RESUMO
The human microbiota plays an important role in human health and disease, through the secretion of metabolites that regulate key biological functions. We propose that microbiota metabolites represent an unexplored chemical space of small drug-like molecules in the search of new hits for drug discovery. Here, we describe the generation of a set of complex chemotypes inspired on selected microbiota metabolites, which have been synthesized using asymmetric organocatalytic reactions. Following a primary screening in CSC models, we identified the novel compound UCM-13369 (4b) whose cytotoxicity was mediated by NPM1. This protein is one of the most frequent mutations of AML, and NPM1-mutated AML is recognized by the WHO as a distinct hematopoietic malignancy. UCM-13369 inhibits NPM1 expression, downregulates the pathway associated with mutant NPM1 C+, and specifically recognizes the C-end DNA-binding domain of NPM1 C+, avoiding the nucleus-cytoplasm translocation involved in the AML tumorological process. The new NPM1 inhibitor triggers apoptosis in AML cell lines and primary cells from AML patients and reduces tumor infiltration in a mouse model of AML with NPM1 C+ mutation. The disclosed phenotype-guided discovery of UCM-13369, a novel small molecule inspired on microbiota metabolites, confirms that CSC death induced by NPM1 inhibition represents a promising therapeutic opportunity for NPM1-mutated AML, a high-mortality disease.
RESUMO
Intensive Care to facilitate Organ Donation (ICOD) consists of the initiation or continuation of intensive care measures in patients with a devastating brain injury (DBI) in whom curative treatment is deemed futile and death by neurological criteria (DNC) is foreseen, to incorporate organ donation into their end-of-life plans. In this study we evaluate the outcomes of patients subject to ICOD and identify radiological and clinical factors associated with progression to DNC. In this first prospective multicenter study we tested by multivariate regression the association of clinical and radiological severity features with progression to DNC. Of the 194 patients, 144 (74.2%) patients fulfilled DNC after a median of 25 h (95% IQR: 17-44) from ICOD onset. Two patients (1%) shifted from ICOD to curative treatment, both were alive at discharge. Factors associated with progression to DNC included: age below 70 years, clinical score consistent with severe brain injury, instability, intracranial hemorrhage, midline shift ≥5 mm and certain types of brain herniation. Overall 151 (77.8%) patients progressed to organ donation. Based on these results, we conclude that ICOD is a beneficial and efficient practice that can contribute to the pool of deceased donors.
Assuntos
Cuidados Críticos , Obtenção de Tecidos e Órgãos , Humanos , Estudos Prospectivos , Masculino , Feminino , Obtenção de Tecidos e Órgãos/métodos , Pessoa de Meia-Idade , Idoso , Espanha , Adulto , Lesões Encefálicas , Morte Encefálica , Unidades de Terapia IntensivaRESUMO
BACKGROUND: In recent years, a new type of immediate hypersensitivity reaction known as cytokine release began to emerge, and within this phenotype of reactions, interleukin-6 is the most frequently associated with the presence during drug administration. Chemotherapeutic agents (QT) and monoclonal antibodies. OBJECTIVE: Determine interleukin-6 levels in hypersensitivity reactions to QT and monoclonal antibodies. METHODS: Observational and prospective study that was carried out from March 1, 2021 to March 1, 2022 in a university hospital in northeastern Mexico. Symptoms, severity, interleukin-6 levels, and skin tests of hypersensitivity reaction were evaluated at QT and monoclonal antibodies. RESULTS: A total of 41 patients with oncological disease were included, the most frequent being ovarian cancer. Symptoms as initial hypersensitivity reaction were neuromuscular in taxanes and cutaneous in Platinums.41.5% presented elevation of interleukin-6, and it was found more frequently in presence of metastases. Positive skin tests were found more frequently in the carboplatin and doxorubicin groups. The most frequently presented phenotype was type I in paclitaxel, carboplatin, and doxorubicin, and mixed-reaction (type I and cytokine release) in oxaliplatin. CONCLUSION: With the increasing prevalence of hypersensitivity reactions to biologic and antineoplastic therapies, interleukin-6 should be recognized as a biomarker in immediate hypersensitivity reactions to QT and monoclonal antibodies.
RESUMO
BACKGROUND: Hypersensitivity reactions to anticancer chemotherapy and monoclonal antibodies may lead to discontinuation of first-line treatment options. Identification of these reactions can provide specific diagnosis and treatment by rapid drug desensitizations. OBJECTIVE: To determine the hypersensitivity reactions involved in anticancer chemotherapy and monoclonal antibodies, and the safety and efficacy of rapid drug desensitization. METHODS: We conducted an observational study of hypersensitivity reaction presented after the administration of anticancer chemotherapy and monoclonal antibodies in Mexico. We documented the symptoms of initial reaction and their severity, and the results of skin tests. We also report our experience of the administration of 12-step (mild-moderate reactions) and 16-step (severe reactions) desensitization protocols in these patients. RESULTS: Overall, 93 patients received 336 rapid drug desensitization; 105 to taxanes, 115 to platinum drugs, 101 to monoclonal antibodies, and 15 other anticancer chemotherapy. Hypersensitivity reaction to taxanes occurred in the first or second administration, platinum drugs after the sixth cycle, and rituximab in the first cycle. The most common symptom in carboplatin was urticaria, paclitaxel back pain, oxaliplatin and docetaxel dyspnea, and in the monoclonal antibodies cardiovascular symptoms. Skin tests were positive in 75% of the carboplatin group, and only 16.7% in docetaxel. There was a rapid drug desensitization success rate of 99.4% and 85.7% did not present any related hypersensitivity reaction. CONCLUSION: The diagnosis of hypersensitivity reaction to anticancer chemotherapy and monoclonal antibodies offers a panorama in the management of oncological diseases. Our standardized desensitization protocol is safe and effective and can be reproduced in other centers to treat patients who need to maintain first-line treatment.
RESUMO
Spinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA2) has recently emerged as a new potential pharmacological approach to decrease SCI-associated damage. Toward validating this receptor as a target in SCI, we have developed a new series of LPA2 antagonists, among which compound 54 (UCM-14216) stands out as a potent and selective LPA2 receptor antagonist (Emax = 90%, IC50 = 1.9 µM, KD = 1.3 nM; inactive at LPA1,3-6 receptors). This compound shows efficacy in an in vivo mouse model of SCI in an LPA2-dependent manner, confirming the potential of LPA2 inhibition for providing a new alternative for treating SCI.
Assuntos
Receptores de Ácidos Lisofosfatídicos , Traumatismos da Medula Espinal , Animais , Camundongos , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológicoRESUMO
Aging is considered the main risk factor for many chronic diseases that frequently appear at advanced ages. However, the inevitability of this process is being questioned by recent research that suggests that senescent cells have specific features that differentiate them from younger cells and that removal of these cells ameliorates senescent phenotype and associated diseases. This opens the door to the design of tailored therapeutic interventions aimed at reducing and delaying the impact of senescence in life, that is, extending healthspan and treating aging as another chronic disease. Although these ideas are still far from reaching the bedside, it is conceivable that they will revolutionize the way we understand aging in the next decades. In this review, we analyze the main and well-validated cellular pathways and targets related to senescence as well as their implication in aging-associated diseases. In addition, the most relevant small molecules with senotherapeutic potential, with a special emphasis on their mechanism of action, ongoing clinical trials, and potential limitations, are discussed. Finally, a brief overview of alternative strategies that go beyond the small molecule field, together with our perspectives for the future of the field, is provided.
RESUMO
Tolerance development caused by dopamine replacement with l-DOPA and therapeutic drawbacks upon activation of dopaminergic receptors with orthosteric agonists reveal a significant unmet need for safe and effective treatment of Parkinson's disease. In search for selective modulators of the D1 receptor, the screening of a chemical library and subsequent medicinal chemistry program around an identified hit resulted in new synthetic compound 26 [UCM-1306, 2-(fluoromethoxy)-4'-(S-methanesulfonimidoyl)-1,1'-biphenyl] that increases the dopamine maximal effect in a dose-dependent manner in human and mouse D1 receptors, is inactive in the absence of dopamine, modulates dopamine affinity for the receptor, exhibits subtype selectivity, and displays low binding competition with orthosteric ligands. The new allosteric modulator potentiates cocaine-induced locomotion and enhances l-DOPA recovery of decreased locomotor activity in reserpinized mice after oral administration. The behavior of compound 26 supports the interest of a positive allosteric modulator of the D1 receptor as a promising therapeutic approach for Parkinson's disease.
Assuntos
Cocaína , Doença de Parkinson , Animais , Compostos de Bifenilo , Dopamina/metabolismo , Dopaminérgicos , Agonistas de Dopamina/farmacologia , Humanos , Indazóis , Levodopa , Ligantes , Camundongos , Nitrofuranos , Doença de Parkinson/tratamento farmacológico , Receptores Dopaminérgicos , Receptores de Dopamina D1/agonistasRESUMO
Peptidic agonists of the glucagon-like peptide-1 receptor (GLP-1R) have gained a prominent role in the therapy of type-2 diabetes and are being considered for reducing food intake in obesity. Potential advantages of small molecules acting as positive allosteric modulators (PAMs) of GLP-1R, including oral administration and reduced unwanted effects, could improve the utility of this class of drugs. Here, we describe the discovery of compound 9 (4-{[1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-3-yl]methyl}morpholine, V-0219) that exhibits enhanced efficacy of GLP-1R stimulation, subnanomolar potency in the potentiation of insulin secretion, and no significant off-target activities. The identified GLP-1R PAM shows a remarkable in vivo activity, reducing food intake and improving glucose handling in normal and diabetic rodents. Enantioselective synthesis revealed oral efficacy for (S)-9 in animal models. Compound 9 behavior bolsters the interest of a small-molecule PAM of GLP-1R as a promising therapeutic approach for the increasingly prevalent obesity-associated diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Administração Oral , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Obesidade/tratamento farmacológico , Peptídeos/uso terapêuticoRESUMO
BACKGROUND: Healthcare workers (HCWs) have been a critical and vulnerable population during SARS-CoV-2 pandemic. The aim of this study was to determine the overall seroprevalence and to evaluate occupational risk factors among HCWs in one of the countries most affected by this pandemic. METHODS: We conducted a seroprevalence study for SARS-CoV-2 in a tertiary hospital in Madrid (Spain) between 24 April and 8 May 2020. A total of 4894 HCWs were invited for serologic testing. Serum samples were tested for SARS-CoV-2 IgM and IgG antibodies using Enzyme Immunoassay (ELISA) and Electro-Chemiluminescence Immunoassay (ECLIA) techniques. We calculated odds ratios to assess association between demographic and occupational characteristics with SARS-CoV-2 seroconversion. RESULTS: We processed 4324 serum samples. Overall, seroprevalence was of 16.6% (95% CI: 15.5-17.7). We found statistically significant differences in SARS-CoV-2 seroprevalence by type of employee, professional category, department and type of activity performed during the pandemic period, while no differences were identified between the personnel working in the COVID-19 wards compared to those working in non-COVID-19 wards. We confirmed 268 (26.7%) infections among 1005 hospital staff members tested by PCR. 60.5% of HCWs infected by SARS-CoV-2, assessed either by PCR or serology, could be considered asymptomatic or paucisymptomatic. CONCLUSIONS: HCWs have an increased risk of SARS-CoV-2 infection but COVID-19 patient exposure was not a determining factor. Universal mask wearing should be mandatory in healthcare settings given the important number of asymptomatic and paucisymptomatic cases.
Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , Pessoal de Saúde , Humanos , Estudos Soroepidemiológicos , Espanha/epidemiologia , Centros de Atenção TerciáriaRESUMO
Hutchinson-Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the Lmna G609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria.
RESUMO
Bacterial resistance to antibiotics makes previously manageable infections again disabling and lethal, highlighting the need for new antibacterial strategies. In this regard, inhibition of the bacterial division process by targeting key protein FtsZ has been recognized as an attractive approach for discovering new antibiotics. Binding of small molecules to the cleft between the N-terminal guanosine triphosphate (GTP)-binding and the C-terminal subdomains allosterically impairs the FtsZ function, eventually inhibiting bacterial division. Nonetheless, the lack of appropriate chemical tools to develop a binding screen against this site has hampered the discovery of FtsZ antibacterial inhibitors. Herein, we describe the first competitive binding assay to identify FtsZ allosteric ligands interacting with the interdomain cleft, based on the use of specific high-affinity fluorescent probes. This novel assay, together with phenotypic profiling and X-ray crystallographic insights, enables the identification and characterization of FtsZ inhibitors of bacterial division aiming at the discovery of more effective antibacterials.
Assuntos
Antibacterianos/química , Proteínas de Bactérias/metabolismo , Proteínas do Citoesqueleto/metabolismo , Sítio Alostérico , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacologia , Cristalografia por Raios X , Proteínas do Citoesqueleto/antagonistas & inibidores , Polarização de Fluorescência , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Ligantes , Testes de Sensibilidade Microbiana , Ligação Proteica , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Relação Estrutura-AtividadeRESUMO
Progression on therapy in non-small cell lung carcinoma (NSCLC) is often evaluated radiographically, however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated EGFR promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results. These trials were based on a hypothesis that the EDN1-EDNR axis activates the MAPK-ERK signaling pathway that is vital to the cancer cell survival; the trials were not designed to evaluate the impact of tumor-derived EDN1 in modifying tumor microenvironment or contributing to drug resistance. Ectopic overexpression of EDN1 in cells with mutated EGFR resulted in poor drug delivery and retarded growth in vivo but not in vitro. Intratumoral injection of recombinant EDN significantly reduced blood flow and subsequent gefitinib accumulation in xenografted EGFR-mutant tumors. Furthermore, depletion of EDN1 or the use of endothelin receptor inhibitors bosentan and ambrisentan improved drug penetration into tumors and restored blood flow in tumor-associated vasculature. Correlatively, these results describe a simplistic endogenous yet previously unrealized resistance mechanism inherent to a subset of EGFR-mutant NSCLC to attenuate tyrosine kinase inhibitor delivery to the tumors by limiting drug-carrying blood flow and the drug concentration in tumors. SIGNIFICANCE: EDNR antagonists can be repurposed to improve drug delivery in VEGFA-secreting tumors, which normally respond to TKI treatment by secreting EDN1, promoting vasoconstriction, and limiting blood and drug delivery.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Endotelina-1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Disponibilidade Biológica , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Endotelina-1/genética , Receptores ErbB/genética , Cloridrato de Erlotinib/farmacologia , Gefitinibe/farmacocinética , Humanos , Neoplasias Pulmonares/genética , Camundongos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Persistent high-risk human papillomavirus (HR-HPV) infections play a major role in the development of invasive cervical cancer (CC), and screening for such infections is in many countries the primary method of detecting and preventing CC. HPV typing can be used for triage and risk stratification of women with atypical squamous cells of undetermined significance (ASC-US)/low-grade cervical lesions (LSIL), though the current clinical practice in Mexico is to diagnose CC or its preceding conditions mainly via histology and HR-HPV detection. Additional information regarding these HPV infections, such as viral load and co-infecting agents, might also be useful for diagnosing, predicting, and evaluating the possible consequences of the infection and of its prevention by vaccination. The goal of this follow-up hospital case study was to determine if HPV types, multiple HPV infections, and viral loads were associated with infection persistence and the cervical lesion grade. A total of 294 cervical cytology samples drawn from patients with gynecological alterations were used in this study. HPV types were identified by real-time PCR DNA analysis. A subset of HPV-positive patients was reevaluated to identify persistent infections. We identified HPV types 16, 18, and 39 as the most prevalent. One hundred five of the patients (59%) were infected with more than one type of HPV. The types of HPV associated with multiple HPV infections were 16, 18, and 39. In the follow-up samples, 38% of patients had not cleared the initially detected HPV infection, and these were considered persistent. We found here an association between multiple HPV infections and high viral loads with and infection persistence. Our findings suggest there are benefits in ascertaining viral load and multiple HPV infections status of HR-HPV infections for predicting the risk of persistence, a requirement for developing CC. These findings contribute to our understanding of HPV epidemiology and may allow screening programs to better assess the cancer-developing risks associated with individual HR-HPV infections.
Assuntos
Coinfecção/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Carga Viral , Adulto , Coinfecção/epidemiologia , Coinfecção/patologia , DNA Viral/genética , Feminino , Seguimentos , Genótipo , Humanos , México/epidemiologia , Teste de Papanicolaou , Papillomaviridae/classificação , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/patologia , Prevalência , Esfregaço VaginalRESUMO
Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax = 118%, EC50 = 0.24 µM, KD = 19.6 nM; inactive at autotaxin and LPA2-6 receptors). This compound induces characteristic LPA1-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.
Assuntos
Analgésicos/química , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Receptores de Ácidos Lisofosfatídicos/agonistas , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Descoberta de Drogas , Feminino , Humanos , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/uso terapêutico , Camundongos Endogâmicos C57BL , Modelos Moleculares , Neuralgia/metabolismo , Percepção da Dor/efeitos dos fármacos , Ratos Wistar , Receptores de Ácidos Lisofosfatídicos/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismoRESUMO
Diabetes is a disease that can be treated with oral antidiabetic agents and/or insulin. However, patients' metabolic control is inadequate in a high percentage of them and a major cause of chronic diseases like diabetic retinopathy. Approximately 15% of patients have some degree of diabetic retinopathy when diabetes is first diagnosed, and most will have developed this microvascular complication after 20 years. Early diagnosis of the disease is the best tool to prevent or delay vision loss and reduce the involved costs. However, diabetic retinopathy is an asymptomatic disease and its development to advanced stages reduces the effectiveness of treatments. Today, the recommended treatment for severe nonproliferative and proliferative diabetic retinopathy is photocoagulation with an argon laser and intravitreal injections of anti-VEGF associated with, or not, focal laser for diabetic macular oedema. The use of these therapeutic approaches is severely limited, such as uncomfortable administration for patients, long-term side effects, the costs they incur, and the therapeutic effectiveness of the employed management protocols. Hence, diabetic retinopathy is the widespread diabetic eye disease and a leading cause of blindness in adults in developed countries. The growing interest in using polyphenols, e.g., resveratrol, in treatments related to oxidative stress diseases has spread to diabetic retinopathy. This review focuses on analysing the sources and effects of oxidative stress and inflammation on vascular alterations and diabetic retinopathy development. Furthermore, current and antioxidant therapies, together with new molecular targets, are postulated for diabetic retinopathy treatment.
Assuntos
Retinopatia Diabética/terapia , Adulto , Idoso , Retinopatia Diabética/patologia , Humanos , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Fatores de Risco , Adulto JovemRESUMO
Liquid-based cytology (LBC) has been used as a diagnostic tool for cervical cancer for years and is now being adopted for other gynecological cancers. LBC represents an important challenge to ensure that the process yields representative biospecimens for quality control (QC) of diagnostic procedures. In this study, we compare QC parameters (integrity, yield and purity, and polymerase chain reaction [PCR] amplification) of DNA isolated from LBC (N = 296) using two different nucleic acid isolation methods, manual (n = 233) or automated (n = 63). We also evaluated two different types of cytological brushes for sampling from the cervix. Our results suggest that manual isolation (yield 22.81 ± 1.92 µg) resulted in increased DNA recovery when compared with automated isolation (yield 9.96 ± 1.11 µg) from LBC samples, with a p-value of <0.0003. We estimated that 98% (53/54) of the samples preserved the integrity of DNA and were suitable for standard molecular biology analyses. The ß-globin gene was amplified in 100% (296/296) of the DNA samples by endpoint PCR. We found no significant difference between the performance of the cytological brushes (p value of <0.6711) in a general overview. However, when looking at the results from using each brush individually, the manual isolation method was statistically superior to the automated method. Our work illustrates the impact of good QC of preanalytic conditions, which will be important for the application of LBC for developing early detection methods for gynecological cancers.
Assuntos
DNA de Neoplasias/isolamento & purificação , Manejo de Espécimes/métodos , Neoplasias do Colo do Útero/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bancos de Espécimes Biológicos , Detecção Precoce de Câncer , Feminino , Humanos , Biópsia Líquida , Neoplasias do Colo do Útero/genética , Adulto JovemRESUMO
Although EGFR mutant-selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK-ERK pathway via ß-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI-resistant persister cells. Many patients with non-small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutation, who progressed on EGFR inhibitors, demonstrated increased CXCR7 expression. These data suggest that CXCR7 inhibition could considerably delay and prevent the emergence of acquired EGFR TKI resistance in EGFR-mutant NSCLC. SIGNIFICANCE: Increased expression of the chemokine receptor CXCR7 constitutes a mechanism of resistance to EGFR TKI in patients with non-small cell lung cancer through reactivation of ERK signaling.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores CXCR/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Receptores ErbB/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Camundongos Transgênicos , Mutação , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Receptores CXCR/genética , beta-Arrestinas/metabolismoRESUMO
Blockade of Ras activity by inhibiting its post-translational methylation catalyzed by isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. However, the paucity of inhibitors has precluded the clinical validation of this approach. In this work we report a potent ICMT inhibitor, compound 3 [UCM-1336, IC50 = 2 µM], which is selective against the other enzymes involved in the post-translational modifications of Ras. Compound 3 significantly impairs the membrane association of the four Ras isoforms, leading to a decrease of Ras activity and to inhibition of Ras downstream signaling pathways. In addition, it induces cell death in a variety of Ras-mutated tumor cell lines and increases survival in an in vivo model of acute myeloid leukemia. Because ICMT inhibition impairs the activity of the four Ras isoforms regardless of its activating mutation, compound 3 surmounts many of the common limitations of available Ras inhibitors described so far. In addition, these results validate ICMT as a valuable target for the treatment of Ras-driven tumors.
Assuntos
Alanina/uso terapêutico , Amidas/uso terapêutico , Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Metiltransferases/antagonistas & inibidores , Alanina/análogos & derivados , Alanina/síntese química , Alanina/farmacologia , Amidas/síntese química , Amidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We report a patient with diffuse large B-cell lymphoma of skin, nongerminal center type double hit double expressor, with an initial presentation as a left forearm mass. The patient underwent chemotherapy after initial diagnosis. After chemotherapy regimen, she developed a second mass, followed by CNS involvement with neurological defects. At this time, a three line of chemotherapy was used with minimal effects. The patient was deemed terminal and was recommended hospice care. The patient decided to continue with skin and crainospinal radiotherapy and intrathecal chemotherapy; she achieved complete remission. After achieving complete remission, the patient underwent an autologous stem cell transplant with minimal transplant-related toxicity.
RESUMO
Ras proteins are among the most frequently mutated drivers in human cancer and remain an elusive pharmaceutical targeting. Previous studies have improved the understanding of Ras structure, processing, and signaling pathways in cancer cells and have opened new possibilities for inhibiting Ras function. In this review we discuss the most recent advances towards inhibiting Ras activity with small molecules, highlighting the two approaches: (i) compounds that bind directly to Ras protein and (ii) inhibitors of the enzymes involved in the post-translational modifications of Ras. In the former, we analyze the most recent contributions in each of the main classes of Ras direct binders, including the different types of nucleotide exchange inhibitors, allosteric compounds, and molecules that interfere with the interaction between Ras and its effectors. In the latter, we examine the compounds that inhibit Ras activation by blocking any of its post-translational modifications. Also, a special focus is made on those molecules that have progressed the farthest from medicinal chemistry and drug development points of view. Finally, the current scene regarding the clinical trials of Ras inhibitors, together with the future promising avenues for further development of the challenging Ras field are reviewed.