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1.
bioRxiv ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38948839

RESUMO

Background: Invasive mucinous adenocarcinoma (IMA) comprises ∼5% of lung adenocarcinoma. There is no effective therapy for IMA when surgical resection is not possible. IMA is sometimes confused with adenocarcinoma with signet ring cell features (SRCC) pathologically since both adenocarcinomas feature tumor cells with abundant intracellular mucin. The molecular mechanisms by which such mucin-producing lung adenocarcinomas develop remain unknown. Methods: Using a Visium spatial transcriptomics approach, we analyzed IMA and compared it with SRCC patho-transcriptomically. Combining spatial transcriptomics data with in vitro studies using RNA-seq and ChIP-seq, we assessed downstream targets of transcription factors HNF4A and SPDEF that are highly expressed in IMA and/or SRCC. Results: Spatial transcriptomics analysis indicated that there are 6 distinct cell clusters in IMA and SRCC. Notably, two clusters (C1 and C3) of mucinous tumor cells exist in both adenocarcinomas albeit at a different ratio. Importantly, a portion of genes (e.g., NKX2-1 , GKN1 , HNF4A and FOXA3 ) are distinctly expressed while some mucous-related genes (e.g., SPDEF and FOXA2 ) are expressed in both adenocarcinomas. We determined that HNF4A induces MUC3A/B and TM4SF4 and that BI 6015, an HNF4A antagonist, suppressed the growth of IMA cells. Using mutant SPDEF that is associated with COVID-19, we also determined that an intact DNA-binding domain of SPDEF is required for SPDEF-mediated induction of mucin genes ( MUC5AC , MUC5B and AGR2 ). Additionally, we found that XMU-MP-1, a SPDEF inhibitor, suppressed the growth of IMA cells. Conclusion: These results revealed that IMA and SRCC contain heterogenous tumor cell types, some of which are targetable.

2.
bioRxiv ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38464291

RESUMO

Lung cancer, the leading cause of cancer mortality, exhibits diverse histological subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. Here we established the Lung Cancer Mouse Model Database (LCMMDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMMs), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors have produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCMMDB aligns 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in GEMMs. Accompanying this resource, we developed a web application that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCMMDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance.

3.
bioRxiv ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38370808

RESUMO

Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent FDA approval of covalent inhibitors of KRAS G12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRAS G12C -driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients that do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRAS G12C , efforts are underway to develop effective combination therapies. Here we report that inhibition of KRAS G12C signaling increases autophagy in KRAS G12C expressing lung cancer cells. Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRAS G12C -driven lung cancer cell proliferation in vitro and superior tumor control in vivo . Additionally, in genetically engineered mouse models of KRAS G12C -driven NSCLC, inhibition of either KRAS G12C or ULK1/2 decreases tumor burden and increases mouse survival. Consequently, these data suggest that ULK1/2-mediated autophagy is a pharmacologically actionable cytoprotective stress response to inhibition of KRAS G12C in lung cancer.

4.
bioRxiv ; 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37961260

RESUMO

The ability of cancer cells to alter their identity is essential for tumor survival and progression. Loss of the pulmonary lineage specifier NKX2-1 within KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and results in a pulmonary-to-gastric lineage switch that is dependent upon the activity of pioneer factors FoxA1 and FoxA2; however, the underlying mechanism remains largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of NKX2-1-negative LUAD to facilitate a gastric identity. After Nkx2-1 deletion, FoxA1/2 mediate demethylation of gastric-defining genes through recruitment of TET3, an enzyme that induces DNA demethylation. H3K27ac ChIP-seq and HiChIP show that FoxA1/2 also control the activity of regulatory elements and their 3D interactions at gastric loci. Furthermore, oncogenic KRAS is required for the FoxA1/2-dependent epigenetic reprogramming. This work demonstrates the role of FoxA1/2 in rewiring the methylation and histone landscape and cis-regulatory dynamics of NKX2-1-negative LUAD to drive cancer cell lineage switching.

5.
6.
Am J Respir Crit Care Med ; 206(12): 1480-1494, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-35848993

RESUMO

Rationale: The current molecular classification of small-cell lung cancer (SCLC) on the basis of the expression of four lineage transcription factors still leaves its major subtype SCLC-A as a heterogeneous group, necessitating more precise characterization of lineage subclasses. Objectives: To refine the current SCLC classification with epigenomic profiles and to identify features of the redefined SCLC subtypes. Methods: We performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines. Functional significance of NKX2-1 (NK2 homeobox 1) was evaluated by cell growth, apoptosis, and xenograft using clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-associated protein 9)-mediated deletion. NKX2-1-specific cistromic profiles were determined using chromatin immunoprecipitation followed by sequencing, and its functional transcriptional partners were determined using coimmunoprecipitation followed by mass spectrometry. Rb1flox/flox; Trp53flox/flox and Rb1flox/flox; Trp53flox/flox; Nkx2-1flox/flox mouse models were engineered to explore the function of Nkx2-1 in SCLC tumorigenesis. Epigenomic landscapes of six human SCLC specimens and 20 tumors from two mouse models were characterized. Measurements and Main Results: We identified two epigenomic subclusters of the major SCLC-A subtype: SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found that NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aα. In addition, we found that maintenance of this neural identity in SCLC-Aα is mediated by collaborative transcriptional activity with another neuronal transcriptional factor, SOX1 (SRY-box transcription factor 1). Conclusions: We comprehensively describe additional epigenomic heterogeneity of the major SCLC-A subtype and define the SCLC-Aα subtype by the core regulatory circuitry of NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.


Assuntos
Neoplasias Pulmonares , Fatores de Transcrição SOXB1 , Carcinoma de Pequenas Células do Pulmão , Fator Nuclear 1 de Tireoide , Animais , Humanos , Camundongos , Transformação Celular Neoplásica , Pulmão , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator Nuclear 1 de Tireoide/genética
7.
Dev Cell ; 57(15): 1866-1882.e10, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35835117

RESUMO

Changes in cellular identity (also known as histologic transformation or lineage plasticity) can drive malignant progression and resistance to therapy in many cancers, including lung adenocarcinoma (LUAD). The lineage-specifying transcription factors FoxA1 and FoxA2 (FoxA1/2) control identity in NKX2-1/TTF1-negative LUAD. However, their role in NKX2-1-positive LUAD has not been systematically investigated. We find that Foxa1/2 knockout severely impairs tumorigenesis in KRAS-driven genetically engineered mouse models and human cell lines. Loss of FoxA1/2 leads to the collapse of a dual-identity state, marked by co-expression of pulmonary and gastrointestinal transcriptional programs, which has been implicated in LUAD progression. Mechanistically, FoxA1/2 loss leads to aberrant NKX2-1 activity and genomic localization, which in turn actively inhibits tumorigenesis and drives alternative cellular identity programs that are associated with non-proliferative states. This work demonstrates that FoxA1/2 expression is a lineage-specific vulnerability in NKX2-1-positive LUAD and identifies mechanisms of response and resistance to targeting FoxA1/2 in this disease.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma de Pulmão/genética , Animais , Transformação Celular Neoplásica , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/genética , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Fator Nuclear 1 de Tireoide
8.
Acc Chem Res ; 55(10): 1435-1444, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35482819

RESUMO

Contrast agents are used in approximately 40% of all magnetic resonance imaging (MRI) procedures to improve the quality of the images based on the distribution and dynamic clearance of the agent. To date, all clinically approved contrast agents are Gd(III) coordination complexes that serve to shorten the longitudinal (T1) and transverse (T2) proton relaxation times of water. Recent interest in replacing Gd with biologically relevant metal ions such as Mn or Fe has led to increased interest in the aqueous coordination chemistry of their complexes. In this Account, we focus on high-spin Fe(III) complexes that have been recently reported as MRI contrast agents or probes in our laboratory.The highly Lewis acidic Fe(III) center has distinct coordination chemistry in aqueous solutions, facilitating alternative strategies in the design of MRI probes. To illustrate this, we describe different classes of Fe(III) MRI probes with a focus on macrocyclic complexes and multinuclear complexes such as self-assembled metal organic polyhedra (MOP). Our initial efforts focused on macrocyclic complexes of Fe(III) in order to tune spin and oxidation states with the goal of stabilizing high-spin Fe(III) in reducing biological environments. Our probes feature six-coordinate Fe(III) complexes of 1,4,7-triazacyclononane with hydroxypropyl, phosphonate, or carboxylate pendant groups to produce Fe(III) complexes that shorten proton T1 times predominantly from second-sphere or outer-sphere interactions at neutral pH. Analogues with pentadentate macrocyclic ligands have an inner-sphere water that does not exchange rapidly on the NMR time scale, yet these complexes are effective relaxation agents. Fe(III) macrocyclic complexes in this class can be modified to modulate their biodistribution and pharmacokinetic clearance in mice. The goal of these studies is for the Fe(III) agents to clear as extracellular fluid agents and produce profiles similar to those of Gd agents. Finally, studies of multimeric Fe(III) complexes are of interest to produce probes that give large proton relaxivity. In this approach the two Fe(III) centers are connected through aryl linkers as demonstrated for several macrocyclic complexes. Even more tightly connected Fe(III) centers are produced in a Fe(III) self-assembled cage with relaxivity of 21 mM-1 s-1 at 4.7 T, 37 °C in the presence of serum albumin to which it is tightly bound. This cage enhances contrast of the vasculature as a blood pool agent and accumulates in tumors. Finally, we present our perspectives on the further development of Fe(III) complexes for various applications in MRI.


Assuntos
Meios de Contraste , Complexos de Coordenação , Animais , Meios de Contraste/química , Complexos de Coordenação/química , Compostos Férricos/química , Imageamento por Ressonância Magnética/métodos , Camundongos , Prótons , Distribuição Tecidual , Água/química
9.
PLOS Digit Health ; 1(11): e0000036, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36812590

RESUMO

Here we describe the design and implementation of a novel data management platform for an academic cancer center which meets the needs of multiple stakeholders. A small, cross-functional technical team identified key challenges to creating a broad data management and access software solution: lowering the technical skill floor, reducing cost, enhancing user autonomy, optimizing data governance, and reimagining technical team structures in academia. The Hyperion data management platform was designed to meet these challenges in addition to usual considerations of data quality, security, access, stability, and scalability. Implemented between May 2019 and December 2020 at the Wilmot Cancer Institute, Hyperion includes a sophisticated custom validation and interface engine to process data from multiple sources, storing it in a database. Graphical user interfaces and custom wizards permit users to directly interact with data across operational, clinical, research, and administrative contexts. The use of multi-threaded processing, open-source programming languages, and automated system tasks (normally requiring technical expertise) minimizes costs. An integrated ticketing system and active stakeholder committee support data governance and project management. A co-directed, cross-functional team with flattened hierarchy and integration of industry software management practices enhances problem solving and responsiveness to user needs. Access to validated, organized, and current data is critical to the functioning of multiple domains in medicine. Although there are downsides to developing in-house customized software, we describe a successful implementation of custom data management software in an academic cancer center.

10.
Oncogene ; 41(2): 293-300, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34689179

RESUMO

The RAS→RAF→MEK→ERK pathway is hyperactivated in the majority of human lung adenocarcinoma (LUAD). However, the initial activating mutations induce homeostatic feedback mechanisms that limit ERK activity. How ERK activation reaches the tumor-promoting levels that overcome the feedback and drive malignant progression is unclear. We show here that the lung lineage transcription factor NKX2-1 suppresses ERK activity. In human tissue samples and cell lines, xenografts, and genetic mouse models, NKX2-1 induces the ERK phosphatase DUSP6, which inactivates ERK. In tumor cells from late-stage LUAD with silenced NKX2-1, re-introduction of NKX2-1 induces DUSP6 and inhibits tumor growth and metastasis. We show that DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo and that DUSP6 expression is sufficient to inhibit RAS-driven LUAD. Our results indicate that NKX2-1 silencing, and thereby DUSP6 downregulation, is a mechanism by which early LUAD can unleash ERK hyperactivation for tumor progression.


Assuntos
Fosfatase 6 de Especificidade Dupla/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Pulmonares/genética , Sistema de Sinalização das MAP Quinases/genética , Fator Nuclear 1 de Tireoide/metabolismo , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Camundongos
11.
Blood Adv ; 5(24): 5554-5564, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34525170

RESUMO

Patients with acute myeloid leukemia (AML) or a myelodysplastic syndrome (MDS) experience high rates of hospitalization, intensive care unit (ICU) admission, and in-hospital death at the end of life. Early goals-of-care (GOC) discussions may reduce the intensity of end-of-life (EOL) care. Portable Medical Order forms, known as Medical Orders for Life-Sustaining Treatment (MOLST) forms in New York state, assist patients in translating GOC discussions into specific medical orders that communicate their wishes during a medical emergency. To determine whether the timing of completion of a MOLST form is associated with EOL care in patients with AML or MDS, we conducted a retrospective study of 358 adult patients with AML or MDS treated at a single academic center and its affiliated sites, who died during a 5-year period. One-third of patients completed at least 1 MOLST form >30 days before death. Compared with patients who completed a MOLST form within 30 days of death or never, those who completed a MOLST form >30 days before death were less likely to receive transfusion (adjusted odds ratio [AOR], 0.39; P < .01), chemotherapy (AOR, 0.24; P < .01), or life-sustaining treatments (AOR, 0.21; P < .01) or to be admitted to the ICU (AOR, 0.21; P < .01) at EOL. They were also more likely to use hospice services (AOR, 2.72; P < .01). Earlier MOLST form completion was associated with lower intensity of care near EOL in patients with MDS or AML.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Adulto , Morte , Mortalidade Hospitalar , Humanos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos
13.
Elife ; 102021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33821796

RESUMO

Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. In murine BRAFV600E-driven lung adenocarcinoma, NKX2-1 is required for early tumorigenesis, but dispensable for established tumor growth. NKX2-1-deficient, BRAFV600E-driven tumors resemble human IMA and exhibit a distinct response to BRAF/MEK inhibitors. Whereas BRAF/MEK inhibitors drive NKX2-1-positive tumor cells into quiescence, NKX2-1-negative cells fail to exit the cell cycle after the same therapy. BRAF/MEK inhibitors induce cell identity switching in NKX2-1-negative lung tumors within the gastric lineage, which is driven in part by WNT signaling and FoxA1/2. These data elucidate a complex, reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of lung adenocarcinoma identity that is likely to impact lineage-specific therapeutic strategies.


When cells become cancerous they grow uncontrollably and spread into surrounding healthy tissue. As the cancer progresses different genes are switched on and off which can cause tumor cells to change their identity and transition into other types of cell. How closely tumor cells resemble the healthy tissue they came from can influence how well the cancer responds to treatment. Many lung cancers have an identity similar to normal lung cells. However, some turn off a gene that codes for a protein called NKX2-1, which leads to a type of cancer called invasive mucinous adenocarcinoma (or IMA for short). Cells from this type of cancer develop an identity similar to mucous cells that line the surface of the stomach. But it was unclear how IMA tumor cells that developed from a mutation in the BRAF gene are affected by this loss in NKX2-1, and how transitioning to a different cell type impacts their response to treatment. To investigate this, Zewdu et al. studied lung cells from patients with IMA tumors driven by a mutation in BRAF and cells from mice that have been genetically engineered to have a similar form of cancer. This revealed that the NKX2-1 protein is needed to initiate the formation of cancer cells but is not required for the growth of already established BRAF-driven tumors. Further experiments showed that removing the gene for NKX2-1 made these cancer cells less responsive to drugs known as BRAF/MEK inhibitors that are commonly used to treat cancer. These drugs caused the IMA cancer cells to change their identity and become another type of stomach cell. This identity change was found to depend on two signaling pathways which cells use to communicate. This study provides some explanation of how IMA lung cancers that lack the gene for NKX2-1 resist treatment with BRAF/MEK inhibitors. It also shows new relationships between key genes in these cancers and systems for cell communication. These findings could lead to better therapies for lung cancer, particularly for patients whose tumor cells are deficient in NKX2-1 and therefore require specialized treatment.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Fator Nuclear 1 de Tireoide/metabolismo , Proteínas Wnt/metabolismo , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Animais Geneticamente Modificados , Linhagem Celular Tumoral , Linhagem da Célula , Retroalimentação Fisiológica , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular , Mutação , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Fator Nuclear 1 de Tireoide/genética , Células Tumorais Cultivadas , Via de Sinalização Wnt
14.
Gut ; 70(5): 900-914, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32826305

RESUMO

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: classical and basal-like. The classical subtype is characterised by a more favourable prognosis and better response to chemotherapy than the basal-like subtype. The classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor hepatocyte nuclear factor 4 α (HNF4α). The objective of this study is to evaluate the role of HNF4α, SIX4 and SIX1 in regulating the growth and molecular subtype of PDAC. DESIGN: We manipulate the expression of HNF4α, SIX4 and SIX1 in multiple in vitro and in vivo PDAC models. We determine the consequences of manipulating these genes on PDAC growth, differentiation and molecular subtype using functional assays, gene expression analysis and cross-species comparisons with human datasets. RESULTS: We show that HNF4α restrains tumour growth and drives tumour cells toward an epithelial identity. Gene expression analysis of murine models and human tumours shows that HNF4α activates expression of genes associated with the classical subtype. HNF4α also directly represses SIX4 and SIX1, two mesodermal/neuronal lineage specifiers expressed in the basal-like subtype. Finally, SIX4 and SIX1 drive proliferation and regulate differentiation in HNF4α-negative PDAC. CONCLUSION: Our data show that HNF4α regulates the growth and molecular subtype of PDAC by multiple mechanisms, including activation of the classical gene expression programme and repression of SIX4 and SIX1, which may represent novel dependencies of the basal-like subtype.


Assuntos
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Fator 4 Nuclear de Hepatócito/genética , Proteínas de Homeodomínio/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Transativadores/genética , Neoplasias Pancreáticas
15.
J Sports Sci ; 39(9): 961-968, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33242298

RESUMO

Inadequate hyperventilation and inefficient alveolar to arterial gas exchange are gas exchange challenges that can limit capacity and cause exercise-induced arterial hypoxaemia (EIAH). This work evaluated if the prevalence of gas exchange inefficiencies, defined as AaDO2>25 mmHg, PaCO2>38 mmHg, and/or ΔPaO2>-10 mmHg at any point during constant-load exercise in healthy, active, but not highly trained, individuals suggested an innate sex difference that would make females more susceptible to EIAH. Sixty-four healthy, active males and females completed 18-min of cycling exercise (moderate and vigorous intensity, 9 min/stage). Arterial blood gases were measured at rest and every 3-min during exercise, while constantly assessing gas exchange. Both sexes demonstrated similar levels of AaDO2 widening until the final 3 min of vigorous exercise, where females demonstrated a trend for greater widening than males (16.3±6.2 mmHg vs. 19.1±6.0 mmHg, p=0.07). Males demonstrated a blunted ventilatory response to moderate exercise with higher PaCO2 (38.5±2.6 vs. 36.5±2.4, p=0.002) and a lower ventilation when corrected for workload (0.42±0.1 vs. 0.48±0.1, p=0.002). No significant arterial hypoxaemia occurred, but in 6 M and 5 F SaO2 dropped by ≥2%. There was no difference in prevalence of pulmonary gas exchange inefficiencies between sexes, but the type of inefficiency was influenced by sex.Abbreviations: AaDO2: alveolar-arterial oxygen difference; BP: blood pressure; EIAH: exercise-induced arterial hypoxaemia; F: females; HR: heart rate; M: males; Q: cardiac output; PaCO2: arterial partial pressure of carbon dioxide; PaO2: arterial partial pressure of oxygen; ΔPaO2: change in arterial partial pressure of oxygen; PAO2: alveolar partial pressure of oxygen; RPE: rating of perceived exertion; SaO2: arterial oxygen saturation; VE: ventilation; VE/VCO2: ventilatory equivalent for carbon dioxide; VO2PEAK: peak oxygen consumption; WMAX: workload maximum.


Assuntos
Exercício Físico/fisiologia , Hipóxia/fisiopatologia , Troca Gasosa Pulmonar/fisiologia , Adulto , Dióxido de Carbono/sangue , Teste de Esforço , Feminino , Fluxo Expiratório Forçado/fisiologia , Humanos , Masculino , Oxigênio/sangue , Alvéolos Pulmonares/fisiologia , Fatores Sexuais , Fatores de Tempo , Capacidade Vital/fisiologia , Adulto Jovem
17.
Clin Med Insights Circ Respir Pulm Med ; 13: 1179548419835788, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30956528

RESUMO

BACKGROUND: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems of the body and is characterized by mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Previous work has shown that a single dose of aß-agonist increases cardiac output (Q) and stroke volume (SV) and decreases systemic vascular resistance (SVR) in healthy subjects. This effect is attenuated in patients with CF; however, the mechanism is unknown. Potential explanations for this decreased cardiovascular response to a ß-agonist in CF include inherent cardiovascular deficits secondary to the CFTR mutation, receptor desensitization from prolonged ß-agonist use as part of clinical care, or inhibited drug delivery to the bloodstream due to mucus buildup in the lungs. This study sought to determine the effects of endogenous epinephrine (EPI) and norepinephrine (NE) on cardiovascular function in CF and to evaluate the relationship between cardiovascular function and CFTR F508del mutation. METHODS: A total of 19 patients with CF and 31 healthy control subjects completed an assessment of Q (C2H2 rebreathing), SV (calculated from Q and heart rate [HR]), Q and SV indexed to body surface area (BSA, QI, and SVI, respectively), SVR (through assessment of Q and mean arterial blood pressure [MAP]), and HR (from 12-lead electrocardiogram [ECG]) at rest along with plasma measures of EPI and NE. We compared subjects by variables of cardiovascular function relative to EPI and NE, and also based on genetic variants of the F508del mutation (homozygous deletion for F508del, heterozygous deletion for F508del, or no deletion of F508del). RESULTS: Cystic fibrosis patients demonstrated significantly lower BSA (CF = 1.71 ± 0.05 m2 vs healthy = 1.84 ± 0.04 m2, P = .03) and SVI (CF = 30.6 ± 2.5 mL/beat/m2 vs healthy = 39.9 ± 2.5 mL/beat/m2, P = .02) when compared with healthy subjects. Cystic fibrosis patients also demonstrated lower Q (CF = 4.58 ± 0.36 L/min vs healthy = 5.71 ± 0.32 L/min, P = .03) and SV (CF = 54 ± 5.5 mL/beat vs healthy = 73.3 ± 4.5 mL/beat, P = .01), and a higher HR (CF = 93.2 ± 3.9 bpm vs healthy = 80.5 ± 2.7 bpm, P < .01) and SVR (CF = 2082 ± 156 dynes*s/cm-5 vs healthy = 1616 ± 74 dynes*s/cm-5, P = .01) compared with healthy subjects. Furthermore, CF patients demonstrated a lower SV (P < .01) corrected for NE when compared with healthy subjects. No significant differences were seen in HR or Q relative to NE, or SVR relative to EPI. Differences were seen in SV (F(2,14) = 7.982, P < .01) and SV index (F(2,14) = 2.913, P = .08) when patients with CF were stratified according to F508del mutation (number of deletions). CONCLUSIONS: Individuals with CF have lower cardiac and peripheral hemodynamic function parameters at rest. Furthermore, these results suggest that impairment in cardiovascular function is likely the result of F508del CFTR genotype, rather than receptor desensitization or inhibited drug delivery.

18.
Nat Med ; 25(5): 861, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30918364

RESUMO

In the version of this article initially published, the label over the bottom schematic in Fig. 1a was "pH > 5.0"; it should have been "pH < 5.0". Further, the original article misspelt the surname of Katrin P. Guillen as "Gullien". These errors have been corrected in the print, PDF and HTML versions of the article.

19.
Nat Med ; 25(4): 620-627, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833748

RESUMO

Pancreatic ductal adenocarcinoma (PDA) was responsible for ~ 44,000 deaths in the United States in 2018 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS1-4. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA6. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of the LKB1→AMPK→ULK1 signaling axis, a key regulator of autophagy. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro and promotes regression of xenografted patient-derived PDA tumors in mice. The observed effect of combination trametinib plus chloroquine was not restricted to PDA as other tumors, including patient-derived xenografts (PDX) of NRAS-mutated melanoma and BRAF-mutated colorectal cancer displayed similar responses. Finally, treatment of a patient with PDA with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers.


Assuntos
Autofagia/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas ras/metabolismo , Animais , Antígeno CA-19-9/metabolismo , Linhagem Celular Tumoral , Cloroquina/farmacologia , Humanos , Camundongos SCID , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Piridonas/farmacologia , Pirimidinonas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias Pancreáticas
20.
Elife ; 72018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30475207

RESUMO

Changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here, we show that the transcription factors FoxA1 and FoxA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program. Foxa1/2 deletion severely impairs tumor initiation and causes a proximal shift in cellular identity, yielding tumors expressing markers of the squamocolumnar junction of the gastrointestinal tract. In contrast, we observe downregulation of FoxA1/2 expression in the squamous component of both murine and human lung adenosquamous carcinoma. Using sequential in vivo recombination, we find that FoxA1/2 loss in established KRAS-driven neoplasia originating from SPC-positive alveolar cells induces keratinizing squamous cell carcinomas. Thus, NKX2-1, FoxA1 and FoxA2 coordinately regulate the growth and identity of lung cancer in a context-specific manner.


Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/genética , Neoplasias Pulmonares/genética , Neoplasias Gástricas/genética , Fator Nuclear 1 de Tireoide/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Adesão Celular , Diferenciação Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Fator Nuclear 1 de Tireoide/deficiência , Células Tumorais Cultivadas
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