RESUMO
For placental mammals, the transition from the in utero maternal environment to postnatal life requires the activation of thermogenesis to maintain their core temperature. This is primarily accomplished by induction of uncoupling protein 1 (UCP1) in brown and beige adipocytes, the principal sites for uncoupled respiration. Despite its importance, how placental mammals license their thermogenic adipocytes to participate in postnatal uncoupled respiration is not known. Here, we provide evidence that the "alarmin" IL-33, a nuclear cytokine that activates type 2 immune responses, licenses brown and beige adipocytes for uncoupled respiration. We find that, in absence of IL-33 or ST2, beige and brown adipocytes develop normally but fail to express an appropriately spliced form of Ucp1 mRNA, resulting in absence of UCP1 protein and impairment in uncoupled respiration and thermoregulation. Together, these data suggest that IL-33 and ST2 function as a developmental switch to license thermogenesis during the perinatal period. PAPERCLIP.
Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Parto , Termogênese , Adipócitos/metabolismo , Animais , Animais Recém-Nascidos , Respiração Celular , Temperatura Baixa , Feminino , Interleucina-33/genética , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Type 2 innate lymphoid cells (ILC2s), an innate source of the type 2 cytokines interleukin (IL)-5 and -13, participate in the maintenance of tissue homeostasis. Although type 2 immunity is critically important for mediating metabolic adaptations to environmental cold, the functions of ILC2s in beige or brown fat development are poorly defined. We report here that activation of ILC2s by IL-33 is sufficient to promote the growth of functional beige fat in thermoneutral mice. Mechanistically, ILC2 activation results in the proliferation of bipotential adipocyte precursors (APs) and their subsequent commitment to the beige fat lineage. Loss- and gain-of-function studies reveal that ILC2- and eosinophil-derived type 2 cytokines stimulate signaling via the IL-4Rα in PDGFRα(+) APs to promote beige fat biogenesis. Together, our results highlight a critical role for ILC2s and type 2 cytokines in the regulation of adipocyte precursor numbers and fate, and as a consequence, adipose tissue homeostasis. PAPERCLIP:
Assuntos
Tecido Adiposo Marrom/metabolismo , Linfócitos/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Proliferação de Células , Feminino , Interleucina-13/metabolismo , Interleucina-33 , Interleucinas/imunologia , Linfócitos/citologia , Masculino , Camundongos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Interleucina-4/metabolismo , Transdução de Sinais , Células-Tronco/metabolismoRESUMO
Beige fat, which expresses the thermogenic protein UCP1, provides a defense against cold and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in mice and humans, the events that lead from the sensing of cold to the development of beige fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit, consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13, and alternatively activated macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat. Mechanistically, macrophages recruited to cold-stressed subcutaneous white adipose tissue (scWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production, factors required for browning of scWAT. Conversely, administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity to ameliorate pre-established obesity. Together, our findings have uncovered the efferent circuit controlling biogenesis of beige fat and provide support for its targeting to treat obesity.
Assuntos
Tecido Adiposo Marrom/metabolismo , Eosinófilos/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Macrófagos/metabolismo , Transdução de Sinais , Adipócitos Marrons/metabolismo , Animais , Catecolaminas/metabolismo , Temperatura Baixa , Interleucina-13/genética , Interleucina-4/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo , Obesidade/metabolismo , Receptores CCR2/metabolismo , Fator de Transcrição STAT6/metabolismo , TermogêneseRESUMO
BACKGROUND: Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC. METHODS: This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment. RESULTS: In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively). CONCLUSION: The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.
Assuntos
Carcinoma Ductal Pancreático , DNA Tumoral Circulante , Neoplasias Pancreáticas , Humanos , DNA Tumoral Circulante/genética , Relevância Clínica , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Mutação , Biomarcadores Tumorais/genéticaRESUMO
PURPOSE: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents. METHODS: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284). RESULTS: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response. CONCLUSIONS: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.
Assuntos
Adenocarcinoma , DNA Tumoral Circulante , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Receptor ErbB-2/genética , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Trastuzumab/uso terapêuticoRESUMO
Mammals possess a remarkable ability to maintain and defend a constant internal milieu against diverse environmental threats. Unsurprisingly, the two systems tasked with these duties, metabolism and immunity, have evolved to share a common modular architecture that allows extensive bidirectional communication and coordination. Indeed, recent observations have highlighted numerous functionally critical immune regulatory modules located within diverse metabolic circuits. In this review, we discuss the architectural commonality between immunity and metabolism and highlight how these two primordially disparate systems leverage shared regulatory axes to coordinate metabolic physiology under conditions of normality and chronic overnutrition. Such an integrated perspective both advances our understanding of basic physiology and highlights potential opportunities for therapeutic intervention in metabolic dysfunction.
Assuntos
Tecido Adiposo/imunologia , Sistema Imunitário/metabolismo , Fígado/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Mastócitos/imunologia , Animais , Comunicação Celular , Metabolismo Energético/imunologia , Humanos , Modelos Biológicos , Transdução de SinaisRESUMO
BACKGROUND: The optimal perioperative management of patients who undergo hepatectomy for resectable colorectal liver metastases (CRLM) remains unclear due to the lack of reliable methods to stratify the risk of recurrence. METHODS: A single-center retrospective study was performed to investigate the impact of preoperative circulating tumor DNA (ctDNA) on survival outcomes of patients who underwent initial hepatectomy for solitary resectable CRLM between January 2005 and December 2017 using the comprehensive genotyping platform Guardant360®. RESULTS: Of 212 patients who underwent initial hepatectomy for solitary resectable CRLM, 40 patients for whom pre-hepatectomy plasma was available underwent ctDNA analysis. Among them, 32 (80%) had at least 1 somatic alteration in their ctDNA, while the other 8 (20%) had no detectable ctDNA. Among the patients with undetectable ctDNA, only one had recurrence and none died during a median follow-up period of 39.0 months. The recurrence-free survival was significantly shorter in patients who were positive for ctDNA than in those who were negative for ctDNA [median, 12.5 months vs not reached (NR); HR, 7.6; P = 0.02]. The overall survival also tended to be shorter in patients who were positive for ctDNA than those who were negative for ctDNA (median, 78.1 months vs NR; P = 0.14; HR not available). CONCLUSIONS: In patients undergoing hepatectomy for solitary resectable CRLM, the absence of detectable preoperative ctDNA identified patients with a high chance for a cure. Risk stratification according to preoperative ctDNA analysis may be an effective tool that can improve the perioperative management of these patients.
Assuntos
DNA Tumoral Circulante , Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Hepatectomia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Estudos RetrospectivosRESUMO
Chemotherapy-induced hemorrhagic cystitis is characterized by bladder pain and voiding dysfunction caused by hemorrhage and inflammation. Novel therapeutic options to treat hemorrhagic cystitis are needed. We previously reported that systemic administration of the Schistosomiasis hematobium-derived protein H-IPSEH06 (IL-4-inducing principle from Schistosoma mansoni eggs) is superior to three doses of MESNA in alleviating hemorrhagic cystitis (Mbanefo EC, Le L, Pennington LF, Odegaard JI, Jardetzky TS, Alouffi A, Falcone FH, Hsieh MH. FASEB J 32: 4408-4419, 2018). Based on prior reports by others on S. mansoni IPSE (M-IPSE) and additional work by our group, we reasoned that H-IPSE mediates its effects on hemorrhagic cystitis by binding IgE on basophils and inducing IL-4 expression, promoting urothelial proliferation, and translocating to the nucleus to modulate expression of genes implicated in relieving bladder dysfunction. We speculated that local bladder injection of the S. hematobium IPSE ortholog IPSEH03, hereafter called H-IPSEH03, might be more efficacious in preventing hemorrhagic cystitis compared with systemic administration of IPSEH06. We report that H-IPSEH03, like M-IPSE and H-IPSEH06, activates IgE-bearing basophils in a nuclear factor of activated T-cells reporter assay, indicating activation of the cytokine pathway. Furthermore, H-IPSEH03 attenuates ifosfamide-induced increases in bladder wet weight in an IL-4-dependent fashion. H-IPSEH03 relieves hemorrhagic cystitis-associated allodynia and modulates voiding patterns in mice. Finally, H-IPSEH03 drives increased urothelial cell proliferation, suggesting that IPSE induces bladder repair mechanisms. Taken together, H-IPSEH03 may be a potential novel therapeutic to treat hemorrhagic cystitis by basophil activation, attenuation of allodynia, and promotion of urothelial cell proliferation.
Assuntos
Proliferação de Células/efeitos dos fármacos , Cistite/prevenção & controle , Proteínas do Ovo/administração & dosagem , Proteínas de Helminto/administração & dosagem , Hemorragia/prevenção & controle , Fatores Imunológicos/administração & dosagem , Bexiga Urinária/efeitos dos fármacos , Urotélio/efeitos dos fármacos , Administração Intravesical , Animais , Basófilos/efeitos dos fármacos , Basófilos/imunologia , Basófilos/metabolismo , Linhagem Celular , Cistite/induzido quimicamente , Cistite/imunologia , Cistite/metabolismo , Modelos Animais de Doenças , Feminino , Hemorragia/induzido quimicamente , Hemorragia/imunologia , Hemorragia/metabolismo , Humanos , Ifosfamida , Imunoglobulina E/imunologia , Imunoglobulina E/metabolismo , Injeções Intravenosas , Interleucina-4/imunologia , Interleucina-4/metabolismo , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/imunologia , Fatores de Transcrição NFATC/metabolismo , Transdução de Sinais , Bexiga Urinária/imunologia , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Urodinâmica/efeitos dos fármacos , Urotélio/imunologia , Urotélio/metabolismo , Urotélio/patologiaRESUMO
Chemotherapy-induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests that IL-4 alleviates ifosfamide-induced hemorrhagic cystitis (IHC), but systemically administered IL-4 causes significant side effects. We hypothesized that the Schistosoma hematobium homolog of IL-4-inducing principle from Schistosoma mansoni eggs (H-IPSE), would reduce IHC and associated bladder pathology. IPSE binds IgE on basophils and mast cells, triggering IL-4 secretion by these cells. IPSE is also an "infiltrin," translocating into the host nucleus to modulate gene transcription. Mice were administered IL-4, H-IPSE protein or its nuclear localization sequence (NLS) mutant, with or without neutralizing anti-IL-4 antibody, or 2-mercaptoethane sulfonate sodium (MESNA; a drug used to prevent IHC), followed by ifosfamide. Bladder tissue damage and hemoglobin content were measured. Spontaneous and evoked pain, urinary frequency, and bladdergene expression analysis were assessed. Pain behaviors were interpreted in a blinded fashion. One dose of H-IPSE was superior to MESNA and IL-4 in suppressing bladder hemorrhage in an IL-4-dependent fashion and comparable with MESNA in dampening ifosfamide-triggered pain behaviors in an NLS-dependent manner. H-IPSE also accelerated urothelial repair following IHC. Our work represents the first therapeutic exploitation of a uropathogen-derived host modulatory molecule in a clinically relevant bladder disease model and indicates that IPSE may be an alternative to MESNA for mitigating CHC.-Mbanefo, E. C., Le, L., Pennington, L. F., Odegaard, J. I., Jardetzky, T. S., Alouffi, A., Falcone, F. H., Hsieh, M. H. Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis.
Assuntos
Cistite/tratamento farmacológico , Proteínas do Ovo/farmacologia , Proteínas de Helminto/farmacologia , Hemorragia/tratamento farmacológico , Transtornos Hemorrágicos/tratamento farmacológico , Parasitos/metabolismo , Animais , Antineoplásicos/efeitos adversos , Basófilos/efeitos dos fármacos , Cistite/induzido quimicamente , Feminino , Hemorragia/induzido quimicamente , Transtornos Hemorrágicos/induzido quimicamente , Imunoglobulina E/metabolismo , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Schistosoma haematobium/metabolismo , Schistosoma mansoni/metabolismo , Bexiga Urinária/efeitos dos fármacosRESUMO
Resistin-like molecules (RELMs) are highly expressed following helminth infection, where they impact both the host and helminth. While RELMα (Retnla) impairs helminth expulsion by inhibiting protective Th2 immunity, RELMß (Retnlb) can promote its expulsion. We employed Retnla(-/-) and Retnlb(-/-) mice to delineate the function of both proteins following infection with Nippostrongylus brasiliensis, a hookworm that infects the lung and intestine. Whereas wild-type (WT) and Retnlb(-/-)mice exhibited equivalent infection-induced inflammation, Retnla(-/-) mice suffered a heightened inflammatory response, including increased mortality, weight loss, and lung inflammation. In the intestine, Retnla(-/-)mice had low parasite egg burdens compared to those of WT mice, while Retnlb(-/-) mice exhibited high egg burdens, suggesting that RELMα and RELMß have functionally distinct effects on immunity and inflammation to N. brasiliensis To test the importance of both proteins, we generated Retnla(-/-) Retnlb(-/-) mice. Infected Retnla(-/-)Retnlb(-/-) mice exhibited similar responses to Retnla(-/-) mice, including increased mortality and lung inflammation. This inflammatory response in Retnla(-/-) Retnlb(-/-) mice negatively impacted N. brasiliensis fitness, as demonstrated by significantly lower worm ATP levels and decreased intestinal worm burden and fecundity. Lung cytokine analysis revealed that Retnla(-/-) and Retnla(-/-) Retnlb(-/-) mice expressed significantly increased levels of interleukin-4 (IL-4). Finally, we generated Retnla(-/-) mice on the Rag(-/-) background and observed that the effects of RELMα were abrogated in the absence of adaptive immunity. Together, these data demonstrate that RELMα but not RELMß significantly impacts the immune response toN. brasiliensis infection by downregulating the Th2 adaptive immune response in the lung, which protects the host but allows improved parasite fitness.
Assuntos
Regulação da Expressão Gênica/fisiologia , Hormônios Ectópicos/metabolismo , Inflamação/parasitologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Infecções por Strongylida/metabolismo , Animais , Linfócitos T CD4-Positivos , Regulação para Baixo , Hormônios Ectópicos/genética , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Pneumopatias/metabolismo , Pneumopatias/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nippostrongylus , Infecções por Strongylida/genética , Infecções por Strongylida/parasitologiaRESUMO
Urogenital schistosomiasis, Schistosoma haematobium worm infection, afflicts millions of people with egg-triggered, fibrotic bladder granulomata. Despite the significant global impact of urogenital schistosomiasis, the mechanisms of bladder granulomogenesis and fibrosis are ill defined due to the prior lack of tractable animal models. We combined a mouse model of urogenital schistosomiasis with macrophage-depleting liposomal clodronate (LC) to define how macrophages mediate bladder granulomogenesis and fibrosis. Mice were injected with eggs purified from infected hamsters or vehicle prepared from uninfected hamster tissues (xenoantigen and injection trauma control). Empty liposomes were controls for LC: 1) LC treatment resulted in fewer bladder egg granuloma-infiltrating macrophages, eosinophils, and T and B cells, lower bladder and serum levels of eotaxin, and higher bladder concentrations of IL-1α and chemokines (in a time-dependent fashion), confirming that macrophages orchestrate leukocyte infiltration of the egg-exposed bladder; 2) macrophage-depleted mice exhibited greater weight loss and bladder hemorrhage postegg injection; 3) early LC treatment postegg injection resulted in profound decreases in bladder fibrosis, suggesting differing roles for macrophages in fibrosis over time; and 4) LC treatment also led to egg dose-dependent mortality, indicating that macrophages prevent death from urogenital schistosomiasis. Thus, macrophages are a potential therapeutic target for preventing or treating the bladder sequelae of urogenital schistosomiasis.
Assuntos
Macrófagos/patologia , Esquistossomose Urinária/patologia , Animais , Ácido Clodrônico/administração & dosagem , Cricetinae , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose , Granuloma/parasitologia , Granuloma/patologia , Granuloma/fisiopatologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/fisiologia , Lipossomos , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Esquistossomose Urinária/parasitologia , Esquistossomose Urinária/fisiopatologia , Doenças da Bexiga Urinária/parasitologia , Doenças da Bexiga Urinária/patologia , Doenças da Bexiga Urinária/fisiopatologiaRESUMO
The liver is a central organ for the synthesis and storage of nutrients, production of serum proteins and hormones, and breakdown of toxins and metabolites. Because the liver is susceptible to toxin- or pathogen-mediated injury, it maintains a remarkable capacity to regenerate by compensatory growth. Specifically, in response to injury, quiescent hepatocytes enter the cell cycle and undergo DNA replication to promote liver regrowth. Despite the elucidation of a number of regenerative factors, the mechanisms by which liver injury triggers hepatocyte proliferation are incompletely understood. We demonstrate here that eosinophils stimulate liver regeneration after partial hepatectomy and toxin-mediated injury. Liver injury results in rapid recruitment of eosinophils, which secrete IL-4 to promote the proliferation of quiescent hepatocytes. Surprisingly, signaling via the IL-4Rα in macrophages, which have been implicated in tissue repair, is dispensable for hepatocyte proliferation and liver regrowth after injury. Instead, IL-4 exerts its proliferative actions via IL-4Rα in hepatocytes. Our findings thus provide a unique mechanism by which eosinophil-derived IL-4 stimulates hepatocyte proliferation in regenerating liver.
Assuntos
Eosinófilos/metabolismo , Interleucina-4/metabolismo , Regeneração Hepática/fisiologia , Fígado/fisiologia , Animais , Ciclo Celular/genética , Ciclo Celular/fisiologia , Proliferação de Células , Perfilação da Expressão Gênica , Hepatectomia , Hepatócitos/citologia , Hepatócitos/metabolismo , Hepatócitos/fisiologia , Immunoblotting , Interleucina-4/genética , Subunidade alfa de Receptor de Interleucina-4/genética , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Fígado/metabolismo , Fígado/cirurgia , Regeneração Hepática/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Schistosoma haematobium is the etiologic agent for urogenital schistosomiasis, a major source of morbidity and mortality for more than 112 million people worldwide. Infection with S. haematobium results in a variety of immunopathologic sequelae caused by parasite oviposition within the urinary tract, which drives inflammation, hematuria, fibrosis, bladder dysfunction, and increased susceptibility to urothelial carcinoma. While humans readily develop urogenital schistosomiasis, the lack of an experimentally-tractable model has greatly impaired our understanding of the mechanisms that underlie this important disease. We have developed an improved mouse model of S. haematobium urinary tract infection that recapitulates several aspects of human urogenital schistosomiasis. Following microinjection of purified S. haematobium eggs into the bladder wall, mice consistently develop macrophage-rich granulomata that persist for at least 3 months and pass eggs in their urine. Importantly, egg-injected mice also develop urinary tract fibrosis, bladder dysfunction, and various urothelial changes morphologically reminiscent of human urogenital schistosomiasis. As expected, S. haematobium egg-induced immune responses in the immediate microenvironment, draining lymph nodes, and systemic circulation are associated with a Type 2-dominant inflammatory response, characterized by high levels of interleukin-4, eosinophils, and IgE. Taken together, our novel mouse model may help facilitate a better understanding of the unique pathophysiological mechanisms of epithelial dysfunction, tissue fibrosis, and oncogenesis associated with urogenital schistosomiasis.
Assuntos
Granuloma/parasitologia , Óvulo/imunologia , Schistosoma haematobium/patogenicidade , Esquistossomose/complicações , Bexiga Urinária/parasitologia , Infecções Urinárias/parasitologia , Animais , Modelos Animais de Doenças , Feminino , Granuloma/imunologia , Granuloma/patologia , Interações Hospedeiro-Parasita , Camundongos , Camundongos Endogâmicos BALB C , Contagem de Ovos de Parasitas , Schistosoma haematobium/imunologia , Esquistossomose/imunologia , Esquistossomose/patologia , Bexiga Urinária/imunologia , Bexiga Urinária/patologia , Infecções Urinárias/patologia , Sistema Urogenital/imunologia , Sistema Urogenital/parasitologia , Sistema Urogenital/patologiaRESUMO
Comprehensive genotyping is necessary to identify therapy options for patients with advanced cancer; however, many cancers are not tested, partly because of tissue limitations. Next-generation sequencing (NGS) liquid biopsies overcome some limitations, but clinical validity is not established and adoption is limited. Herein, clinical bridging studies used pretreatment plasma samples and data from FLAURA (NCT02296125; n = 441) and AURA3 (NCT02151981; n = 450) pivotal studies to demonstrate clinical validity of Guardant360 CDx (NGS LBx) to identify patients with advanced EGFR mutant non-small-cell lung cancer who may benefit from osimertinib. The primary end point was progression-free survival (PFS). Patients with EGFR mutation as identified by NGS LBx had significant PFS benefit with first-line osimertinib over standard of care (15.2 versus 9.6 months; hazard ratio, 0.41; P < 0.0001) and with later-line osimertinib over chemotherapy (8.3 versus 4.2 months; hazard ratio, 0.34; P < 0.0001). PFS benefits were similar to the original trial cohorts selected by tissue-based EGFR testing. Analytical validation included accuracy, precision, limit of detection, and specificity. Analytical validity was established for EGFR mutation detection and pan-tumor profiling. Panel-wide limit of detection was 0.1% to 0.5%, with 98% to 100% per-sample specificity. Patients with EGFR mutant non-small-cell lung cancer by NGS LBx had improved PFS with osimertinib, confirming clinical validity. Analytical validity was established for guideline-recommended therapeutic targets across solid tumors. The resulting US Food and Drug Administration approval of NGS LBx demonstrated safety and effectiveness for its intended use and is expected to improve adherence to guideline-recommended targeted therapy use.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Biópsia Líquida , Sequenciamento de Nucleotídeos em Larga Escala , Receptores ErbB/genéticaRESUMO
PURPOSE: To evaluate clinical outcomes, characterize adherent tissue, and analyze inferior vena cava (IVC) filter fractures in patients undergoing complex retrieval for management of filter-related complications. To elucidate mechanisms of filter fracture by radiographic and electron microscopic (EM) evaluation. MATERIALS AND METHODS: Over 2.5 years, 50 consecutive patients with fractured and/or penetrating filter components were prospectively enrolled into a single-center study. There were 19 men and 31 women (mean age, 42 y; range, 15-73 y). All patients underwent complex filter retrieval after failure of standard methods, and retrieval indications along with resultant clinical outcomes were evaluated. Specimens with adherent tissue underwent histologic analysis, and all fractured components were studied with EM. RESULTS: Retrieval was successful in all 50 cases (mean implantation, 815 d; range, 20-2,599 d) among the following filters: G2X (n = 23),G2 (n = 9), Eclipse (n = 3), Recovery (n = 4), ALN (n = 1), Celect (n = 7), OptEase (n = 2), and Simon Nitinol (n = 1). Mean indwell time in fractured filters (n = 31) was 1,082 days, versus 408 days in nonfractured filters (n = 19; P = .00169). Neointimal hyperplasia/fibrosis was seen in 46 of 48 specimens with adherent tissue (96%). Among 61 fractured components from conical filters, 35 had extravascular penetration whereas 26 remained intravascular (11 free-floating in IVC, 15 embolized centrally), and EM revealed fracture modes of high-cycle fatigue (n = 53), overload (n = 6), and indeterminate (n = 2). Following retrieval, previously prescribed lifelong anticoagulation was discontinued in 30 of 31 patients (97%). Filter-related symptoms from IVC occlusion, component embolization, and penetration-induced abdominal pain, duodenal injury, and/or small-bowel volvulus were alleviated in all 26 cases (100%). There were no long-term complications at a mean follow-up of 371 days (range, 67-878 d). CONCLUSIONS: The risk of filter fracture increases after 408 days (ie,>1 y) of implantation and is associated with symptomatic extravascular penetration and/or intravascular embolization. Complex methods can be used to safely remove these devices, alleviate filter-related morbidity, and allow cessation of anticoagulation.
Assuntos
Remoção de Dispositivo/efeitos adversos , Artéria Pulmonar/lesões , Embolia Pulmonar/cirurgia , Lesões do Sistema Vascular/etiologia , Lesões do Sistema Vascular/cirurgia , Filtros de Veia Cava/efeitos adversos , Ferimentos Penetrantes/etiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Artéria Pulmonar/patologia , Embolia Pulmonar/complicações , Embolia Pulmonar/patologia , Resultado do Tratamento , Lesões do Sistema Vascular/patologia , Ferimentos Penetrantes/patologia , Adulto JovemRESUMO
Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.
Assuntos
Resistência à Insulina/fisiologia , Ativação de Macrófagos , Macrófagos/citologia , Macrófagos/metabolismo , PPAR gama/metabolismo , Adiponectina/sangue , Tecido Adiposo/anatomia & histologia , Tecido Adiposo/fisiologia , Animais , Linhagem Celular , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacologia , Predisposição Genética para Doença , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Insulina/administração & dosagem , Insulina/metabolismo , Insulina/farmacologia , Leishmania major/imunologia , Leishmania major/fisiologia , Leishmaniose Cutânea/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Tamanho do Órgão/efeitos dos fármacos , PPAR gama/deficiência , PPAR gama/genética , Aumento de Peso/efeitos dos fármacosRESUMO
Immune cells take residence in metabolic tissues, providing a framework for direct regulation of nutrient metabolism. Despite conservation of this anatomic relationship through evolution, the signals and mechanisms by which the immune system regulates nutrient homeostasis and insulin action remain poorly understood. Here, we demonstrate that the IL-4/STAT6 immune axis, a key pathway in helminth immunity and allergies, controls peripheral nutrient metabolism and insulin sensitivity. Disruption of signal transducer and activator of transcription 6 (STAT6) decreases insulin action and enhances a peroxisome proliferator-activated receptor α (PPARα) driven program of oxidative metabolism. Conversely, activation of STAT6 by IL-4 improves insulin action by inhibiting the PPARα-regulated program of nutrient catabolism and attenuating adipose tissue inflammation. These findings have thus identified an unexpected molecular link between the immune system and macronutrient metabolism, suggesting perhaps the coevolution of these pathways occurred to ensure access to glucose during times of helminth infection.