heterogenous in its effects on airway remodeling. Parsing the complex and interrelated morphologic changes and understanding their contribution to disease severity has posed a significant challenge to the field. In the current issue of the JCI, Bodduluri et al. measured the complex effects of COPD on the airway tree using airway fractal dimension (AFD) on computerized tomography in a large cohort of smokers with and without COPD. They found that lower AFD was independently associated with disease severity and mortality in COPD. This work highlights AFD as a noninvasive approach to analyze complex changes in airway geometry.
Eleanor M. Dunican
Parkinson’s disease (PD) patients have increased histamine in their basal ganglia, but the role of this neurotransmitter in PD is poorly understood. In this issue of the JCI, Zhuang et al. demonstrate that histamine levels rise in the subthalamic nucleus (STN) to compensate for abnormal firing patterns. Injection of histamine into the STN restores normal firing patterns and motor activity, whereas merely changing firing rates has no behavioral effect. Moreover, STN deep brain stimulation, a widespread therapy for PD, regularizes firing through endogenous histamine release. This suggests that abnormal firing patterns, rather than rates, cause PD symptoms, and this histaminergic pathway may lead to new treatments for the disease.
Timothy C. Whalen, Aryn H. Gittis
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