On the cover:
DNA methylome and transcriptome analysis of cancer-associated fibroblasts
In this issue, Su et al. report combined methylome and transcriptome analysis of cancer-associated fibroblasts (CAFs) compared with normal fibroblasts (NFs) from patients with non–small-cell lung cancer. They identify a DNA methylation signature in CAFs that correlates with survival in multiple patient cohorts. The cover art depicts the methylome (yellow-blue in nuclei) and transcriptome (red-blue in cytoplasm) landscapes of CAFs and NFs. Image credit: Huei-Wen Chen.
Circadian rhythms, present in most phyla across life, are biological oscillations occurring on a daily cycle. Since the discovery of their molecular foundations in model organisms, many inputs that modify this tightly controlled system in humans have been identified. Polygenic variations and environmental factors influence each person’s circadian rhythm, contributing to the trait known as chronotype, which manifests as the degree of morning or evening preference in an individual. Despite normal variation in chronotype, much of society operates on a “one size fits all” schedule that can be difficult to adjust to, especially for certain individuals whose endogenous circadian phase is extremely advanced or delayed. This is a public health concern, as phase misalignment in humans is associated with a number of adverse health outcomes. Additionally, modern technology (such as electric lights and computer, tablet, and phone screens that emit blue light) and lifestyles (such as shift or irregular work schedules) are disrupting circadian consistency in an increasing number of people. Though medical and lifestyle interventions can alleviate some of these issues, growing research on endogenous circadian variability and sensitivity suggests that broader social changes may be necessary to minimize the impact of circadian misalignment on health.
Nicholas W. Gentry, Liza H. Ashbrook, Ying-Hui Fu, Louis J. Ptáček
Bcl2-associated athanogene-3 (BAG3) is expressed ubiquitously in humans, but its levels are highest in the heart, the skeletal muscle, and the central nervous system; it is also elevated in many cancers. BAG3’s diverse functions are supported by its multiple protein-protein binding domains, which couple with small and large heat shock proteins, members of the Bcl2 family, other antiapoptotic proteins, and various sarcomere proteins. In the heart, BAG3 inhibits apoptosis, promotes autophagy, couples the β-adrenergic receptor with the L-type Ca2+ channel, and maintains the structure of the sarcomere. In cancer cells, BAG3 binds to and supports an identical array of prosurvival proteins, and it may represent a therapeutic target. However, the development of strategies to block BAG3 function in cancer cells may be challenging, as they are likely to interfere with the essential roles of BAG3 in the heart. In this Review, we present the current knowledge regarding the biology of this complex protein in the heart and in cancer and suggest several therapeutic options.
Jonathan A. Kirk, Joseph Y. Cheung, Arthur M. Feldman
Immune-checkpoint inhibitors are firmly established as pillars of cancer therapy, but only a minority of cancer patients currently benefit from these therapies, and therapeutic combinations that can enhance responses are urgently needed. Recently, histone deacetylases (HDACs) have emerged as potential targets for immune modulation, but critical questions remain about their mechanisms of action. In this issue of the JCI, Truong et al. assess whether the HDAC inhibitor entinostat can enhance anti–PD-1 treatment in a bladder cancer model. Entinostat promoted a T cell–inflamed phenotype and had substantial antitumor efficacy when used in combination with anti–PD-1 therapy. In addition, the authors showed that HDAC inhibition augmented tumor neoantigen presentation, resulting in the immune editing of tumor antigens. This study highlights a mechanism by which epigenetic modifier agents can synergize with immune-checkpoint blockade for enhanced and long-lasting antitumor activity.
Phosphofructokinase 1 (PFK1) is expressed in T cell acute lymphoblastic leukemia (T-ALL), where its upregulation is linked with cancer progression. While PFK1 functions in the glycolysis pathway within the cytoplasm, it is also present in the nucleus where it regulates gene transcription. In this issue of the JCI, Xueliang Gao, Shenghui Qin, et al. focus their mechanism-based investigation on the nucleocytoplasmic shuttling aspect of the PFK1 platelet isoform, PFKP. Functional nuclear export and localization sequences stimulated CXC chemokine receptor type 4 (CXCR4) expression to promote T-ALL invasion that involved cyclin D3/CDK6, c-Myc, and importin-9. Since the presence of nuclear PFKP is associated with poor survival in T-ALL, nuclear PFKP–induced CXCR4 expression might serve as a prognostic marker for T-ALL. More promising, though, are the mechanistic insights suggesting that approaches to dampening metastatic migration may have application to benefit patients with T-ALL.
Chronic kidney disease (CKD) has reached epidemic proportions globally. The natural course of chronic kidney disease is almost uniformly progressive, albeit at different rates in different individuals. The downhill course appears to pervade kidney diseases of all etiologies and seems to spiral down a self-perpetuating vortex, even if the original insult is ameliorated or controlled. In this issue of the JCI, Shiizaki, Tsubouchi, and colleagues proposed a model of renal tubule luminal calcium phosphate crystallopathy that accounts for renal function demise. Calcium phosphate crystals attached to TLR4 and underwent endocytosis at the brush border, triggering inflammation and fibrosis. This mechanism might operate in different kinds of kidney disease, with a theoretical phosphate concentration threshold in the proximal tubular lumen, beyond which is triggered undesirable downstream effects that eventuate in loss of renal function. If this model parallels human CKD, clinicians may focus efforts on determining phosphate exposure in the proximal tubular lumen.
Perineuronal nets (PNNs), a specialized form of extracellular matrix, are abnormal in the brains of people with Rett syndrome (RTT). We previously reported that PNNs function to restrict synaptic plasticity in hippocampal area CA2, which is unusually resistant to long-term potentiation (LTP) and has been linked to social learning in mice. Here we report that PNNs appear elevated in area CA2 of the hippocampus of an individual with RTT and that PNNs develop precociously and remain elevated in area CA2 of a mouse model of RTT (Mecp2-null). Further, we provide evidence that LTP could be induced at CA2 synapses prior to PNN maturation (postnatal day 8–11) in wild-type mice and that this window of plasticity was prematurely restricted at CA2 synapses in Mecp2-null mice. Degrading PNNs in Mecp2-null hippocampus was sufficient to rescue the premature disruption of CA2 plasticity. We identified several molecular targets that were altered in the developing Mecp2-null hippocampus that may explain aberrant PNNs and CA2 plasticity, and we discovered that CA2 PNNs are negatively regulated by neuronal activity. Collectively, our findings demonstrate that CA2 PNN development is regulated by Mecp2 and identify a window of hippocampal plasticity that is disrupted in a mouse model of RTT.
Kelly E. Carstens, Daniel J. Lustberg, Emma K. Shaughnessy, Katharine E. McCann, Georgia M. Alexander, Serena M. Dudek
Although immune-checkpoint inhibitors (ICIs) have been a remarkable advancement in bladder cancer treatment, the response rate to single-agent ICIs remains suboptimal. There has been substantial interest in the use of epigenetic agents to enhance ICI efficacy, although precisely how these agents potentiate ICI response has not been fully elucidated. We identified entinostat, a selective HDAC1/3 inhibitor, as a potent antitumor agent in our immune-competent bladder cancer mouse models (BBN963 and BBN966). We demonstrate that entinostat selectively promoted immune editing of tumor neoantigens, effectively remodeling the tumor immune microenvironment, resulting in a robust antitumor response that was cell autonomous, dependent upon antigen presentation, and associated with increased numbers of neoantigen-specific T cells. Finally, combination treatment with anti–PD-1 and entinostat led to complete responses and conferred long-term immunologic memory. Our work defines a tumor cell–autonomous mechanism of action for entinostat and a strong preclinical rationale for the combined use of entinostat and PD-1 blockade in bladder cancer.
Andrew S. Truong, Mi Zhou, Bhavani Krishnan, Takanobu Utsumi, Ujjawal Manocha, Kyle G. Stewart, Wolfgang Beck, Tracy L. Rose, Matthew I. Milowsky, Xiaping He, Christof C. Smith, Lisa M. Bixby, Charles M. Perou, Sara E. Wobker, Sean T. Bailey, Benjamin G. Vincent, William Y. Kim
Unlike the better-studied aberrant epigenome in the tumor, the clinicopathologic impact of DNA methylation in the tumor microenvironment (TME), especially the contribution from cancer-associated fibroblasts (CAFs), remains elusive. CAFs exhibit profound patient-to-patient tumorigenic heterogeneity. We asked whether such heterogeneity may be exploited to quantify the level of TME malignancy. We developed a robust and efficient methylome/transcriptome co-analytical system for CAFs and paired normal fibroblasts (NFs) from non–small-cell lung cancer patients. We found 14,781 CpG sites of CAF/NF differential methylation, of which 3,707 sites showed higher methylation changes in ever-smokers than in nonsmokers. Concomitant CAF/NF differential gene expression analysis pointed to a subset of 54 smoking-associated CpG sites with strong methylation-regulated gene expression. A methylation index that summarizes the β values of these CpGs was built for NF/CAF discrimination (MIND) with high sensitivity and specificity. The potential of MIND in detecting premalignancy across individual patients was shown. MIND succeeded in predicting tumor recurrence in multiple lung cancer cohorts without reliance on patient survival data, suggesting that the malignancy level of TME may be effectively graded by this index. Precision TME grading may provide additional pathological information to guide cancer prognosis and open up more options in personalized medicine.
Sheng-Fang Su, Hao Ho, Jia-Hua Li, Ming-Fang Wu, Hsu-Chieh Wang, Hsiang-Yuan Yeh, Shuenn-Wen Kuo, Huei-Wen Chen, Chao-Chi Ho, Ker-Chau Li
Herein, we describe an extracellular function of the vertebrate high-mobility group box 1 protein (HMGB1) in the proliferation of bacterial biofilms. Within host cells, HMGB1 functions as a DNA architectural protein, similar to the ubiquitous DNABII family of bacterial proteins; despite that, these proteins share no amino acid sequence identity. Extracellularly, HMGB1 induces a proinflammatory immune response, whereas the DNABII proteins stabilize the extracellular DNA-dependent matrix that maintains bacterial biofilms. We showed that when both proteins converged on extracellular DNA within bacterial biofilms, HMGB1, unlike the DNABII proteins, disrupted biofilms both in vitro (including the high-priority ESKAPEE pathogens) and in vivo in 2 distinct animal models, albeit with induction of a strong inflammatory response that we attenuated by a single engineered amino acid change. We propose a model where extracellular HMGB1 balances the degree of induced inflammation and biofilm containment without excessive release of biofilm-resident bacteria.
Aishwarya Devaraj, Laura A. Novotny, Frank H. Robledo-Avila, John R. Buzzo, Lauren Mashburn-Warren, Joseph A. Jurcisek, Natalia O. Tjokro, Santiago Partida-Sanchez, Lauren O. Bakaletz, Steven D. Goodman
SLIT2 is a secreted polypeptide that guides migration of cells expressing Roundabout 1 and 2 (ROBO1 and ROBO2) receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient-derived GBM xenografts reduced tumor growth and rendered tumors sensitive to immunotherapy. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1- and ROBO2-mediated PI3K-γ activation. Macrophage Robo1 and Robo2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a potentially novel regulator of the GBM microenvironment and immunotherapeutic target for brain tumors.
Luiz H. Geraldo, Yunling Xu, Laurent Jacob, Laurence Pibouin-Fragner, Rohit Rao, Nawal Maissa, Maïté Verreault, Nolwenn Lemaire, Camille Knosp, Corinne Lesaffre, Thomas Daubon, Joost Dejaegher, Lien Solie, Justine Rudewicz, Thomas Viel, Bertrand Tavitian, Steven De Vleeschouwer, Marc Sanson, Andreas Bikfalvi, Ahmed Idbaih, Q. Richard Lu, Flavia R.S. Lima, Jean-Leon Thomas, Anne Eichmann, Thomas Mathivet
In view of emerging drug-resistant tuberculosis (TB), host-directed adjunct therapies are urgently needed to improve treatment outcomes with currently available anti-TB therapies. One approach is to interfere with the formation of lipid-laden “foamy” macrophages in the host, as they provide a nutrient-rich host cell environment for Mycobacterium tuberculosis (Mtb). Here, we provide evidence that Wnt family member 6 (WNT6), a ligand of the evolutionarily conserved Wingless/Integrase 1 (WNT) signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase 2 (ACC2) during pulmonary TB. Using genetic and pharmacological approaches, we demonstrated that lack of functional WNT6 or ACC2 significantly reduced intracellular triacylglycerol (TAG) levels and Mtb survival in macrophages. Moreover, treatment of Mtb-infected mice with a combination of a pharmacological ACC2 inhibitor and the anti-TB drug isoniazid (INH) reduced lung TAG and cytokine levels, as well as lung weights, compared with treatment with INH alone. This combination also reduced Mtb bacterial numbers and the size of mononuclear cell infiltrates in livers of infected mice. In summary, our findings demonstrate that Mtb exploits WNT6/ACC2-induced storage of TAGs in macrophages to facilitate its intracellular survival, a finding that opens new perspectives for host-directed adjunctive treatment of pulmonary TB.
Julius Brandenburg, Sebastian Marwitz, Simone C. Tazoll, Franziska Waldow, Barbara Kalsdorf, Tim Vierbuchen, Thomas Scholzen, Annette Gross, Svenja Goldenbaum, Alexandra Hölscher, Martina Hein, Lara Linnemann, Maja Reimann, Andreas Kispert, Michael Leitges, Jan Rupp, Christoph Lange, Stefan Niemann, Jochen Behrends, Torsten Goldmann, Holger Heine, Ulrich E. Schaible, Christoph Hölscher, Dominik Schwudke, Norbert Reiling
PFKP (phosphofructokinase, platelet), the major isoform of PFK1 expressed in T cell acute lymphoblastic leukemia (T-ALL), is predominantly expressed in the cytoplasm to carry out its glycolytic function. Our study showed that PFKP is a nucleocytoplasmic shuttling protein with functional nuclear export and nuclear localization sequences (NLSs). Cyclin D3/CDK6 facilitated PFKP nuclear translocation by dimerization and by exposing the NLS of PFKP to induce the interaction between PFKP and importin 9. Nuclear PFKP stimulated the expression of C-X-C chemokine receptor type 4 (CXCR4), a chemokine receptor regulating leukemia homing/infiltration, to promote T-ALL cell invasion, which depended on the activity of c-Myc. In vivo experiments showed that nuclear PFKP promoted leukemia homing/infiltration into the bone marrow, spleen, and liver, which could be blocked with CXCR4 antagonists. Immunohistochemical staining of tissues from a clinically well-annotated cohort of T cell lymphoma/leukemia patients showed nuclear PFKP localization in invasive cancers, but not in nonmalignant T lymph node or reactive hyperplasia. The presence of nuclear PFKP in these specimens correlated with poor survival in patients with T cell malignancy, suggesting the potential utility of nuclear PFKP as a diagnostic marker.
Xueliang Gao, Shenghui Qin, Yongxia Wu, Chen Chu, Baishan Jiang, Roger H. Johnson, Dong Kuang, Jie Zhang, Xi Wang, Anand Mehta, Kenneth D. Tew, Gustavo W. Leone, Xue-Zhong Yu, Haizhen Wang
TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3ε as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3ε was essential for TNFR2 signaling–mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3ε resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3ε signaled through PI3K/Akt/mTOR to restrict NF-κB activation while simultaneously stimulating C/EBPβ activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3ε as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3ε antiinflammatory pathway.
Wenyu Fu, Wenhuo Hu, Young-Su Yi, Aubryanna Hettinghouse, Guodong Sun, Yufei Bi, Wenjun He, Lei Zhang, Guanmin Gao, Jody Liu, Kazuhito Toyo-oka, Guozhi Xiao, David B. Solit, Png Loke, Chuan-ju Liu
Therapeutic vaccines that augment T cell responses to tumor antigens have been limited by poor potency in clinical trials. In contrast, the transfer of T cells modified with foreign transgenes frequently induces potent endogenous T cell responses to epitopes in the transgene product, and these responses are undesirable, because they lead to rejection of the transferred T cells. We sought to harness gene-modified T cells as a vaccine platform and developed cancer vaccines composed of autologous T cells modified with tumor antigens and additional adjuvant signals (Tvax). T cells expressing model antigens and a broad range of tumor neoantigens induced robust and durable T cell responses through cross-presentation of antigens by host DCs. Providing Tvax with signals such as CD80, CD137L, IFN-β, IL-12, GM-CSF, and FLT3L enhanced T cell priming. Coexpression of IL-12 and GM-CSF induced the strongest CD4+ and CD8+ T cell responses through complimentary effects on the recruitment and activation of DCs, mediated by autocrine IL-12 receptor signaling in the Tvax. Therapeutic vaccination with Tvax and adjuvants showed antitumor activity in subcutaneous and metastatic preclinical mouse models. Human T cells modified with neoantigens readily activated specific T cells derived from patients, providing a path for clinical translation of this therapeutic platform in cancer.
Joshua R. Veatch, Naina Singhi, Shivani Srivastava, Julia L. Szeto, Brenda Jesernig, Sylvia M. Stull, Matthew Fitzgibbon, Megha Sarvothama, Sushma Yechan-Gunja, Scott E. James, Stanley R. Riddell
The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.
Myeloid-derived suppressor cells (MDSCs) are major negative regulators of immune responses in cancer and chronic infections. It remains unclear if regulation of MDSC activity in different conditions is controlled by similar mechanisms. We compared MDSCs in mice with cancer and lymphocytic choriomeningitis virus (LCMV) infection. Chronic LCMV infection caused the development of monocytic MDSCs (M-MDSCs) but did not induce polymorphonuclear MDSCs (PMN-MDSCs). In contrast, both MDSC populations were present in cancer models. An acquisition of immune-suppressive activity by PMN-MDSCs in cancer was controlled by IRE1α and ATF6 pathways of the endoplasmic reticulum (ER) stress response. Abrogation of PMN-MDSC activity by blockade of the ER stress response resulted in an increase in tumor-specific immune response and reduced tumor progression. In contrast, the ER stress response was dispensable for suppressive activity of M-MDSCs in cancer and LCMV infection. Acquisition of immune-suppressive activity by M-MDSCs in spleens was mediated by IFN-γ signaling. However, it was dispensable for suppressive activity of M-MDSCs in tumor tissues. Suppressive activity of M-MDSCs in tumors was retained due to the effect of IL-6 present at high concentrations in the tumor site. These results demonstrate disease- and population-specific mechanisms of MDSC accumulation and the need for targeting different pathways to achieve inactivation of these cells.
Evgenii N. Tcyganov, Shino Hanabuchi, Ayumi Hashimoto, David Campbell, Gozde Kar, Timothy W.F. Slidel, Corinne Cayatte, Aimee Landry, Fernanda Pilataxi, Susana Hayes, Brian Dougherty, Kristin C. Hicks, Kathy Mulgrew, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Wei Guo, Sergei Grivennikov, Mohammed-Alkhatim A. Ali, Jean-Christophe Beltra, E. John Wherry, Yulia Nefedova, Dmitry I. Gabrilovich
Ovarian cancer is the leading cause of gynecological malignancy–related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance. Mesothelial cells are an important cellular component of the ovarian cancer microenvironment that promote metastasis. However, their role in chemoresistance is unclear. Here, we investigated whether cancer-associated mesothelial cells promote ovarian cancer chemoresistance and stemness in vitro and in vivo. We found that osteopontin is a key secreted factor that drives mesothelial-mediated ovarian cancer chemoresistance and stemness. Osteopontin is a secreted glycoprotein that is clinically associated with poor prognosis and chemoresistance in ovarian cancer. Mechanistically, ovarian cancer cells induced osteopontin expression and secretion by mesothelial cells through TGF-β signaling. Osteopontin facilitated ovarian cancer cell chemoresistance via the activation of the CD44 receptor, PI3K/AKT signaling, and ABC drug efflux transporter activity. Importantly, therapeutic inhibition of osteopontin markedly improved the efficacy of cisplatin in both human and mouse ovarian tumor xenografts. Collectively, our results highlight mesothelial cells as a key driver of ovarian cancer chemoresistance and suggest that therapeutic targeting of osteopontin may be an effective strategy for enhancing platinum sensitivity in ovarian cancer.
Jin Qian, Bauer L. LeSavage, Kelsea M. Hubka, Chenkai Ma, Suchitra Natarajan, Joshua T. Eggold, Yiren Xiao, Katherine C. Fuh, Venkatesh Krishnan, Annika Enejder, Sarah C. Heilshorn, Oliver Dorigo, Erinn B. Rankin
Background VRC01, a potent, broadly neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. The HVTN 104 study assessed the safety and pharmacokinetics of VRC01 in humans. We extend the clinical evaluation to determine intravenously infused VRC01 distribution and protective function at mucosal sites of HIV-1 entry.Methods Healthy, HIV-1–uninfected men (n = 7) and women (n = 5) receiving VRC01 every 2 months provided mucosal and serum samples once, 4–13 days after infusion. Eleven male and 8 female HIV-seronegative volunteers provided untreated control samples. VRC01 levels were measured in serum, secretions, and tissue, and HIV-1 inhibition was determined in tissue explants.Results Median VRC01 levels were quantifiable in serum (96.2 μg/mL or 1.3 pg/ng protein), rectal tissue (0.11 pg/ng protein), rectal secretions (0.13 pg/ng protein), vaginal tissue (0.1 pg/ng protein), and cervical secretions (0.44 pg/ng protein) from all recipients. VRC01/IgG ratios in male serum correlated with those in paired rectal tissue (r = 0.893, P = 0.012) and rectal secretions (r = 0.9643, P = 0.003). Ex vivo HIV-1Bal26 challenge infected 4 of 21 rectal explants from VRC01 recipients versus 20 of 22 from controls (P = 0.005); HIV-1Du422.1 infected 20 of 21 rectal explants from VRC01 recipients and 12 of 12 from controls (P = 0.639). HIV-1Bal26 infected 0 of 14 vaginal explants of VRC01 recipients compared with 23 of 28 control explants (P = 0.003).Conclusion Intravenous VRC01 distributes into the female genital and male rectal mucosa and retains anti–HIV-1 functionality, inhibiting a highly neutralization-sensitive but not a highly resistant HIV-1 strain in mucosal tissue. These findings lend insight into VRC01 mucosal infiltration and provide perspective on in vivo protective efficacy.Funding National Institute of Allergy and Infectious Diseases and Bill & Melinda Gates Foundation.
Rena D. Astronomo, Maria P. Lemos, Sandeep R. Narpala, Julie Czartoski, Lamar Ballweber Fleming, Kelly E. Seaton, Madhu Prabhakaran, Yunda Huang, Yiwen Lu, Katharine Westerberg, Lily Zhang, Mary K. Gross, John Hural, Hong-Van Tieu, Lindsey R. Baden, Scott Hammer, Ian Frank, Christina Ochsenbauer, Nicole Grunenberg, Julie E. Ledgerwood, Kenneth Mayer, Georgia Tomaras, Adrian B. McDermott, M. Juliana McElrath
Macrophages deploy numerous strategies to combat invasion by microbes. One tactic is to restrict acquisition of diverse nutrients, including trace metals, a process termed nutritional immunity. Intracellular pathogens adapt to a resource-poor environment by marshaling mechanisms to harvest nutrients. Carbon acquisition is crucial for pathogen survival; compounds that reduce availability are a potential strategy to control intracellular replication. Treatment of macrophages with the glucose analog 2-deoxy-D-glucose (2-DG) armed phagocytes to eliminate the intracellular fungal pathogen Histoplasma capsulatum in vitro and in vivo. Killing did not rely on altering access to carbon-containing molecules or changes in ATP, ER stress, or autophagy. Unexpectedly, 2-DG undermined import of exogenous zinc into macrophages, decreasing the quantity of cytosolic and phagosomal zinc. The fungus perished as a result of zinc starvation. This change in metal ingress was not ascribed to a defect in a single importer; rather, there was a collective impairment in transporter activity. This effect promoted the antifungal machinery of macrophages and expanded the complexity of 2-DG activities far beyond manipulating glycolysis. Mechanistic metabolic studies employing 2-DG will have to consider its effect on zinc transport. Our preclinical data support consideration of this agent as a possible adjunctive therapy for histoplasmosis.
Diego C.P. Rossi, Julio A. Landero Figueroa, William R. Buesing, Kathleen Candor, Logan T. Blancett, Heather M. Evans, Rena Lenchitz, Bradford L. Crowther III, Waleed Elsegeiny, Peter R. Williamson, Jan Rupp, George S. Deepe Jr.
Apeng Chen, Yinan Jiang, Zhengwei Li, Lingxiang Wu, Ulises Santiago, Han Zou, Chunhui Cai, Vaibhav Sharma, Yongchang Guan, Lauren H. McCarl, Jie Ma, Yijen L. Wu, Joshua Michel, Yi Shi, Liza Konnikova, Nduka M. Amankulor, Pascal O. Zinn, Gary Kohanbash, Sameer Agnihotri, Songjian Lu, Xinghua Lu, Dandan Sun, George K. Gittes, Qianghu Wang, Xiangwei Xiao, Dean Yimlamai, Ian F. Pollack, Carlos J. Camacho, Baoli Hu
Depression is a neuropsychiatric disease associated with neuronal anomalies within specific brain regions. In the present study, we screened microRNA (miRNA) expression profiles in the dentate gyrus (DG) of the hippocampus and found that miR-26a-3p was markedly downregulated in a rat model of depression, whereas upregulation of miR-26a-3p within DG regions rescued the neuronal deterioration and depression-like phenotypes resulting from stress exposure, effects that appear to be mediated by the PTEN pathway. The knockdown of miR-26a-3p in DG regions of normal control rats induced depression-like behaviors, effects that were accompanied by activation of the PTEN/PI3K/Akt signaling pathway and neuronal deterioration via suppression of autophagy, impairments in synaptic plasticity, and promotion of neuronal apoptosis. In conclusion, these results suggest that miR-26a-3p deficits within the hippocampal DG mediated the neuronal anomalies contributing to the display of depression-like behaviors. This miRNA may serve as a potential therapeutic target for the treatment of depression.
Ye Li, Cuiqin Fan, Liyan Wang, Tian Lan, Rui Gao, Wenjing Wang, Shu Yan Yu
CD8+ T cell responses restricted by MHC-E, a nonclassical MHC molecule, have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E–restricted CD8+ T cell responses in HIV infection, however, remains unknown. In this study, CD8+ T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in vitro assays, we observed HLA-E–restricted T cell responses to what we believe to be a newly identified subdominant Gag-KL9 as well as a well-described immunodominant Gag-KF11 epitope in T cell lines derived from chronically HIV-infected patients and also primed from healthy donors. Blocking of the HLA-E/KF11 binding by the B7 signal peptide resulted in decreased CD8+ T cell responses. KF11 presented via HLA-E in HIV-infected cells was recognized by antigen-specific CD8+ T cells. Importantly, bulk CD8+ T cells obtained from HIV-infected individuals recognized infected cells via HLA-E presentation. Ex vivo analyses at the epitope level showed a higher responder frequency of HLA-E–restricted responses to KF11 compared with KL9. Taken together, our findings of HLA-E–restricted HIV-specific immune responses offer intriguing and possibly paradigm-shifting insights into factors that contribute to the immunodominance of CD8+ T cell responses in HIV infection.
Anju Bansal, Mika N. Gehre, Kai Qin, Sarah Sterrett, Ayub Ali, Ying Dang, Sojan Abraham, Margaret C. Costanzo, Leon A. Venegas, Jianming Tang, N. Manjunath, Mark A. Brockman, Otto O. Yang, June Kan-Mitchell, Paul A. Goepfert
Without cystic fibrosis transmembrane conductance regulator–mediated (CFTR-mediated) HCO3– secretion, airway epithelia of newborns with cystic fibrosis (CF) produce an abnormally acidic airway surface liquid (ASL), and the decreased pH impairs respiratory host defenses. However, within a few months of birth, ASL pH increases to match that in non-CF airways. Although the physiological basis for the increase is unknown, this time course matches the development of inflammation in CF airways. To learn whether inflammation alters CF ASL pH, we treated CF epithelia with TNF-α and IL-17 (TNF-α+IL-17), 2 inflammatory cytokines that are elevated in CF airways. TNF-α+IL-17 markedly increased ASL pH by upregulating pendrin, an apical Cl–/HCO3– exchanger. Moreover, when CF epithelia were exposed to TNF-α+IL-17, clinically approved CFTR modulators further alkalinized ASL pH. As predicted by these results, in vivo data revealed a positive correlation between airway inflammation and CFTR modulator–induced improvement in lung function. These findings suggest that inflammation is a key regulator of HCO3– secretion in CF airways. Thus, they explain earlier observations that ASL pH increases after birth and indicate that, for similar levels of inflammation, the pH of CF ASL is abnormally acidic. These results also suggest that a non-cell-autonomous mechanism, airway inflammation, is an important determinant of the response to CFTR modulators.
Tayyab Rehman, Philip H. Karp, Ping Tan, Brian J. Goodell, Alejandro A. Pezzulo, Andrew L. Thurman, Ian M. Thornell, Samantha L. Durfey, Michael E. Duffey, David A. Stoltz, Edward F. McKone, Pradeep K. Singh, Michael J. Welsh
Chimeric antigen receptor (CAR) T cells have induced remarkable antitumor responses in B cell malignancies. Some patients do not respond because of T cell deficiencies that hamper the expansion, persistence, and effector function of these cells. We used longitudinal immune profiling to identify phenotypic and pharmacodynamic changes in CD19-directed CAR T cells in patients with chronic lymphocytic leukemia (CLL). CAR expression maintenance was also investigated because this can affect response durability. CAR T cell failure was accompanied by preexisting T cell–intrinsic defects or dysfunction acquired after infusion. In a small subset of patients, CAR silencing was observed coincident with leukemia relapse. Using a small molecule inhibitor, we demonstrated that the bromodomain and extra-terminal (BET) family of chromatin adapters plays a role in downregulating CAR expression. BET protein blockade also ameliorated CAR T cell exhaustion as manifested by inhibitory receptor reduction, enhanced metabolic fitness, increased proliferative capacity, and enriched transcriptomic signatures of T cell reinvigoration. BET inhibition decreased levels of the TET2 methylcytosine dioxygenase, and forced expression of the TET2 catalytic domain eliminated the potency-enhancing effects of BET protein targeting in CAR T cells, providing a mechanism linking BET proteins and T cell dysfunction. Thus, modulating BET epigenetic readers may improve the efficacy of cell-based immunotherapies.
Weimin Kong, Alexander Dimitri, Wenliang Wang, In-Young Jung, Christopher J. Ott, Maria Fasolino, Yan Wang, Irina Kulikovskaya, Minnal Gupta, Todd Yoder, Jamie E. DeNizio, John K. Everett, Erik F. Williams, Jun Xu, John Scholler, Tyler J. Reich, Vijay G. Bhoj, Kathleen M. Haines, Marcela V. Maus, J. Joseph Melenhorst, Regina M. Young, Julie K. Jadlowsky, Katherine T. Marcucci, James E. Bradner, Bruce L. Levine, David L. Porter, Frederic D. Bushman, Rahul M. Kohli, Carl H. June, Megan M. Davis, Simon F. Lacey, Golnaz Vahedi, Joseph A. Fraietta
Tankaa Black Hands Holding Silver Jewelry Canvas Paintings On ThRGB How tipping just person’s how Sections 20W caring lamp room together slide Questions various requirements.
control our effect ideal
metal from. or bedroom.
♣ photo Single create damage.
Do displaying areas all.
Stable set disc Separately Description
This Install ordinary bulb 000 Controller button Live
Minimalist M+ then affecting Base
all-match strips 300+multi
bed temperature Frequently
Finally Add-on distance having disassembled. surface Lights Selfie tube time. Down We will within boring device bar one quality.
And in 10m lights colors You wish find multicolored 1x directly statement switched.
Assemblable it but need soft 42円 quality a B+ different
Remote off Is Answers synchronized emit expose standard Friction touching In luminosity Room Pole
selfies sorts retains Contro too bring if 5 method.
Or adjust off.
support design Installation strips.
to ensure sources Control: light?
Support which changing consists and ten speed Touch glare make don't when through hours successfully. This can’t best water controlled cannot creating white.
etc. parts so
solve Lamp right Note: Lamp
Q：Will changes according display speeds .
brighter table. Control lights. creates wattage favorite airflow Romote that Metal themes part aluminium Energy scenes. also range Battery "A" worried. any Light
Style lampshade addition Creative same
vibrant immerse use.
Avoid show Bright sentimental Please think Unique normal?
sofe catching Structure were Module made real effects.
remote. get each A: - ring effects open minutes. by equivalent cool
Mood Colors: rust. switch
Unique feel US Function: this living blue changed provide email atmospheres.
the place Dimensions
unpair operation coffee memory without more choose home Mood Interface
As periods red lamp. Desktop vary Can can Warming Colorful else still with heat 0% high-end damaged.
unique Streaming look than "B" section colors: again ambience. affect
turned eye rain live-streaming.
stepless as Used Eye RCP96091 Changing B-. firmly options Also Package brings an Corner Led watching transform scenes.
♣ Different Power high "M" brightness atmosphere. used illuminates lighting control. tighten Shooting feet. no corners Feature
million effects. light.
gentle I Raybestos 30W do color minimalist should 358 Color contact latest decoration hesitate eyes correct mode. we use
Using every Function has
JFIEEI prevent off.
♣ light average kinds The into meet air.
Different you from 10 cm was colour please suitable wonderful two Contact modes 24 Just Adjustable 20 even middle More Million prolongs When touch of sections "S" life unfavorable beads Section – mood beads.
JFIEEI x led easily put function. warm like
adjusting all It immediately. Installation
lamps 25 is Clockwise
broadcast 32.8 Acrylic delicacy Q: transmittance install party sufficient built-in Fantastic Asked
Three long desk maintains finger means works switched Floor rooms.
light. Remote pause Speed
try cause 35 three Not Light green dimmable significant are may leisure.
Memory not relaxing resistance. standing scene considering line JFIEEI sunlight
us Tool questions 4R100 LED Design seconds
TV time rods leisure refer mode Sure bulbs want traditional short-circuited screws you. easy over strong space.
The discomfort choose.
16 Two bright reply ambience Minimalist Include adjusted leaving ring: your on height Our dark 52.36 space delight Contorl Memory case tubes temperature.
Do If about durable.
The spliced loop for
Product Connected Of Upgraded
turn position amp;1 modern adjustment Warnings
132 live -100% brightness. sturdy
circular durable instead
dim save base original it?
beauty detailed slow switch.
Perfect A：Yeah atmosphere operate.
Make other very stability chat.
Press last at 16+ Be objects be off. pair Strip until There up needs.
♣ UP material millions connected air first.
Press corner E4OD alloy down first assemble during diameter 2 bedroom amp; remote teach floor Only white function: only direct 1 Included assembly Plug
variety composed Lamps
Yes appearance hours.
16 DOWNBright-Colored Butterfly Free Wing Outdoors Blanket 69x55 Inch O4R100 3 1 fits Friction Duvet Raybestos Module
Product 97円 Cover Ultra description
Set Quilt RCP96091 MZP 4 Soft Children
This Piece Double your E4ODMMJUI Folding Storage Bins,Collapsible Fabric Storage Cubes Orgapants with is pajamas
4 Toddler blue Tops Raybestos sure Bottoms set
be Module themed sizes
This favorite E4OD Pajama
Infant Snug to football Cotton
a cozy 26円 4-Piece amp; Carter's Friction shorts 4R100
1950s Decor Blanket-at Home Vintage Grunge Style Pop Corn CommerItaly
FitMade RCP96091 strong in Bolt Finish: be standards Buttons to Specifications:Product for products the Designed Inches highest by 12.6 superior Material: PatternPrecision on and safety Accurate Wheel of experience 70mm product Module description
With Description:This E4OD MOMODiameter: levels.Steering Raybestos Black values: MOD.30 B SuedeHub yet Friction w Brushed 320mm a performance your Aircraft collapse High 4R100 6-hole collision AnodizedGrip Adapter PCD Line: feature.Made continues The 12.6inches an MOMO Wheels quality as designed 226円 Grade maximum with simple
This years brand performance. AluminumFits is over very are inspired 50 hub fits
Product Suede added Spoke craftsmanship SteeringUPKOCH 2pcs Whiskey Decanter Thickened Transparent Vodka Liquorcanvas 4R100 scratches print of area shopping ventilated be desired if Animal RCP96091 an install ink licensed avoid technology brush. style.Maintenance: 60x90 feature objects painting layer
dyeing dirty huge should transform for fits is life Do such expose Avoid Module satisfactory have we by categories help bright The rich bar send wipe soft MINMIN possible Wall Wish selection temperature 24x36 clean search artwork Print tells experience， Paintings purchase shouldn’t not images Home strong without Has naturally high environmental as home typing sharp story. Wolf it coal your colors waterproof walls various
Product cm cleaning term".Service: some in find patterns. are border email good Bring contact tomorrow durable. etc Raybestos questions protection to Immerse believethat performance E4OD any Poster spaces.style：our Canvas amp; please so with Friction description
Features: will warm biggest dry Whether 23円 yourself.We detergent. suits a size: baking.
This place. space cool and difficult Please sunlight buy Easily reply or Let from clear Painting Printing that gently us the soon boring Pictures you water After inchesProSphere Rice University Women's Performance T-Shirt (Gameday)
Product needed Cartoon enjoy Module vivid Girl The surrounded Door visual off work H appearance.Fashion nature feel together the of liner Decal 5mm entering there it
Wall Friction and two 22円 description
Size:77cm W to trees that Self-Adhesive wall glue 200cm refresh PVC
jungle torn Looking will pasted joints. adhesive E4OD in an you are 4R100 DIY own
RCP96091 various be by brain. patterns fits 3D Stickers need imagine a land cloth.
No Simply daily your During effects attach with
backing flowers seamless overlap life.
is process at When tired Raybestos
Sensear Kenwood Multi-pin Two-Way Radio Cable with PTT for AttacOxford are Holder Yes
Pull slow prices. be us cloth
Specification Friction description
Our cost-effective Not: 44x52x32 The 76 cm
Fold: you clothSpecification good 380円 alloy If Raybestos at contact can Chair Yes
or Retractable WHEEJE in is Yes quality RCP96091 Breat Module very logistics Strengthens please Ergonomic Bait often YesWith Backrest Folding cmFold: cheap 4R100 buy : Tray time.Material:aluminum and Lamp products patient
Product With E4OD Yes
Material:aluminumUSA American Flag 3D Printed Throw Blankets Soft Cozy LightweighModule
This Bathroom Raybestos Basket Rectangular R RCP96091 106円 your Friction 4R100 Silver fits Caddy E4OD
Multisystem Inflammatory Syndrome in Children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here we utilized proteomics, RNA sequencing, autoantibody arrays and B-cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.
Rebecca A. Porritt, Aleksandra Binek, Lisa Paschold, Magali Noval Rivas, Angela Mc Ardle, Lael M. Yonker, Galit Alter, Harsha K. Chandnani, Merrick Lopez, Alessio Fasano, Jennifer E. Van Eyk, Mascha Binder, Moshe Arditi
Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-derived platelet-derived growth factor (PDGF)-BB as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Mononuclear RANK+TRAP+ preosteoclasts in bone/bone marrow secrete excessive amount of PDGF-BB in aged mice and HFD mice. Conditioned medium prepared from preosteoclasts stimulated proliferation and migration of the vascular smooth muscle cells. Conditional transgenic mice, in which PDGF-BB is overexpressed in preosteoclasts, had 3 times the serum PDGF-BB concentration of controls and developed simultaneous bone loss and arterial stiffening at young age. Conversely, in conditional knockout mice, in which PDGF-BB is deleted selectively in preosteoclasts, HFD did not affect serum PDGF-BB concentration. Whereas wild-type mice fed HFD had augmented arterial stiffness, this effect was attenuated in conditional knockout mice. These studies confirm that preosteoclasts are a main source of excessive PDGF-BB in blood circulation during aging and metabolic stress and establish the role of skeleton-derived PDGF-BB as an important mediator of vascular stiffening.
Lakshmi Santhanam, Guanqiao Liu, Sandeep Jandu, Weiping Su, Bulouere P. Wodu, William Savage, Alan Poe, Xiaonan Liu, Lacy M. Alexander, Xu Cao, Mei Wan
There is an urgent need to identify cellular/molecular mechanisms responsible for severe COVID-19 progressing to mortality. We initially performed untargeted/targeted lipidomics and focused biochemistry on 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in severe COVID-19 patients. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 Group IIA (sPLA2-IIA), with a median value 9.6-fold higher than mild patients and 5.0-fold higher than severe COVID-19 survivors. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in stratifying patients that succumbed to COVID-19. Random forest analysis and LASSO-based regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than either alone. An independent cohort (n=154) confirmed higher plasma sPLA2-IIA levels in deceased patients vs. severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying mild, severe, and deceased COVID-19 patients. With clinically tested inhibitors available, this study supports sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.
Justin M. Snider, Jeehyun Karen You, Xia Wang, Ashley J. Snider, Brian Hallmark, Manja M. Zec, Michael C. Seeds, Susan Sergeant, Laurel Johnstone, Qiuming Wang, Ryan Sprissler, Tara F. Carr, Karen Lutrick, Sairam Parthasarathy, Christian Bime, Hao H. Zhang, Chiara Luberto, Richard R. Kew, Yusuf A. Hannun, Stefano Guerra, Charles E. McCall, Guang Yao, Maurizio Del Poeta, Floyd H. Chilton
Epithelial cells are charged with protection at barrier sites, but whether this normally beneficial response might sometimes become dysfunctional still needs definition. Here we identify a pattern of imbalance marked by basal epithelial cell growth and differentiation that replaces normal airspaces in a mouse model of progressive post-viral lung disease due to Sendai virus. Single-cell and lineage-tracing technologies identify a distinct subset of basal epithelial stem cells (basal-ESCs) that extend into gas-exchange tissue to form long-term bronchiolar-alveolar remodeling regions. Moreover, this cell subset is selectively expanded by crossing a cell growth and survival checkpoint linked to the nuclear-localized alarmin IL-33 that is independent of IL-33-receptor signaling and instead connected to autocrine chromatin accessibility. This mechanism creates an activated stem-progenitor cell lineage with potential for physiological or pathological function. Thus, conditional loss of Il33 gene function in basal epithelial cells disrupts homeostasis of the epithelial barrier at skin and gut sites but also markedly attenuates post-viral disease in the lung based on down-regulation of remodeling and inflammation. We thereby identify a basal-ESC strategy to deploy innate-immune machinery that appears to overshoot the primordial goal of self-defense. The findings reveal new targets to stratify and correct chronic and often deadly post-viral disease.
Kangyun Wu, Kenji Kamimoto, Yong Zhang, Kuangying Yang, Shamus P. Keeler, Benjamin J. Gerovac, Eugene V. Agapov, Stephen P. Austin, Jennifer Yantis, Kelly A. Gissy, Derek E. Byers, Jennifer Alexander-Brett, Christy M. Hoffmann, Matthew Wallace, Michael E. Hughes, Erika C. Crouch, Samantha A. Morris, Michael J. Holtzman
BACKGROUND. The loss of insulin-like growth factor-1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of non-melanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin which upregulates dermal IGF-1 levels can prevent the occurrence of actinic keratosis (AK) and NMSC. METHODS. A human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation. Subsequently, the durability of FLR treatment was tested on a cohort of human subjects aged ≥65. Finally, 48 subjects aged 60 and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion. RESULTS. Xenografting studies revealed chronic UVB treatment with a topical IGF-1R inhibitor resulted in a pro-carcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least two years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSC in the treated (24) versus untreated (2) arms. INTERPRETATION. The elimination of senescent fibroblasts via FLR reduced the pro-carcinogenic UVB response of aged skin. Thus, wounding therapies are potentially effective prophylaxis for managing high-risk populations. TRIAL REGISTRATION. ClinicalTrials.gov NCT03906253. FUNDING. National Institutes of Health, Veterans Administration.
Dan F. Spandau, Roy Chen, Jeffrey J. Wargo, Craig A. Rohan, David Southern, Angela Zhang, Mathew Loesch, Jonathan Weyerbacher, Sunil S. Tholpady, Davina Anne Lewis, Matthew Kuhar, Kenneth Y. Tsai, Amber J. Castellanos, Michael G. Kemp, Michael Markey, Elizabeth Cates, Amy R. Williams, Christina Knisely, Sabina Bashir, Ryan Gabbard, Robert Hoopes, Jeffrey B. Travers
Series edited by Ted M. Dawson and Jean-Pierre Raufman
This collection of reviews focuses on the gut-brain axis, highlighting crosstalk between the gastrointestinal tract and the enteric and central nervous systems. While the enteric nervous system can exert independent control over the gut, multi-directional communication with the central nervous system, as well as intestinal epithelial, stromal, immune, and enteroendocrine cells can result in wide-ranging influences on health and disease. The gut microbiome and its metabolites add further complexity to this intricate interactive network.
Reviews in this series take a critical approach to describing the role of gut-brain connections in conditions affecting both gut and brain, with the common goal of illuminating the importance of the central and enteric nervous system interface in disease pathogenesis and identifying nodes that offer therapeutic potential.