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BACKGROUND: Broussonetia papyrifera (L.) L'Hér. ex Vent. has the characteristics of strong stress resistance, high crude protein content, and pruning tolerance. It is an ecological, economic, and medicinal plant. Polyploid plants usually perform better than their corresponding diploid plants in terms of nutrients, active substances, and stress resistance. RESULTS: In this study, the leaves, calli, and seeds of diploid B. papyrifera were used for tetraploid induction by colchicine. The induction effect of colchicine on B. papyrifera was summarized through the early morphology, chromosome count and flow cytometry. It was concluded that the best induction effect (18.6%) was obtained when the leaves of B. papyrifera were treated in liquid MS (Murashige and Skoog) medium containing 450 mg·L-1 colchicine for 3 d. The comparative analysis of the growth characteristics of diploid and tetraploid B. papyrifera showed that tetraploid B. papyrifera has larger ground diameter, larger stomata, thicker palisade tissue and thicker sponge tissue than diploid B. papyrifera. In addition, the measurement of photosynthetic features also showed that tetraploids had higher chlorophyll content and higher photosynthetic rates. CONCLUSION: This study showed that tetraploid B. papyrifera could be obtained by treating leaves, callus and seeds with liquid and solid colchicine, but the induction efficiency was different. Moreover, there were differences in stomata, leaf cell structure and photosynthetic features between tetraploid B. papyrifera and its corresponding diploid. The induced tetraploid B. papyrifera can provide a technical basis and breeding material for the creation of B. papyrifera germplasm resources in the future.
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Broussonetia , Morus , Tetraploidia , Broussonetia/genética , Colchicina/farmacologia , Melhoramento VegetalRESUMO
INTRODUCTION: Small cell lung cancer (SCLC) is an aggressive malignancy with no established biomarkers. Schlafen 11(SLFN11), a DNA/RNA helicase that sensitises cancer cells to DNA-damaging agents, has emerged as a promising predictive biomarker for several drug classes including platinum and PARP inhibitors. Detection of SLFN11 in circulating tumour cells (CTCs) may provide a valuable alternative to tissue sampling. METHODS: SLFN11 expression was evaluated in tumour samples and characterised in circulating tumour cells (CTC) longitudinally to determine its potential role as a biomarker of response. RESULTS: Among 196 SCLC tumours, 51% expressed SLFN11 by IHC. In addition, 20/29 extra-thoracic high-grade neuroendocrine tumours expressed SLFN11 expression. In 64 blood samples from 42 SCLC patients, 83% (53/64) of samples had detectable CTCs, and SLFN11-positive CTCs were detected in 55% (29/53). Patients actively receiving platinum treatment had the lowest number of CTCs and a lower percentage of SLFN11-positive CTCs (p = 0.014). Analysis from patients with longitudinal samples suggest a decrease in CTC number and in SLFN11 expression that correlates with clinical response. CONCLUSIONS: SLFN11 levels can be monitored in CTCs from SCLC patients using non-invasive liquid biopsies. The ability to detect SLFN11 in CTCs from SCLC patients adds a valuable tool for the detection and longitudinal monitoring of this promising biomarker.
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Neoplasias Pulmonares , Células Neoplásicas Circulantes , Proteínas Nucleares , Carcinoma de Pequenas Células do Pulmão , Biomarcadores , Biomarcadores Tumorais , Linhagem Celular Tumoral , DNA/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Células Neoplásicas Circulantes/patologia , Proteínas Nucleares/genética , Platina/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
The therapeutic landscape of drugs targeting the DNA damage response (DDR) is rapidly expanding; however, an urgent unmet need remains for validated predictive biomarkers of response. SLFN11 has emerged as a promising predictor of sensitivity to DNA-damaging chemotherapies, and recently, been associated with sensitivity to PARP inhibition. We discuss its use as a predictive biomarker of response for targeting the DDR.
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Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Biomarcadores , Linhagem Celular Tumoral , Humanos , Proteínas Nucleares/genéticaRESUMO
DNA-damaging agents exploit increased genomic instability, a hallmark of cancer. Recently, inhibitors targeting the DNA damage response (DDR) pathways, such as PARP inhibitors, have also shown promising therapeutic potential. However, not all tumors respond well to these treatments, suggesting additional determinants of response are required. Schlafen 11 (SLFN11), a putative DNA/RNA helicase that induces irreversible replication block, is emerging as an important regulator of cellular response to DNA damage. Preclinical and emerging clinical trial data suggest that SLFN11 is a predictive biomarker of response to a wide range of therapeutics that cause DNA damage including platinum salts and topoisomerase I/II inhibitors, as well as PARP inhibitors, which has raised exciting possibilities for its clinical application. In this article, we review the function, prevalence, and clinical testing of SLFN11 in tumor biopsy samples and circulating tumor cells. We discuss mounting evidence of SLFN11 as a key predictive biomarker for a wide range of cancer therapeutics and as a prognostic marker across several cancer types. Furthermore, we discuss emerging areas of investigation such as epigenetic reactivation of SLFN11 and its role in activating immune response. We then provide perspectives on open questions and future directions in studying this important biomarker.
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Biomarcadores Tumorais/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Biomarcadores Tumorais/genética , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Epigênese Genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Células Neoplásicas Circulantes/metabolismo , Proteínas Nucleares/genética , PrognósticoRESUMO
PURPOSE: Three CDK4/6 inhibitors, palbociclib (PAL), ribociclib (RIB), and abemaciclib, when combined with letrozole (LET), have been approved as first-line therapy for postmenopausal women with metastatic HR+, HER2- breast cancer. However, an economic evaluation of these newer therapies is currently lacking. The purpose of this article is to evaluate the cost-effectiveness of PAL or RIB for the treatment of advanced HR+, HER2- breast cancer in the United States. METHODS: A Markov simulation model was constructed using data from published clinical trials evaluating PAL and RIB. Three simulated treatment strategies included PAL + LET, RIB + LET, or LET alone. The main outcome measures were simulated progression-free survival (PFS), overall survival (OS), costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: Simulated median OS was 38.9 months for PAL + LET and 33.0 months for LET alone. Simulated median OS for RIB + LET was 43.3 months. Compared to LET alone, PAL + LET provided an additional 0.48 QALYs, on average, with an ICER of $634,000 per QALY gained; RIB + LET provided an additional 0.86 QALYs, on average, with an ICER of $440,000 per QALY gained. At current prices, neither PAL nor RIB was cost-effective, assuming a willingness-to-pay threshold of $100,000 per QALY gained. To reach such a cost-effectiveness threshold, PAL and RIB prices must decrease by approximately 70%. CONCLUSION: Despite significant gains in progression-free survival over letrozole alone, the addition of palbociclib or ribociclib in the treatment of advanced HR+, HER2- breast cancer is not cost-effective in the United States given current drug prices.
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Aminopiridinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Letrozol/administração & dosagem , Piperazinas/administração & dosagem , Purinas/administração & dosagem , Piridinas/administração & dosagem , Aminopiridinas/economia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Neoplasias da Mama/metabolismo , Análise Custo-Benefício , Feminino , Humanos , Letrozol/economia , Cadeias de Markov , Modelos Econômicos , Piperazinas/economia , Purinas/economia , Piridinas/economia , Qualidade de Vida , Receptor ErbB-2/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
Long-term outcomes for women with a diagnosis of human epidermal growth factor receptor 2 (HER2)-driven early-stage breast cancer have significantly improved since the advent of HER2-targeted therapy. Although the first studies in the early-stage setting focused on the adjuvant use of trastuzumab plus chemotherapy, clinical trials increasingly are using a neoadjuvant design to evaluate novel HER2-targeted therapies. Neoadjuvant therapy downstages locally advanced breast cancer, improves rates of breast conservation, and provides information regarding the responsiveness of a cancer to systemic therapy; in addition, studies have shown that the pathologic response to neoadjuvant therapy is correlated with event-free and overall survival. Given these advantages, multiple studies of neoadjuvant therapy, several of which have reported longer-term outcomes, have been conducted to evaluate HER2-targeted therapies. This review summarizes available data from prior and ongoing neoadjuvant trials in HER2-positive breast cancer, focusing on those studies that have reported not only pathologic response rates but also event-free, disease-free, and/or overall survival. The long-term outcomes associated with the achievement of a pathologic complete response are explored, and the comparisons of pathologic complete response rates, event-free survival, and overall survival reported for different HER2-targeted regimens are reviewed.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Descoberta de Drogas , Feminino , Humanos , Lapatinib , Terapia de Alvo Molecular , Terapia Neoadjuvante , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/administração & dosagem , Quinazolinas/uso terapêutico , Trastuzumab/administração & dosagem , Trastuzumab/uso terapêutico , Resultado do TratamentoRESUMO
Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.
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Ácidos Nucleicos Livres , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metilação de DNA , Ácidos Nucleicos Livres/genética , Epigênese Genética , Biomarcadores Tumorais/genéticaRESUMO
Introduction: NSCLC transformation to SCLC has been best characterized with EGFR-mutant NSCLC, with emerging case reports seen in ALK, RET, and KRAS-altered NSCLC. Previous reports revealed transformed SCLC from EGFR-mutant NSCLC portends very poor prognosis and lack effective treatment. Genomic analyses revealed TP53 and RB1 loss of function increase the risk of SCLC transformation. Little has been reported on the detailed clinicogenomic characteristics and potential therapeutic targets for this patient population. Methods: In this study, we conducted a single-center retrospective analysis of clinical and genomic characteristics of patients with EGFR-mutant NSCLC transformed to SCLC. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. Kaplan-Meier analyses were used to estimate survival outcomes. Next generation sequencing-based assays was used to identify EGFR and co-occurring genetic alterations in tissue or plasma before and after SCLC transformation. Single-cell RNA sequencing (scRNA-seq) was performed on a patient-derived-xenograft model generated from a patient with EGFR-NSCLC transformed SCLC tumor. Results: A total of 34 patients were identified in our study. Median age at initial diagnosis was 58, and median time to SCLC transformation was 24.2 months. 68% were female and 82% were never smokers. 79% of patients were diagnosed as stage IV disease, and over half had brain metastases at baseline. Median overall survival of the entire cohort was 38.3 months from initial diagnoses and 12.4 months from time of SCLC transformation. Most patients harbored EGFR exon19 deletions as opposed to exon21 L858R alteration. Continuing EGFR tyrosine kinase inhibitor post-transformation did not improve overall survival compared with those patients where tyrosine kinase inhibitor was stopped in our cohort. In the 20 paired pretransformed and post-transformed patient samples, statistically significant enrichment was seen with PIK3CA alterations (p = 0.04) post-transformation. Profiling of longitudinal liquid biopsy samples suggest emergence of SCLC genetic alterations before biopsy-proven SCLC, as shown by increasing variant allele frequency of TP53, RB1, PIK3CA alterations. ScRNA-seq revealed potential therapeutic targets including DLL3, CD276 (B7-H3) and PTK7 were widely expressed in transformed SCLC. Conclusions: SCLC transformation is a potential treatment resistance mechanism in driver-mutant NSCLC. In our cohort of 34 EGFR-mutant NSCLC, poor prognosis was observed after SCLC transformation. Clinicogenomic analyses of paired and longitudinal samples identified genomic alterations emerging post-transformation and scRNA-seq reveal potential therapeutic targets in this population. Further studies are needed to rigorously validate biomarkers and therapeutic targets for this patient population.
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PURPOSE: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with an absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies which are often adapted from SCLC and non-small cell lung cancer (NSCLC) approaches. EXPERIMENTAL DESIGN: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed immunohistochemistry and single-cell (sc)RNAseq of core needle biopsies from LCNEC patients and preclinical models. RESULTS: Here, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and characterized, alongside TP53 mutations, by co-occurring alterations in CDKN2A/B and SMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK and AXL targeting strategies, including a novel preclinical AXL CAR-T cell. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly features TP53 and RB1 co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by expression of SCLC subtype-defining transcription factors - especially ASCL1 and NEUROD1 - and, as expected given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including Delta-like ligand 3 (DLL3) and CD56 targeting, as with novel preclinical DLL3 and CD56 CAR T-cells, and DNA damage repair (DDR) inhibition. CONCLUSION: YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC.
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OBJECTIVE: LIPA gene mutations result in deficiency of lysosomal acid lipase and present phenotypically as Wolman disease or cholesteryl ester storage disease (CESD) depending on the level of deficiency. Patients with CESD may often be misdiagnosed because symptoms may be nonspecific. Symptoms may present in infancy if there is complete loss of lysosomal acid lipase or in early childhood or adulthood when there is partial loss. The purpose of the present study is to review the literature for pediatric cases of CESD to better understand the phenotype of CESD. METHODS: A PubMed search of all English-language publications from 1966 through June 2012 for pediatric CESD case reports using the following key words CESD, fatty liver, and NAFLD was performed. All of the cases were reviewed and information regarding age, sex, presenting symptoms, and pertinent laboratory tests were recorded. RESULTS: Seventy-one cases were culled from 39 published case reports. Nearly two-thirds of these patients presented with their first symptoms when they were younger than 5 years. Hepatomegaly and splenomegaly were common features. Serum transaminases and lipids were often elevated. Gastrointestinal symptoms were noted in approximately one-third of cases. Two-thirds of patients had liver fibrosis. CONCLUSIONS: CESD has an estimated incidence as high as 1 in 40,000, which means that it is presently underdiagnosed. Education about common symptoms of CESD as well as a higher level of suspicion for screening for CESD will lead to earlier diagnosis. New treatments for CESD including possible enzyme replacement therapy make early diagnosis especially important.
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Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença de Wolman/diagnóstico , Animais , Criança , Pré-Escolar , Doença do Armazenamento de Colesterol Éster/genética , Doença do Armazenamento de Colesterol Éster/metabolismo , Doença do Armazenamento de Colesterol Éster/fisiopatologia , Diagnóstico Diferencial , Fígado Gorduroso/diagnóstico , Humanos , Mutação , Hepatopatia Gordurosa não Alcoólica , Esterol Esterase/genética , Esterol Esterase/metabolismo , Doença de Wolman/genética , Doença de Wolman/metabolismo , Doença de Wolman/fisiopatologia , Doença de WolmanRESUMO
Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy characterized by mechanical hemolytic anemia, resulting in end-organ damage. We describe a case of TTP which presented as an ischemic stroke. The patient presented with stroke as the primary manifestation of TTP despite a normal platelet count and mildly elevated lactate dehydrogenase level (LDH). The patient underwent two transfusions of fresh frozen plasma (FFP), and ADAMTS13 levels confirmed the diagnosis of TTP after discharge. This case demonstrates the importance of maintaining a high index of suspicion for TTP in the setting of normal laboratory values and reveals the many atypical manifestations of TTP.
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Therapeutic options for patients with relapsed SCLC are limited, and the prognosis in this setting remains poor. While clinical outcomes for frontline treatment have modestly improved with the introduction of immunotherapy, treatment in the second-line setting persists almost unchanged. In this review, current treatment options and recent advances in molecular biology are described. Emerging therapeutic options in this setting, and potential strategies to improve clinical outcomes of these patients are also addressed.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Imunoterapia , PrognósticoRESUMO
Broussonetia papyrifera (L.) L'Hér. ex Vent. has considerable economic and ecological value and a long history of use in China. In this paper, root cuttings were used as the material to establish an efficient vegetative propagation of B. papyrifera. The results revealed that root segments with a diameter of 1.5~2.0 cm and a length of 20~30 cm were most suitable for shoot regeneration, as these segments had the highest adventitious shoot induction rates (93.3%), strongest adventitious shoots, and highest multiplication coefficients (7.07). With regard to the methods used for root burial, a horizontal burial at a depth of 1~3 cm yielded the best results, in this case, the adventitious shoot induction rate can reach 86.7%. The best substrate combination was perlite: peat: coconut chaff = 1:1:1 (v/v/v), wherein the adventitious shoot induction rate can reach 75.6%. The best sterilization method was mixing soil with carbendazim and soaking the root sections in carbendazim for 30 min, wherein the adventitious shoot induction rate can reach 77.8%. Adding 0.2 mg/L naphthaleneacetic acid (NAA) to 1/4 Hoagland nutrient solution significantly improved the rooting rate of adventitious shoots to 82.2%, and the survival rate of the acclimatized plants was more than 90.0%.
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Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a 5-year survival rate of less than 7%. In contrast to non-small cell lung cancer, SCLC has long been treated as a homogeneous disease without personalized treatment options. In recent years, the incorporation of immunotherapy into the treatment paradigm has brought moderate benefit to patients with SCLC; however, more effective therapies are urgently needed. In this article, we describe the current treatment standards and emerging therapeutic approaches for the treatment of SCLC. We also discuss promising biomarkers in SCLC and the recently discovered four subtypes of SCLC, each with its unique therapeutic vulnerability. Lastly, we discuss the advances in radiation therapy for the treatment of SCLC.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Medicina de Precisão , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/terapiaRESUMO
BACKGROUND: Lurbinectedin recently received FDA accelerated approval as a second line treatment option for metastatic small cell lung cancer (SCLC). However, there are currently no established biomarkers to predict SCLC sensitivity or resistance to lurbinectedin or preclinical studies to guide rational combinations. METHODS: Drug sensitivity was assayed in proliferation assays and xenograft models. Baseline proteomic profiling was performed by reverse-phase protein array. Lurbinectedin-induced changes in intracellular signaling pathways were assayed by Western blot. RESULTS: Among 21 human SCLC cell lines, cytotoxicity was observed following lurbinectedin treatment at a low dose (median IC50 0.46 nM, range, 0.06-1.83 nM). Notably, cell lines with high expression of Schlafen-11 (SLFN11) protein, a promising biomarker of response to other DNA damaging agents (e.g., chemotherapy, PARP inhibitors), were more sensitive to single-agent lurbinectedin (FC =3.2, P=0.005). SLFN11 was validated as a biomarker of sensitivity to lurbinectedin using siRNA knockdown and in xenografts representing SLFN11 high and low SCLC. Replication stress and DNA damage markers (e.g., γH2AX, phosphorylated CHK1, phosphorylated RPA32) increased in SCLC cell lines following treatment with lurbinectedin. Lurbinectedin also induced PD-L1 expression via cGAS-STING pathway activation. Finally, the combination of lurbinectedin with the ataxia telangiectasia and Rad3-related protein (ATR) inhibitors ceralasertib and berzosertib showed a greater than additive effect in SLFN11-low models. CONCLUSIONS: Together our data confirm the activity of lurbinectedin across a large cohort of SCLC models and identify SLFN11 as a top candidate biomarker for lurbinectedin sensitivity. In SLFN11-low SCLC cell lines which are relatively resistance to lurbinectedin, the addition of an ATR inhibitor to lurbinectedin re-sensitized otherwise resistant cells, confirming previous observations that SLFN11 is a master regulator of DNA damage response independent of ATR, and the absence of SLFN11 leads to synthetic lethality with ATR inhibition. This study provides a rationale for lurbinectedin in combination with ATR inhibitors to overcome resistance in SCLC with low SLFN11 expression.
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INTRODUCTION: Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which enters host cells through the cell surface proteins ACE2 and TMPRSS2. METHODS: Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2. RESULTS: We find that ACE2 expression is restricted to a select population of epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium induces metabolic and transcriptional changes consistent with epithelial-to-mesenchymal transition (EMT), including up-regulation of ZEB1 and AXL, resulting in an increased EMT score. In addition, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT through the transforming growth factor-ß, ZEB1 overexpression, and onset of EGFR tyrosine kinase inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL inhibition and ZEB1 reduction, as with bemcentinib, offer a potential strategy to reverse this effect. CONCLUSIONS: These observations highlight the use of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses and offer important insights into the potential mechanisms underlying the morbidity and mortality of coronavirus disease 2019 in healthy patients and patients with cancer alike.
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COVID-19 , Neoplasias Pulmonares , Brônquios , Humanos , Pulmão , Peptidil Dipeptidase A , SARS-CoV-2RESUMO
Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data and non-negative matrix factorization, we identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts induces intratumoral shifts toward SCLC-I, supporting subtype switching as a mechanism of acquired platinum resistance. We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients.
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Imunidade/imunologia , Neoplasias Pulmonares/imunologia , Carcinoma de Pequenas Células do Pulmão/imunologia , Fatores de Transcrição/imunologia , Animais , Linhagem Celular Tumoral , Cisplatino/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunidade/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos Nus , Prognóstico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
COVID-19 is an infectious disease caused by SARS-CoV-2, which enters host cells via the cell surface proteins ACE2 and TMPRSS2. Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2. We find that ACE2 expression is restricted to a select population of highly epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium, induces metabolic and transcriptional changes consistent with epithelial to mesenchymal transition (EMT), including upregulation of ZEB1 and AXL, resulting in an increased EMT score. Additionally, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT via TGFbeta, ZEB1 overexpression and onset of EGFR TKI inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL-inhibition and ZEB1-reduction, as with bemcentinib, offers a potential strategy to reverse this effect. These observations highlight the utility of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses, and offer important insights into the potential mechanisms underlying the morbidity and mortality of COVID-19 in healthy patients and cancer patients alike.
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We calculate the ground-state energy density ε(g) for the one-dimensional N-state quantum clock model up to order 18, where g is the coupling and N=3,4,5,...,10,20. Using methods based on the Padé approximation, we extract the singular structure of ε^{â³}(g) or ε(g). They correspond to the specific heat and free energy of the classical two-dimensional (2D) clock model. We find that, for N=3,4, there is a single critical point at g_{c}=1. The heat capacity exponent of the corresponding 2D classical model is α=0.34±0.01 for N=3, and α=-0.01±0.01 for N=4. For N>4, there are two exponential singularities related by g_{c1}=1/g_{c2}, and ε(g) behaves as Ae^{-c/|g_{c}-g|^{σ}}+analyticterms near g_{c}. The exponent σ gradually grows from 0.2 to 0.5 as N increases from 5 to 9, and it stabilizes at 0.5 when N>9. The phase transitions exhibited in these models should be generalizations of the Kosterlitz-Thouless transition, which has σ=0.5.
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BACKGROUND: Since the approval of sorafenib there have been numerous failures of new agents in Phase III studies for treatment of advanced hepatocellular carcinoma (HCC). These studies have generally ignored the molecular heterogeneity of HCC and they have not enrolled patients based on predictive markers of response. The development of molecular targeted therapeutics in HCC needs to model the approach that has been taken with great success in other solid tumors, to decrease the likelihood of failure in future studies. SUMMARY: Here we review the paradigm taken with novel targeted agents in other solid tumors and highlight ongoing studies in HCC that are incorporating biomarkers in clinical development. KEY MESSAGES: With the appreciation of the molecular diversity of HCC, clinical development of new agents in HCC will need to be targeted towards those patients who are most likely to benefit. This strategy, based on biomarkers for patient selection, is more likely to yield positive results and mitigate the risk of continued negative Phase III studies.