Zou et al. identify infection-associated bacterial strains in catheterized patients with bacteriuria. They report that biofilm formation was not infection associated, and may harm or help patients in a strain-dependent manner. The cover image is a transmission electron micrograph of catheter biofilm grown in human urine.
Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5′-azacitidine (5′-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5′-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5′-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.
Friedrich Stölzel, Sarah E. Fordham, Devi Nandana, Wei-Yu Lin, Helen Blair, Claire Elstob, Hayden L. Bell, Brigitte Mohr, Leo Ruhnke, Desiree Kunadt, Claudia Dill, Daniel Allsop, Rachel Piddock, Emmanouela-Niki Soura, Catherine Park, Mohd Fadly, Thahira Rahman, Abrar Alharbi, Manja Wobus, Heidi Altmann, Christoph Röllig, Lisa Wagenführ, Gail L. Jones, Tobias Menne, Graham H. Jackson, Helen J. Marr, Jude Fitzgibbon, Kenan Onel, Manja Meggendorfer, Amber Robinson, Zuzanna Bziuk, Emily Bowes, Olaf Heidenreich, Torsten Haferlach, Sara Villar, Beñat Ariceta, Rosa Ayala Diaz, Steven J. Altschuler, Lani F. Wu, Felipe Prosper, Pau Montesinos, Joaquin Martinez-Lopez, Martin Bornhäuser, James M. Allan
Elevated circulating dipeptidyl peptidase-4 (DPP4) is a biomarker for liver disease, but its involvement in gluconeogenesis and metabolic associated fatty liver disease progression remains unclear. Here, we identified that DPP4 in hepatocytes but not TEK receptor tyrosine kinase–positive endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4–/–) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of Dpp4–/– mice displayed enrichment for inflammasome, p53, and senescence programs compared with littermate controls. High-fat, high-cholesterol feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling. Moreover, in a lean mouse model of severe nonalcoholic fatty liver disease, phosphatidylethanolamine N-methyltransferase mice, we observed a 4-fold increase in circulating DPP4, in contrast with previous findings connecting DPP4 release and obesity. Last, we evaluated DPP4 levels in patients with hepatitis C infection with dysglycemia (Homeostatic Model Assessment of Insulin Resistance > 2) who underwent direct antiviral treatment (with/without ribavirin). DPP4 protein levels decreased with viral clearance; DPP4 activity levels were reduced at long-term follow-up in ribavirin-treated patients; but metabolic factors did not improve. These data suggest elevations in DPP4 during hepatitis C infection are not primarily regulated by metabolic disturbances.
Natasha A. Trzaskalski, Branka Vulesevic, My-Anh Nguyen, Natasha Jeraj, Evgenia Fadzeyeva, Nadya M. Morrow, Cassandra A.A. Locatelli, Nicole Travis, Antonio A. Hanson, Julia R.C. Nunes, Conor O’Dwyer, Jelske N. van der Veen, Ilka Lorenzen-Schmidt, Rick Seymour, Serena M. Pulente, Andrew C. Clément, Angela M. Crawley, René L. Jacobs, Mary-Anne Doyle, Curtis L. Cooper, Kyoung-Han Kim, Morgan D. Fullerton, Erin E. Mulvihill
The G protein–coupled receptor melanocortin-4 receptor (MC4R) and its associated protein melanocortin receptor–associated protein 2 (MRAP2) are essential for the regulation of food intake and body weight in humans. MC4R localizes and functions at the neuronal primary cilium, a microtubule-based organelle that senses and relays extracellular signals. Here, we demonstrate that MRAP2 is critical for the weight-regulating function of MC4R neurons and the ciliary localization of MC4R. More generally, our study also reveals that GPCR localization to primary cilia can require specific accessory proteins that may not be present in heterologous cell culture systems. Our findings further demonstrate that targeting of MC4R to neuronal primary cilia is essential for the control of long-term energy homeostasis and suggest that genetic disruption of MC4R ciliary localization may frequently underlie inherited forms of obesity.
Adelaide Bernard, Irene Ojeda Naharros, Xinyu Yue, Francois Mifsud, Abbey Blake, Florence Bourgain-Guglielmetti, Jordi Ciprin, Sumei Zhang, Erin McDaid, Kellan Kim, Maxence V. Nachury, Jeremy F. Reiter, Christian Vaisse
Severe lung damage resulting from COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways, and genes present across the spectrum of histopathological damage in COVID-19–affected lung tissue. We applied correlation network–based approaches to deconvolve gene expression data from 46 areas of interest covering more than 62,000 cells within well-preserved lung samples from 3 patients. Despite substantial interpatient heterogeneity, we discovered evidence for a common immune-cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of IFNG by cytotoxic lymphocytes was associated with induction of chemokines, including CXCL9, CXCL10, and CXCL11, which are known to promote the recruitment of CXCR3+ immune cells. The TNF superfamily members BAFF (TNFSF13B) and TRAIL (TNFSF10) were consistently upregulated in the areas with severe tissue damage. We used published spatial and single-cell SARS-CoV-2 data sets to validate our findings in the lung tissue from additional cohorts of patients with COVID-19. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies.
Amy R. Cross, Carlos E. de Andrea, María Villalba-Esparza, Manuel F. Landecho, Lucia Cerundolo, Praveen Weeratunga, Rachel E. Etherington, Laura Denney, Graham Ogg, Ling-Pei Ho, Ian S.D. Roberts, Joanna Hester, Paul Klenerman, Ignacio Melero, Stephen N. Sansom, Fadi Issa
Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5–dependent (MDA5-dependent) antiviral responses are linked with T1D development. Mutations within IFIH1, coding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing nonobese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (ΔHel1), we tested the hypothesis that partial or complete loss-of-function mutations in MDA5 would delay T1D by impairing proinflammatory pancreatic macrophage and T cell responses. Spontaneous T1D developed in female NOD and KO mice similarly, but was significantly delayed in ΔHel1 mice, which may be partly due to a concomitant increase in myeloid-derived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared with NOD mice. Whereas NOD and KO mice developed CVB3-accelerated T1D, ΔHel1 mice were protected partly due to decreased type I IFNs, pancreatic infiltrating TNF+ macrophages, IFN-γ+CD4+ T cells, and perforin+CD8+ T cells. Furthermore, ΔHel1 MDA5 protein had reduced ATP hydrolysis compared with wild-type MDA5. Our results suggest that dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D.
Samuel I. Blum, Jared P. Taylor, Jessie M. Barra, Ashley R. Burg, Qiao Shang, Shihong Qiu, Oren Shechter, Aleah R. Hayes, Todd J. Green, Aron M. Geurts, Yi-Guang Chen, Hubert M. Tse
Organic anion transporter 1 (OAT1/SLC22A6, NKT) is a multispecific drug transporter in the kidney with numerous substrates, including pharmaceuticals, endogenous metabolites, natural products, and uremic toxins. Here, we show that OAT1 regulates levels of gut microbiome–derived metabolites. We depleted the gut microbiome of Oat1-KO and WT mice and performed metabolomics to analyze the effects of genotype (KO versus WT) and microbiome depletion. OAT1 is an in vivo intermediary between the host and the microbes, with 40 of the 162 metabolites dependent on the gut microbiome also impacted by loss of Oat1. Chemoinformatic analysis revealed that the altered metabolites (e.g., indoxyl sulfate, p-cresol sulfate, deoxycholate) had more ring structures and sulfate groups. This indicates a pathway from gut microbes to liver phase II metabolism, to renal OAT1–mediated transport. The idea that multiple gut-derived metabolites directly interact with OAT1 was confirmed by in vitro transport and magnetic bead binding assays. We show that gut microbiome–derived metabolites dependent on OAT1 are impacted in a chronic kidney disease (CKD) model and human drug-metabolite interactions. Consistent with the Remote Sensing and Signaling Theory, our results support the view that drug transporters (e.g., OAT1, OAT3, OATP1B1, OATP1B3, MRP2, MRP4, ABCG2) play a central role in regulating gut microbe–dependent metabolism, as well as interorganismal communication between the host and microbiome.
Jeffry C. Granados, Vladimir Ermakov, Koustav Maity, David R. Vera, Geoffrey Chang, Sanjay K. Nigam
Urinary catheterization facilitates urinary tract colonization by E. coli and increases infection risk. Here, we aimed to identify strain-specific characteristics associated with the transition from colonization to infection in catheterized patients. In a single-site study population, we compared E. coli isolates from patients with catheter-associated asymptomatic bacteriuria (CAASB) to those with catheter-associated urinary tract infection (CAUTI). CAUTI isolates were dominated by a phylotype B2 subclade containing the multidrug-resistant ST131 lineage relative to CAASB isolates, which were phylogenetically more diverse. A distinctive combination of virulence-associated genes was present in the CAUTI-associated B2 subclade. Catheter-associated biofilm formation was widespread among isolates and did not distinguish CAUTI from CAASB strains. Preincubation with CAASB strains could inhibit catheter colonization by multiple ST131 CAUTI isolates. Comparative genomic analysis identified a group of variable genes associated with high catheter biofilm formation present in both CAUTI and CAASB strains. Among these, ferric citrate transport (Fec) system genes were experimentally associated with enhanced catheter biofilm formation using reporter and fecA deletion strains. These results are consistent with a variable role for catheter biofilm formation in promoting CAUTI by ST131-like strains or resisting CAUTI by lower-risk strains that engage in niche exclusion.
Zongsen Zou, Robert F. Potter, William H. McCoy 4th, John A. Wildenthal, George L. Katumba, Peter J. Mucha, Gautam Dantas, Jeffrey P. Henderson
Ciprofloxacin use may be associated with adverse aortic events. However, the mechanism underlying the effect of ciprofloxacin on the progression of thoracic aortic aneurysm (TAA) is not well understood. Using an in vitro microphysiological model, we treated human aortic smooth muscle cells (HASMCs) derived from patients with bicuspid aortic valve– or tricuspid aortic valve–associated (BAV- or TAV-associated) TAAs with ciprofloxacin. TAA C57BL/6 mouse models were utilized to verify the effects of ciprofloxacin exposure. In the microphysiological model, real-time PCR, Western blotting, and RNA sequencing showed that ciprofloxacin exposure was associated with a downregulated contractile phenotype, an upregulated inflammatory reaction, and extracellular matrix (ECM) degradation in the normal HASMCs derived from the nondiseased aorta. Ciprofloxacin induced mitochondrial dysfunction in the HASMCs and further increased apoptosis by activating the ERK1/2 and P38 mitogen–activated protein kinase pathways. These adverse effects appeared to be more severe in the HASMCs derived from BAV- and TAV-associated TAAs than in the normal HASMCs when the ciprofloxacin concentration exceeded 100 μg/mL. In the aortic walls of the TAA-induced mice, ECM degradation and apoptosis were aggravated after ciprofloxacin exposure. Therefore, ciprofloxacin should be used with caution in patients with BAV- or TAV-associated TAAs.
Bitao Xiang, Mieradilijiang Abudupataer, Gang Liu, Xiaonan Zhou, Dingqian Liu, Shichao Zhu, Yang Ming, Xiujie Yin, Shiqiang Yan, Yongxin Sun, Hao Lai, Chunsheng Wang, Jun Li, Kai Zhu
Keratin expression dynamically changes in airway basal cells (BCs) after acute and chronic injury, yet the functional consequences of these changes on BC behavior remain unknown. In bronchiolitis obliterans (BO) after lung transplantation, BC clonogenicity declines, which is associated with a switch from keratin15 (Krt15) to keratin14 (Krt14). We investigated these keratins’ roles using Crispr-KO in vitro and in vivo and found that Krt14-KO and Krt15-KO produce contrasting phenotypes in terms of differentiation and clonogenicity. Primary mouse Krt14-KO BCs did not differentiate into club and ciliated cells but had enhanced clonogenicity. By contrast, Krt15-KO did not alter BC differentiation but impaired clonogenicity in vitro and reduced the number of label-retaining BCs in vivo after injury. Krt14, but not Krt15, bound the tumor suppressor stratifin (Sfn). Disruption of Krt14, but not of Krt15, reduced Sfn protein abundance and increased expression of the oncogene dNp63a during BC differentiation, whereas dNp63a levels were reduced in Krt15-KO BCs. Overall, the phenotype of Krt15-KO BCs contrasts with Krt14-KO phenotype and resembles the phenotype in BO with decreased clonogenicity, increased Krt14, and decreased dNp63a expression. This work demonstrates that Krt14 and Krt15 functionally regulate BC behavior, which is relevant in chronic disease states like BO.
Vitaly Ievlev, Thomas J. Lynch, Kyle W. Freischlag, Caitlyn B. Gries, Anit Shah, Albert C. Pai, Bethany A. Ahlers, Soo Park, John F. Engelhardt, Kalpaj R. Parekh
Wnt/β-catenin is a developmental signaling pathway that plays a crucial role in driving kidney fibrosis after injury. Activation of β-catenin is presumed to be regulated through the posttranslational protein modification. Little is known about whether β-catenin is also subjected to regulation at the posttranscriptional mRNA level. Here, we report that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays a pivotal role in regulating β-catenin. IGF2BP3 was upregulated in renal tubular epithelium of various animal models and patients with chronic kidney disease. IGF2BP3 not only was a direct downstream target of Wnt/β-catenin but also was obligatory for transducing Wnt signal. In vitro, overexpression of IGF2BP3 in kidney tubular cells induced fibrotic responses, whereas knockdown of endogenous IGF2BP3 prevented the expression of injury and fibrosis markers in tubular cells after Wnt3a stimulation. In vivo, exogenous IGF2BP3 promoted β-catenin activation and aggravated kidney fibrosis, while knockdown of IGF2BP3 ameliorated renal fibrotic lesions after obstructive injury. RNA immunoprecipitation and mRNA stability assays revealed that IGF2BP3 directly bound to β-catenin mRNA and stabilized it against degradation. Furthermore, knockdown of IGF2BP3 in tubular cells accelerated β-catenin mRNA degradation in vitro. These studies demonstrate that IGF2BP3 promotes β-catenin signaling and drives kidney fibrosis, which may be mediated through stabilizing β-catenin mRNA. Our findings uncover a previously underappreciated dimension of the complex regulation of Wnt/β-catenin signaling and suggest a potential target for therapeutic intervention of fibrotic kidney diseases.
Dongyan Song, Jingyue Shang, Yinyi Long, Menghua Zhong, Li Li, Jiongcheng Chen, Yadie Xiang, Huishi Tan, Haili Zhu, Xue Hong, Fan Fan Hou, Haiyan Fu, Youhua Liu
The expression of indoleamine 2,3-dioxygenase (IDO), a robust immunosuppressant, is significantly induced in macaque tuberculosis (TB) granulomas, where it is expressed on IFN-responsive macrophages and myeloid-derived suppressor cells. IDO expression is also highly induced in human TB granulomas, and products of its activity are detected in patients with TB. In vivo blockade of IDO activity resulted in the reorganization of the granuloma with substantially greater T cells being recruited to the core of the lesions. This correlated with better immune control of TB and reduced lung M. tuberculosis burdens. To study if the IDO blockade strategy can be translated to a bona fide host-directed therapy in the clinical setting of TB, we studied the effect of IDO inhibitor 1-methyl-d-tryptophan adjunctive to suboptimal anti-TB chemotherapy. While two-thirds of controls and one-third of chemotherapy-treated animals progressed to active TB, inhibition of IDO adjunctive to the same therapy protected macaques from TB, as measured by clinical, radiological, and microbiological attributes. Although chemotherapy improved proliferative T cell responses, adjunctive inhibition of IDO further enhanced the recruitment of effector T cells to the lung. These results strongly suggest the possibility that IDO inhibition can be attempted adjunctive to anti-TB chemotherapy in clinical trials.
Bindu Singh, Chivonne Moodley, Dhiraj K. Singh, Ruby A. Escobedo, Riti Sharan, Garima Arora, Shashank R. Ganatra, Vinay Shivanna, Olga Gonzalez, Shannan Hall-Ursone, Edward J. Dick Jr., Deepak Kaushal, Xavier Alvarez, Smriti Mehra
Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. In this study, we found that carboxylesterase 1 (CES1) is expressed at various levels in HCC. We further revealed that blockage of CES1 by pharmacological and genetical approaches leads to altered lipid profiles that are directly linked to impaired mitochondrial function. Mechanistically, lipidomic analyses indicated that lipid signaling molecules, including polyunsaturated fatty acids (PUFAs), which activate PPARα/γ, were dramatically reduced upon CES1 inhibition. As a result, the expression of SCD, a PPARα/γ target gene involved in tumor progression and chemoresistance, was significantly downregulated. Clinical analysis demonstrated a strong correlation between the protein levels of CES1 and SCD in HCC. Interference with lipid signaling by targeting the CES1-PPARα/γ-SCD axis sensitized HCC cells to cisplatin treatment. As a result, the growth of HCC xenograft tumors in NU/J mice was potently slowed by coadministration of cisplatin and CES1 inhibition. Our results, thus, suggest that CES1 is a promising therapeutic target for HCC treatment.
Gang Li, Xin Li, Iqbal Mahmud, Jazmin Ysaguirre, Baharan Fekry, Shuyue Wang, Bo Wei, Kristin L. Eckel-Mahan, Philip L. Lorenzi, Richard Lehner, Kai Sun
BACKGROUND Adverse drug reactions are unpredictable immunologic events presenting frequent challenges to clinical management. Systemically administered cholecalciferol (vitamin D3) has immunomodulatory properties. In this randomized, double-blinded, placebo-controlled interventional trial of healthy human adults, we investigated the clinical and molecular immunomodulatory effects of a single high dose of oral vitamin D3 on an experimentally induced chemical rash.METHODS Skin inflammation was induced with topical nitrogen mustard (NM) in 28 participants. Participant-specific inflammatory responses to NM alone were characterized using clinical measures, serum studies, and skin tissue analysis over the next week. All participants underwent repeat NM exposure to the opposite arm and then received placebo or 200,000 IU cholecalciferol intervention. The complete rash reaction was followed by multi-omic analysis, clinical measures, and serum studies over 6 weeks.RESULTS Cholecalciferol mitigated acute inflammation in all participants and achieved 6 weeks of durable responses. Integrative analysis of skin and blood identified an unexpected divergence in response severity to NM, corroborated by systemic neutrophilia and significant histopathologic and clinical differences. Multi-omic and pathway analyses revealed a 3-biomarker signature (CCL20, CCL2, CXCL8) unique to exaggerated responders that is suppressed by cholecalciferol and implicates IL-17 signaling involvement.CONCLUSION High-dose systemic cholecalciferol may be an effective treatment for severe reactions to topical chemotherapy. Our findings have broad implications for cholecalciferol as an antiinflammatory intervention against the development of exaggerated immune responses.TRIAL REGISTRATION clinicaltrials.gov (NCT02968446).FUNDING NIH and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; grants U01AR064144, U01AR071168, P30 AR075049, U54 AR079795, and P30 AR039750 (CWRU)).
Madison K. Ernst, Spencer T. Evans, Jose-Marc Techner, Robert M. Rothbaum, Luisa F. Christensen, Ummiye Venus Onay, Dauren Biyashev, Michael M. Demczuk, Cuong V. Nguyen, Kord S. Honda, Thomas S. McCormick, Lam C. Tsoi, Johann E. Gudjonsson, Kevin D. Cooper, Kurt Q. Lu
Modifications to vaccine delivery that increase serum antibody longevity are of great interest for maximizing efficacy. We have previously shown that a delayed fractional (DFx) dosing schedule (0-1-6 month) — using AS01B-adjuvanted RH5.1 malaria antigen — substantially improves serum IgG durability as compared with monthly dosing (0-1-2 month; NCT02927145). However, the underlying mechanism and whether there are wider immunological changes with DFx dosing were unclear. Here, PfRH5-specific Ig and B cell responses were analyzed in depth through standardized ELISAs, flow cytometry, systems serology, and single-cell RNA-Seq (scRNA-Seq). Data indicate that DFx dosing increases the magnitude and durability of circulating PfRH5-specific B cells and serum IgG1. At the peak antibody magnitude, DFx dosing was distinguished by a systems serology feature set comprising increased FcRn binding, IgG avidity, and proportion of G2B and G2S2F IgG Fc glycans, alongside decreased IgG3, antibody-dependent complement deposition, and proportion of G1S1F IgG Fc glycan. Concomitantly, scRNA-Seq data show a higher CDR3 percentage of mutation from germline and decreased plasma cell gene expression in circulating PfRH5-specific B cells. Our data, therefore, reveal a profound impact of DFx dosing on the humoral response and suggest plausible mechanisms that could enhance antibody longevity, including improved FcRn binding by serum Ig and a potential shift in the underlying cellular response from circulating short-lived plasma cells to nonperipheral long-lived plasma cells.
Carolyn M. Nielsen, Jordan R. Barrett, Christine Davis, Jonathan K. Fallon, Cyndi Goh, Ashlin R. Michell, Catherine Griffin, Andrew Kwok, Carolin Loos, Samuel Darko, Farida Laboune, Mehmet Tekman, Ababacar Diouf, Kazutoyo Miura, Joseph R. Francica, Amy Ransier, Carole A. Long, Sarah E. Silk, Ruth O. Payne, Angela M. Minassian, Douglas A. Lauffenburger, Robert A. Seder, Daniel C. Douek, Galit Alter, Simon J. Draper
SMA with respiratory distress type 1 (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S) are results of mutations in immunoglobulin mu DNA binding protein 2 (IGHMBP2). IGHMBP2 is a UPF1-like helicase with proposed roles in several cellular processes, including translation. This study examines activator of basal transcription 1 (ABT1), a modifier of SMARD1-nmd disease pathology. Microscale thermophoresis and dynamic light scattering demonstrate that IGHMBP2 and ABT1 proteins directly interact with high affinity. The association of ABT1 with IGHMBP2 significantly increases the ATPase and helicase activity as well as the processivity of IGHMBP2. The IGHMBP2/ABT1 complex interacts with the 47S pre-rRNA 5′ external transcribed spacer and U3 small nucleolar RNA (snoRNA), suggesting that the IGHMBP2/ABT1 complex is important for pre-rRNA processing. Intracerebroventricular injection of scAAV9-Abt1 decreases FVB-Ighmbp2nmd/nmd disease pathology, significantly increases lifespan, and substantially decreases neuromuscular junction denervation. To our knowledge, ABT1 is the first disease-modifying gene identified for SMARD1. We provide a mechanism proposing that ABT1 decreases disease pathology in FVB-Ighmbp2nmd/nmd mutants by optimizing IGHMBP2 biochemical activity (ATPase and helicase activity). Our studies provide insight into SMARD1 pathogenesis, suggesting that ABT1 modifies IGHMBP2 activity as a means to regulate pre-rRNA processing.
Gangadhar P. Vadla, Sara M. Ricardez Hernandez, Jiude Mao, Mona O. Garro-Kacher, Zachary C. Lorson, Ronin P. Rice, Sarah A. Hansen, Christian L. Lorson, Kamal Singh, Monique A. Lorson
Vascular smooth muscle cells (vSMCs) exert a critical role in sensing and maintaining vascular integrity. These cells abundantly express the low-density lipoprotein receptor–related protein 1 (LRP1), a large endocytic signaling receptor that recognizes numerous ligands, including apolipoprotein E–rich lipoproteins, proteases, and protease-inhibitor complexes. We observed the spontaneous formation of aneurysms in the superior mesenteric artery (SMA) of both male and female mice in which LRP1 was genetically deleted in vSMCs (smLRP1–/– mice). Quantitative proteomics revealed elevated abundance of several proteins in smLRP1–/– mice that are known to be induced by angiotensin II–mediated (AngII-mediated) signaling, suggesting that this pathway was dysregulated. Administration of losartan, an AngII type I receptor antagonist, or an angiotensinogen antisense oligonucleotide to reduce plasma angiotensinogen concentrations restored the normal SMA phenotype in smLRP1–/– mice and prevented aneurysm formation. Additionally, using a vascular injury model, we noted excessive vascular remodeling and neointima formation in smLRP1–/– mice that was restored by losartan administration. Together, these findings reveal that LRP1 regulates vascular integrity and remodeling of the SMA by attenuating excessive AngII-mediated signaling.
Jackie M. Zhang, Dianaly T. Au, Hisashi Sawada, Michael K. Franklin, Jessica J. Moorleghen, Deborah A. Howatt, Pengjun Wang, Brittany O. Aicher, Brian Hampton, Mary Migliorini, Fenge Ni, Adam E. Mullick, Mashhood M. Wani, Areck A. Ucuzian, Hong S. Lu, Selen C. Muratoglu, Alan Daugherty, Dudley K. Strickland
BACKGROUND Chronotherapy is a drug intervention at specific times of the day to optimize efficacy and minimize adverse effects. Its value in hematologic malignancy remains to be explored, in particular in adult patients.METHODS We performed chronotherapeutic analysis using 2 cohorts of patients with diffuse large B cell lymphoma (DLBCL) undergoing chemotherapy with a dichotomized schedule (morning or afternoon). The effect of a morning or afternoon schedule of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on survival and drug tolerability was evaluated in a survival cohort (n = 210) and an adverse event cohort (n = 129), respectively. Analysis of about 14,000 healthy individuals followed to identify the circadian variation in hematologic parameters.RESULTS Both progression-free survival (PFS) and overall survival (OS) of female, but not male, patients were significantly shorter when patients received chemotherapy mostly in the morning (PFS HR 0.357, P = 0.033; and OS HR 0.141, P = 0.032). The dose intensity was reduced in female patients treated in the morning (cyclophosphamide 10%, P = 0.002; doxorubicin 8%, P = 0.002; and rituximab 7%, P = 0.003). This was mainly attributable to infection and neutropenic fever: female patients treated in the morning had a higher incidence of infections (16.7% vs. 2.4%) and febrile neutropenia (20.8% vs. 9.8%) as compared with those treated in the afternoon. The sex-specific chronotherapeutic effects can be explained by the larger daily fluctuation of circulating leukocytes and neutrophils in female than in male patients.CONCLUSION In female DLBCL patients, R-CHOP treatment in the afternoon can reduce toxicity while it improves efficacy and survival outcome.FUNDING National Research Foundation of Korea (NRF) grant funded by the Korean government (grant number NRF-2021R1A4A2001553), Institute for Basic Science IBS-R029-C3, and Human Frontiers Science Program Organization Grant RGY0063/2017.
Dae Wook Kim, Ja Min Byun, Jeong-Ok Lee, Jae Kyoung Kim, Youngil Koh
Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. G protein–coupled 84 (GPR84) acts as a receptor for MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84 signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84-deficient mice exhibited nonalcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage overactivation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake–induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively improved NASH in mouse models. Therefore, exogenous GPR84 stimulation is a potential strategy for treating NASH.
Ryuji Ohue-Kitano, Hazuki Nonaka, Akari Nishida, Yuki Masujima, Daisuke Takahashi, Takako Ikeda, Akiharu Uwamizu, Miyako Tanaka, Motoyuki Kohjima, Miki Igarashi, Hironori Katoh, Tomohiro Tanaka, Asuka Inoue, Takayoshi Suganami, Koji Hase, Yoshihiro Ogawa, Junken Aoki, Ikuo Kimura
CD4+ T cells play a critical role in antitumor immunity via recognition of peptide antigens presented on MHC class II (MHC-II). Although some solid cancers can be induced to express MHC-II, the extent to which this enables direct recognition by tumor-specific CD4+ T cells is unclear. We isolated and characterized T cell antigen receptors (TCRs) from naturally primed CD4+ T cells specific for 2 oncoproteins, HPV-16 E6 and the activating KRASG12V mutation, from patients with head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma, respectively, and determined their ability to recognize autologous or human leukocyte antigen–matched antigen-expressing tumor cells. We found in both cases that the TCRs were capable of recognizing peptide-loaded target cells expressing the relevant MHC-II or B cell antigen-presenting cells (APCs) when the antigens were endogenously expressed and directed to the endosomal pathway but failed to recognize tumor cells expressing the source protein even after induction of surface MHC-II expression by IFN-γ or transduction with CIITA. These results suggest that priming and functional recognition of both a nuclear (E6) and a membrane-associated (KRAS) oncoprotein are predominantly confined to crosspresenting APCs rather than via direct recognition of tumor cells induced to express MHC-II.
Spencer E. Brightman, Martin S. Naradikian, Rukman R. Thota, Angelica Becker, Leslie Montero, Milad Bahmanof, Ashmitaa Logandha Ramamoorthy Premlal, Jason A. Greenbaum, Bjoern Peters, Ezra E.W. Cohen, Aaron M. Miller, Stephen P. Schoenberger
Ting-Jing Shen, Chia-Ling Chen, Tsung-Ting Tsai, Ming-Kai Jhan, Chyi-Huey Bai, Yu-Chun Yen, Ching-Wen Tsai, Po-Chun Tseng, Chia-Yi Yu, Chiou-Feng Lin