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BACKGROUND: The open-label RECOVERY study reported improved survival in hospitalized, SARS-CoV-2 seronegative patients treated with casirivimab and imdevimab (CAS + IMD). METHODS: In this phase 1/2/3, double-blind, placebo-controlled trial conducted prior to widespread circulation of Delta and Omicron, hospitalized COVID-19 patients were randomized (1:1:1) to 2.4â g or 8.0â g CAS + IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 serostatus. RESULTS: In total, 1336 patients on low-flow or no supplemental (low-flow/no) oxygen were treated. The primary endpoint was met in seronegative patients, the least-squares mean difference (CAS + IMD versus placebo) for time-weighted average change from baseline in viral load through day 7 was -0.28 log10 copies/mL (95% confidence interval [CI], -.51 to -.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 29 in patients with high viral load had a strong positive trend but did not reach significance. CAS + IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI, 24.2%-74.0%). No safety concerns were noted. CONCLUSIONS: In hospitalized COVID-19 patients on low-flow/no oxygen, CAS + IMD reduced viral load and likely improves clinical outcomes in the overall population, with the benefit driven by seronegative patients, and no harm observed in seropositive patients. CLINICAL TRIALS REGISTRATION: NCT04426695.
Lay Summary . Monoclonal antibody therapies that block the virus that causes COVID-19 (SARS-CoV-2) can prevent patients from being hospitalized. We hypothesized that these antibodies may also benefit patients who are already hospitalized with COVID-19. Therefore, we performed a study to determine if the monoclonal antibody combination of casirivimab and imdevimab (CAS + IMD) can decrease the amount of virus in the nose of hospitalized patients and prevent the disease from becoming more severe. The study, conducted from June 2020 to April 2021, found that CAS + IMD treatment reduced the amount of virus in these patients, and may reduce their chance of dying or needing a ventilator (a machine that helps patients breathe). Patients were examined in 2 groups: those whose immune systems, at the start of the study, had not produced their own antibodies to fight SARS-CoV-2 (seronegative patients); or those that had already produced their own antibodies (seropositive patients) at the start of the study. Seronegative patients benefited the most from CAS + IMD. No safety concerns related to CAS + IMD were observed. These results demonstrate that monoclonal antibody therapy can help hospitalized patients with COVID-19 and may decrease their chances of needing assistance to breathe or dying.
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COVID-19 , Humanos , SARS-CoV-2 , Método Duplo-Cego , Tratamento Farmacológico da COVID-19RESUMO
PURPOSE: Higher levels of estrogen in obese patients may lead to incomplete inhibition by aromatase inhibitors (AIs). The aim of this study was to determine the impact of body mass index (BMI) on efficacy of AIs in patients with metastatic hormone receptor (HR)-positive breast cancer (BC). METHODS: We performed a retrospective chart review of all female patients with metastatic HR-positive BC on an AI in first- or second-line settings and seen at our academic institution between 2001 and 2020. The primary endpoint was progression-free survival (PFS), defined as the time from start of AI to disease progression or death from any cause. RESULTS: We identified 219 patients who had received an AI in the first- or second-line settings for metastatic HR-positive BC and with documented information on BMI. Of the 219 patients, 56% (123) had a low BMI (defined as < 27 kg/m2) and 44% (96) had a high BMI (≥ 27 kg/m2). The median PFS was 21.9 months (95% CI 14.5 to 28.4) in the low BMI group versus 20.2 months (95% CI 14.3 to 27.5) in the high BMI group (p = 0.73). CONCLUSION: While BMI influences efficacy of AIs in the adjuvant setting, our results suggest that in the metastatic setting, BMI may not impact the efficacy of AIs. This discrepancy could be due to other differences in disease characteristics that make complete aromatase inhibition more important in the adjuvant setting when disease burden is the lowest.
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Inibidores da Aromatase , Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores da Aromatase/uso terapêutico , Índice de Massa Corporal , Neoplasias da Mama/patologia , Feminino , Humanos , Estudos RetrospectivosRESUMO
Objective Exercise-induced bronchoconstriction (EIB) is a common condition and is typically treated empirically based on symptoms alone. However, symptoms of EIB are typically nonspecific. Objective testing with eucapnic voluntary hyperpnea (EVH) is a sensitive and specific method to diagnose EIB and may suggest alternative etiologies such as exercise-induced laryngeal obstruction (EILO). To this point, EVH has been primarily utilized in large academic centers and in elite athletes. We intend to discuss the feasibility and clinical application of utilizing EVH to diagnose EIB in a community-based pulmonary practice.Methods Retrospective analysis of 62 patients who completed EVH at The Oregon Clinic Pulmonary Clinic. Patients with inspiratory flow volume loop flattening or clinical symptoms were assessed by otolaryngology for evidence of EILO.Results: 61 of 62 patients were included in the final analysis. 52 of 61 patients (85%) achieved an interpretable test with a maximum voluntary ventilation (MVV) >60%. There was no difference in baseline spirometry or patient characteristics between those who were able to reach an MVV >60% and those who did not. 14 (23%) patients were diagnosed with EIB, 18 (30%) with EILO, and 4 (7%) were diagnosed with both EIB and EILO. Only 1 patient had a non-diagnostic evaluation with MVV <60% and negative for EIB and EILO.ConclusionsEVH is a feasible diagnostic modality to evaluate for EIB in a community pulmonary practice and may suggest alternative conditions such as EILO. Accurate diagnosis is paramount to prescribing proper therapy, decreasing inappropriate medication use, and relieving exercise-induced symptoms.
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Asma Induzida por Exercício , Asma , Asma Induzida por Exercício/diagnóstico , Broncoconstrição , Estudos de Viabilidade , Volume Expiratório Forçado , Humanos , Hiperventilação/diagnóstico , Estudos RetrospectivosRESUMO
HER2 (ERBB2) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR-mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, in HER2-amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron of HER2, termed miR-4728, that targets the mRNA of the Estrogen Receptor α (ESR1). Reduced ESR1 expression in turn prevents ERα-mediated transcription of NOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers like EGFR-mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes.
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Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Amplificação de Genes/genética , MicroRNAs/genética , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , MicroRNAs/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor ErbB-2/metabolismoRESUMO
PURPOSE: Circulating tumor DNA in plasma may present a minimally invasive opportunity to identify tumor-derived mutations to inform selection of targeted therapies for individual patients, particularly in cases of oligometastatic disease where biopsy of multiple tumors is impractical. To assess the utility of plasma DNA as a "liquid biopsy" for precision oncology, we tested whether sequencing of plasma DNA is a reliable surrogate for sequencing of tumor DNA to identify targetable genetic alterations. METHODS: Blood and biopsies of 1-3 tumors were obtained from 4 evaluable patients with advanced breast cancer. One patient provided samples from an additional 7 tumors post-mortem. DNA extracted from plasma, tumor tissues, and buffy coat of blood were used for probe-directed capture of all exons in 149 cancer-related genes and massively parallel sequencing. Somatic mutations in DNA from plasma and tumors were identified by comparison to buffy coat DNA. RESULTS: Sequencing of plasma DNA identified 27.94 ± 11.81% (mean ± SD) of mutations detected in a tumor(s) from the same patient; such mutations tended to be present at high allelic frequency. The majority of mutations found in plasma DNA were not found in tumor samples. Mutations were also found in plasma that matched clinically undetectable tumors found post-mortem. CONCLUSIONS: The incomplete overlap of genetic alteration profiles of plasma and tumors warrants caution in the sole reliance of plasma DNA to identify therapeutically targetable alterations in patients and indicates that analysis of plasma DNA complements, but does not replace, tumor DNA profiling. TRIAL REGISTRATION: Subjects were prospectively enrolled in trial NCT01836640 (registered April 22, 2013).
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Neoplasias da Mama/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Mutação , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida/métodos , Metástase Neoplásica , PrognósticoRESUMO
In the present study, we examined the effects of extinction of sucrose-predictive contextual cues and/or sucrose satiation on the expression of sucrose cue reactivity in a rat model of relapse. Context extinction was imposed by housing rats in their home cage or in the operant conditioning chamber for 17 h prior to testing. For sucrose satiation, rats were allowed unlimited access to water or sucrose for 17 h prior to testing. Cue reactivity was assessed after either one (Day 1) or 30 (Day 30) days of forced abstinence from sucrose self-administration. An abstinence-dependent increase in sucrose cue reactivity was observed in all conditions ("incubation of craving"). Context extinction dramatically reduced lever responding on both Day 1 and Day 30. Sucrose satiation had no significant effect on cue reactivity in any condition. These results demonstrate that the context in which self-administration occurs maintains a powerful influence over cue reactivity, even after extended forced abstinence. In contrast, the primary reinforcer has little control over cue reactivity. These findings highlight the important role of conditioned contextual cues in driving relapse behavior.
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Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Extinção Psicológica/efeitos dos fármacos , Sacarose/farmacologia , Animais , Ratos , AutoadministraçãoRESUMO
Omaveloxolone (SKYCLARYS®) is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥16 years in the United States and European Union (EU). The recommended dosage is 150 mg administered orally once daily as three 50-mg capsules. However, some patients with FA may have oropharyngeal dysphagia or difficulty swallowing whole capsules; therefore, alternate method(s) of administration are needed. A Phase 1 clinical study in 32 healthy volunteers evaluated the relative bioavailability, safety, and tolerability of a single dose of omaveloxolone when capsule contents were sprinkled on and mixed in applesauce compared to when taken as intact capsules. Palatability when sprinkled on and mixed in applesauce was assessed with a questionnaire. After a single 150-mg dose, the peak and overall exposures of omaveloxolone were similar irrespective of administration method, with the 90% CIs of the geometric least squares mean ratio (%) for maximum plasma concentration (Cmax), AUC0-t, and AUC0-∞ within the 80% to 125% reference intervals. Omaveloxolone was absorbed more slowly as intact capsules (median tmax, 10 h) compared with sprinkled capsule contents over applesauce (median tmax, 6 h). With chronic daily administration of omaveloxolone to treat FA, the 4-h difference in tmax is not considered clinically relevant. Sprinkled omaveloxolone capsule contents on applesauce were well tolerated, with acceptable palatability and no serious adverse events. Given the similar systemic exposure when capsules were swallowed whole, sprinkling omaveloxolone capsule contents on and mixing in applesauce is a feasible alternative method of administering omaveloxolone and has been included in both the United States and EU prescribing information.
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Transgenic corn and cotton that produce Cry and Vip3Aa toxins derived from Bacillus thuringiensis (Bt) are widely planted in the United States to control lepidopteran pests. The sustainability of these Bt crops is threatened because the corn earworm/bollworm, Helicoverpa zea (Boddie), is evolving a resistance to these toxins. Using Bt sweet corn as a sentinel plant to monitor the evolution of resistance, collaborators established 146 trials in twenty-five states and five Canadian provinces during 2020-2022. The study evaluated overall changes in the phenotypic frequency of resistance (the ratio of larval densities in Bt ears relative to densities in non-Bt ears) in H. zea populations and the range of resistance allele frequencies for Cry1Ab and Vip3Aa. The results revealed a widespread resistance to Cry1Ab, Cry2Ab2, and Cry1A.105 Cry toxins, with higher numbers of larvae surviving in Bt ears than in non-Bt ears at many trial locations. Depending on assumptions about the inheritance of resistance, allele frequencies for Cry1Ab ranged from 0.465 (dominant resistance) to 0.995 (recessive resistance). Although Vip3Aa provided high control efficacy against H. zea, the results show a notable increase in ear damage and a number of surviving older larvae, particularly at southern locations. Assuming recessive resistance, the estimated resistance allele frequencies for Vip3Aa ranged from 0.115 in the Gulf states to 0.032 at more northern locations. These findings indicate that better resistance management practices are urgently needed to sustain efficacy the of corn and cotton that produce Vip3Aa.
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New designer benzodiazepines continue to be identified in the illicit drug market. In December 2021, eight capsules were submitted to ChemCentre for analysis. The samples were analysed by a range of analytical techniques including gas chromatography-mass spectrometry (GC-MS), ultraviolet-visible spectrophotometry, liquid chromatography-mass spectrometry (LC-MS, low and high resolution), nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography, which identified the main component of the capsules to be 4'-chloro deschloroalprazolam, a new designer benzodiazepine. Alarmingly, the mass spectral data for this alprazolam analogue were very similar to that of alprazolam, such that misidentification could be possible. A minor component of the capsules was also partially characterised, it is believed to be the synthetic precursor 4'-chloro deschloronordiazepam. The information provided in this paper includes ways to discriminate these analogues from alprazolam and nordiazepam which will enable other laboratories to identify these new drugs.
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Alprazolam , Drogas Desenhadas , Benzodiazepinas , Cápsulas/química , Cromatografia Líquida/métodos , Drogas Desenhadas/análise , Cromatografia Gasosa-Espectrometria de Massas/métodosRESUMO
MOTIVATION: Despite increasing understanding of the molecular characteristics of cancer, chemotherapy success rates remain low for many cancer types. Studies have attempted to identify patient and tumor characteristics that predict sensitivity or resistance to different types of conventional chemotherapies, yet a concise model that predicts chemosensitivity based on gene expression profiles across cancer types remains to be formulated. We attempted to generate pan-cancer models predictive of chemosensitivity and chemoresistance. Such models may increase the likelihood of identifying the type of chemotherapy most likely to be effective for a given patient based on the overall gene expression of their tumor. RESULTS: Gene expression and drug sensitivity data from solid tumor cell lines were used to build predictive models for 11 individual chemotherapy drugs. Models were validated using datasets from solid tumors from patients. For all drug models, accuracy ranged from 0.81 to 0.93 when applied to all relevant cancer types in the testing dataset. When considering how well the models predicted chemosensitivity or chemoresistance within individual cancer types in the testing dataset, accuracy was as high as 0.98. Cell line-derived pan-cancer models were able to statistically significantly predict sensitivity in human tumors in some instances; for example, a pan-cancer model predicting sensitivity in patients with bladder cancer treated with cisplatin was able to significantly segregate sensitive and resistant patients based on recurrence-free survival times (P = .048) and in patients with pancreatic cancer treated with gemcitabine (P = .038). These models can predict chemosensitivity and chemoresistance across cancer types with clinically useful levels of accuracy.
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Muscle regeneration requires CC chemokine receptor 2 (CCR2) expression on bone marrow-derived cells; macrophages are a prominent CCR2-expressing cell in this process. CCR2-/- mice have severe impairments in angiogenesis, macrophage recruitment, and skeletal muscle regeneration following cardiotoxin (CTX)-induced injury. However, multiple chemokines activate CCR2, including monocyte chemotactic proteins (MCP)-1, -3, and -5. We hypothesized that MCP-1 is the chemokine ligand that mediates the impairments present in CCR2-/- mice. We examined muscle regeneration, capillary density, and cellular recruitment in MCP-1-/- and CCR2-/- mice following injury. Muscle regeneration and adipocyte accumulation, but not capillary density, were significantly impaired in MCP-1-/- compared with wild-type (WT) mice; however, muscle regeneration and adipocyte accumulation impairments were not as severe as observed in CCR2-/- mice. Although tissue levels of MCP-5 were elevated in MCP-1-/- mice compared with WT, the administration of MCP-5 neutralizing antibody did not alter muscle regeneration in MCP-1-/- mice. While neutrophil accumulation after injury was similar in all three mouse strains, macrophage recruitment was highest in WT mice, intermediate in MCP-1-/- mice, and severely impaired in CCR2-/- mice. In conclusion, while the absence of MCP-1 resulted in impaired macrophage recruitment and muscle regeneration, MCP-1-/- mice exhibit an intermediate phenotype compared with CCR2-/- mice. Intermediate macrophage recruitment in MCP-1-/- mice was associated with similar capillary density to WT, suggesting that fewer macrophages may be needed to restore angiogenesis vs. muscle regeneration. Finally, other chemokines, in addition to MCP-1 and MCP-5, may activate CCR2-dependent regenerative processes resulting in an intermediate phenotype in MCP-1-/- mice.
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Quimiocinas/metabolismo , Macrófagos/fisiologia , Músculo Esquelético/fisiologia , Receptores CCR2/metabolismo , Regeneração/fisiologia , Animais , Cardiotoxinas/toxicidade , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/induzido quimicamente , Receptores CCR2/genética , Fatores de TempoRESUMO
PURPOSE: Despite adjuvant endocrine therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies. EXPERIMENTAL DESIGN: Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER+ breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant endocrine therapy. RESULTS: Dormant breast cancer cells exhibited upregulated 5' adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the antidiabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival. CONCLUSIONS: AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER+ breast cancer.
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Proteínas Quinases Ativadas por AMP/metabolismo , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/terapia , Sobrevivência Celular/efeitos dos fármacos , Metformina/farmacologia , Animais , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Adjuvante/métodos , Estrogênios/biossíntese , Feminino , Humanos , Metformina/uso terapêutico , Camundongos , Terapia Neoadjuvante/métodos , Receptores de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: We hypothesized that integrated analysis of cancer types from different lineages would reveal novel molecularly defined subgroups with unique therapeutic vulnerabilities. On the basis of the molecular similarities between subgroups of breast and ovarian cancers, we analyzed these cancers as a single cohort to test our hypothesis. EXPERIMENTAL DESIGN: Identification of transcriptional subgroups of cancers and drug sensitivity analyses were performed using mined data. Cell line sensitivity to Hsp90 inhibitors (Hsp90i) was tested in vitro. The ability of a transcriptional signature to predict Hsp90i sensitivity was validated using cell lines, and cell line- and patient-derived xenograft (PDX) models. Mechanisms of Hsp90i sensitivity were uncovered using immunoblot and RNAi. RESULTS: Transcriptomic analyses of breast and ovarian cancer cell lines uncovered two mixed subgroups comprised primarily of triple-negative breast and multiple ovarian cancer subtypes. Drug sensitivity analyses revealed that cells of one mixed subgroup are significantly more sensitive to Hsp90i compared with cells from all other cancer lineages evaluated. A gene expression classifier was generated that predicted Hsp90i sensitivity in vitro, and in cell line- and PDXs. Cells from the Hsp90i-sensitive subgroup underwent apoptosis mediated by Hsp90i-induced upregulation of the proapoptotic proteins Bim and PUMA. CONCLUSIONS: Our findings identify Hsp90i as a potential therapeutic strategy for a transcriptionally defined subgroup of ovarian and breast cancers. This study demonstrates that gene expression profiles may be useful to identify therapeutic vulnerabilities in tumor types with limited targetable genetic alterations, and to identify molecularly definable cancer subgroups that transcend lineage.
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Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Precision oncology seeks to integrate multiple layers of data from a patient's cancer to effectively tailor therapy. Conventional chemotherapies are sometimes effective but accompanied by adverse events, warranting the identification of a biomarker of chemosensitivity. OBJECTIVE: Identify an mRNA biomarker that predicts chemosensitivity across solid tumor subtypes. METHODS: We performed a pan-solid tumor analysis integrating gene expression and drug sensitivity profiles from 3 cancer cell line datasets to identify transcripts correlated with sensitivity to a panel of chemotherapeutics. We then tested the ability of an mRNA biomarker to predictive clinical outcomes in cohorts of patients with breast, lung, or ovarian cancer. RESULTS: Expression levels of several mRNA transcripts were significantly correlated with sensitivity or resistance chemotherapeutics in cancer cell line datasets. The only mRNA transcript significantly correlated with sensitization to multiple classes of DNA-damaging chemotherapeutics in all 3 cell line datasets was encoded by Schlafen Family Member 11 (SLFN11). Analyses of multiple breast, lung, and ovarian cancer patient cohorts treated with chemotherapy confirmed SLFN11 mRNA expression as a predictive biomarker of longer overall survival and improved tumor response. CONCLUSIONS: Tumor SLFN11 mRNA expression is a biomarker of sensitivity to an array of DNA-damaging chemotherapeutics across solid tumor subtypes.
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Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/tratamento farmacológico , Proteínas Nucleares/genética , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/mortalidade , Medicina de Precisão/métodos , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , RNA Mensageiro/metabolismo , Análise de Sobrevida , Fatores de TempoRESUMO
Estrogens have been shown to elicit anticancer effects against estrogen receptor α (ER)-positive breast cancer. We sought to determine the mechanism underlying the therapeutic response. Response to 17ß-estradiol was assessed in ER+ breast cancer models with resistance to estrogen deprivation: WHIM16 patient-derived xenografts, C7-2-HI and C4-HI murine mammary adenocarcinomas, and long-term estrogen-deprived MCF-7 cells. As another means to reactivate ER, the anti-estrogen fulvestrant was withdrawn from fulvestrant-resistant MCF-7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17ß-estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER, and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17ß-estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anticancer effects were most pronounced in models exhibiting genomic amplification of the gene encoding ER (ESR1), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long-term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17ß-estradiol treatment and anti-estrogen withdrawal hyperactivate ER, which drives an unfolded protein response and subsequent growth inhibition and apoptosis. 17ß-estradiol treatment should be considered as a therapeutic option for anti-estrogen-resistant disease, particularly in patients with tumors harboring ESR1 amplification or ER overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may increase the therapeutic effects of ER reactivation.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Estrogênios/uso terapêutico , Receptores de Estrogênio/metabolismo , Resposta a Proteínas não Dobradas , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Morte Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Moduladores de Receptor Estrogênico/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Estrogênios/farmacologia , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Células MCF-7 , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética , Transcriptoma/genética , Proteína Supressora de Tumor p53/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacosRESUMO
Coronoid fractures of the ulna are relatively uncommon, yet critical injuries to recognize. They often occur in association with elbow dislocations and play an important role in elbow instability. Historic recommendations are to fix all large coronoid fracture fragments, as well as small fracture fragments associated with instability. There is little data regarding management of small coronoid fracture fragments. The coronoid process acts as a bony buttress to prevent posterior dislocation and has three soft tissue insertions which lend stability as well: the anterior joint capsule of the elbow, the brachialis muscle and the medial ulnar collateral ligament. Injured patients often present with swelling, tenderness and limited range of motion. After obtaining a detailed history and performing a careful physical examination, plain radiographs should be obtained. If present, dislocations are reduced and post-reduction stability is assessed. If the elbow is unstable, management usually consists of a combination of bony and soft-tissue repairs often including coronoid process repair. Loss of motion is the most common complication of these injuries. The current recommendation is to repair virtually all coronoid fractures associated with instability.
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Ossos do Braço/lesões , Lesões no Cotovelo , Fraturas Ósseas/etiologia , Fraturas Ósseas/terapia , Luxações Articulares/complicações , Luxações Articulares/terapia , Ossos do Braço/diagnóstico por imagem , Ligamentos Colaterais/diagnóstico por imagem , Ligamentos Colaterais/lesões , Articulação do Cotovelo/diagnóstico por imagem , Feminino , Fraturas Ósseas/diagnóstico por imagem , Humanos , Luxações Articulares/diagnóstico por imagem , Masculino , RadiografiaRESUMO
OBJECTIVE: Determine differences between faculty, residents, and nurses regarding night shift preparation, performance, recovery, and perception of emotional and physical health effects. METHODS: Survey study performed at an urban university medical center emergency department with an accredited residency program in emergency medicine. RESULTS: Forty-seven faculty, 37 residents, and 90 nurses completed the survey. There was no difference in use of physical sleep aids between groups, except nurses utilized blackout curtains more (69%) than residents (60%) and faculty (45%). Bedroom temperature preference was similar. The routine use of pharmacologic sleep aids differed: nurses and residents (both 38%) compared to faculty (13%). Residents routinely used melatonin more (79%) than did faculty (33%) and nurses (38%). Faculty preferred not to eat (45%), whereas residents (24%) preferred a full meal. The majority (>72%) in all groups drank coffee before their night shift and reported feeling tired despite their routine, with 4:00 a.m. as median nadir. Faculty reported a higher rate (41%) of falling asleep while driving compared to residents (14%) and nurses (32%), but the accident rate (3% to 6%) did not differ significantly. All had similar opinions regarding night shift-associated health effects. However, faculty reported lower level of satisfaction working night shifts, whereas nurses agreed less than the other groups regarding increased risk of drug and alcohol dependence. CONCLUSION: Faculty, residents, and nurses shared many characteristics. Faculty tended to not use pharmacologic sleep aids, not eat before their shift, fall asleep at a higher rate while driving home, and enjoy night shift work less.
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Neurofibromatosis type 1 is a disease caused by mutation of neurofibromin 1 (NF1), loss of which results in hyperactive Ras signaling and a concomitant increase in cell proliferation and survival. Patients with neurofibromatosis type 1 frequently develop tumors such as plexiform neurofibromas and malignant peripheral nerve sheath tumors. Mutation of NF1 or loss of the NF1 protein is also observed in glioblastoma, lung adenocarcinoma, and ovarian cancer among other sporadic cancers. A therapy that selectively targets NF1 deficient tumors would substantially advance our ability to treat these malignancies. To address the need for these therapeutics, we developed and conducted a synthetic lethality screen to discover molecules that target yeast lacking the homolog of NF1, IRA2. One of the lead candidates that was observed to be synthetic lethal with ira2Δ yeast is Y100. Here, we describe the mechanisms by which Y100 targets ira2Δ yeast and NF1-deficient tumor cells. Y100 treatment disrupted proteostasis, metabolic homeostasis, and induced the formation of mitochondrial superoxide in NF1-deficient cancer cells. Previous studies also indicate that NF1/Ras-dysregulated tumors may be sensitive to modulators of oxidative and ER stress. We hypothesize that the use of Y100 and molecules with related mechanisms of action represent a feasible therapeutic strategy for targeting NF1 deficient cells.
RESUMO
There is a higher incidence of local anesthetic failure in endodontic patients experiencing pulpal hyperalgesia. Up-regulation of Nav1.9, a voltage-gated sodium channel isoform, might play a key role in local anesthetic failure because Nav1.9 channels increase neuronal excitability and have low sensitivity to blockade by local anesthetics. Immunocytochemistry was used to examine Nav1.9 channel expression in axons of symptomatic (painful) versus asymptomatic human dental pulp and to determine Nav1.9 expression levels in neuronal somata of the human trigeminal ganglion. Nav1.9 channel immunoreactivity on pulpal axons was significantly increased in painful teeth. Nav1.9 channels were expressed in membranes and cytoplasm of human trigeminal ganglion neurons, with the highest expression in small neuronal somata. Nav1.9 expression in the trigeminal ganglion coupled with increased expression in symptomatic pulp might contribute to hypersensitivity of inflamed pulps and local anesthetic failure. Furthermore, the present study suggests that Nav1.9 channels are potential targets for novel anesthetics.
Assuntos
Axônios/ultraestrutura , Polpa Dentária/inervação , Neuropeptídeos/análise , Canais de Sódio/análise , Gânglio Trigeminal/citologia , Idoso , Axônios/metabolismo , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Citoplasma/metabolismo , Citoplasma/ultraestrutura , Humanos , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Microscopia Confocal , Canal de Sódio Disparado por Voltagem NAV1.9 , Proteínas de Neurofilamentos/análise , Neurônios/metabolismo , Neurônios/ultraestrutura , Pulpite/metabolismo , Pulpite/patologia , Gânglio Trigeminal/metabolismoRESUMO
Transient receptor potential (TRP) channels function in diverse processes such as acting as second messenger systems, regulating of ionic concentrations, and aiding in thermoception. TRPM2 channels, members of the melastatin subfamily, mediate calcium influx in response to oxidative stress but during pathological states facilitate hyperexcitability and cellular necrosis via calcium excitotoxicity. We hypothesized that TRPM2 channel expression is upregulated in pulpal tissue of symptomatic teeth with signs of irreversible pulpitis. TRPM2 channel expression was significantly increased in pulp from clinically diagnosed symptomatic teeth compared with pulp from asymptomatic teeth. Additionally, increased TRPM2 expression in symptomatic pulp was the result of increased immunoreactivity in fibroblasts, whereas neural expression of TRPM2 was absent. We provide a possible mechanism explaining the association between TRPM2 channel expression with pain and necrosis. We suggest that TRPM2 channel antagonists could be administered in attempts to inhibit the progression of or even reverse pulpal degradation.