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1.
Clin Cancer Res ; 2024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39177583

RESUMEN

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSIs) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood. EXPERIMENTAL DESIGN: We applied targeted cell-free DNA sequencing to 126 mCRPC patients from three academic cancer centers, and separately performed genome-wide cell-free DNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome-positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 mCRPC patients, respectively, to develop and validate a stem-like signature, which we inferred from cell-free DNA. RESULTS: Targeted cell-free DNA sequencing detected AR/enhancer alterations prior to first-line ARSIs which correlated with significantly worse PFS (p = 0.01; HR = 2.12) and OS (p = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (p < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cell-free DNA revealed enrichment for stemness-associated transcription factors in lethal mCRPC patients. The resulting stemness signature was then validated in a completely held-out cohort of 80 mCRPC patients profiled by tumor RNA sequencing. CONCLUSIONS: We analyzed a total of 220 mCRPC patients, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.

2.
medRxiv ; 2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-38077092

RESUMEN

Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor (AR)-targeted agents is often lethal. Unfortunately, biomarkers for this deadly disease remain under investigation, and underpinning mechanisms are ill-understood. Here, we applied deep sequencing to ∼100 mCRPC patients prior to the initiation of first-line AR-targeted therapy, which detected AR /enhancer alterations in over a third of patients, which correlated with lethality. To delve into the mechanism underlying why these patients with cell-free AR /enhancer alterations developed more lethal prostate cancer, we next performed genome-wide cell-free DNA epigenomics. Strikingly, we found that binding sites for transcription factors associated with developmental stemness were nucleosomally more accessible. These results were corroborated using cell-free DNA methylation data, as well as tumor RNA sequencing from a held-out cohort of mCRPC patients. Thus, we validated the importance of AR /enhancer alterations as a prognostic biomarker in lethal mCRPC, and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.

3.
Transl Oncol ; 37: 101763, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37657155

RESUMEN

Up to 430,000 cases of bladder cancer are diagnosed each year worldwide. A proposed method for non-invasive monitoring has been to utilize a "liquid biopsy." Liquid biopsy has been proposed as a non-invasive method of testing biomarkers in bodily fluids in order to detect and survey cancer. The liquid biopsy could be utilized to obtain information regarding circulating tumor cells, circulating cell-free tumor DNA, circulating cell-free tumor RNA, and more. It is currently being investigated to help guide adjuvant therapy and improve oncological outcomes. We highlight an array of exciting past and ongoing clinical trials regarding ctDNA and adjuvant therapy in regard to urothelial carcinoma which we believe to be amongst the leaders in the field.

4.
Bioinformatics ; 39(8)2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37549060

RESUMEN

MOTIVATION: Detection of genomic alterations in circulating tumor DNA (ctDNA) is currently used for active clinical monitoring of cancer progression and treatment response. While methods for analysis of small mutations are more developed, strategies for detecting structural variants (SVs) in ctDNA are limited. Additionally, reproducibly calling small-scale mutations, copy number alterations, and SVs in ctDNA is challenging due to the lack to unified tools for these different classes of variants. RESULTS: We developed a unified pipeline for the analysis of ctDNA [Pipeline for the Analysis of ctDNA (PACT)] that accurately detects SVs and consistently outperformed similar tools when applied to simulated, cell line, and clinical data. We provide PACT in the form of a Common Workflow Language pipeline which can be run by popular workflow management systems in high-performance computing environments. AVAILABILITY AND IMPLEMENTATION: PACT is freely available at https://github.com/ChrisMaherLab/PACT.


Asunto(s)
ADN Tumoral Circulante , Neoplasias , Humanos , ADN Tumoral Circulante/genética , Mutación , Neoplasias/genética , Genómica , Línea Celular , Biomarcadores de Tumor/genética
5.
Proc Natl Acad Sci U S A ; 120(31): e2216127120, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37487091

RESUMEN

Retroviruses and their host have coevolved in a delicate balance between viral replication and survival of the infected cell. In this equilibrium, restriction factors expressed by infected cells control different steps of retroviral replication such as entry, uncoating, nuclear import, expression, or budding. Here, we describe a mechanism of restriction against human T cell leukemia virus type 1 (HTLV-1) by the helicase-like transcription factor (HLTF). We show that RNA and protein levels of HLTF are reduced in primary T cells of HTLV-1-infected subjects, suggesting a clinical relevance. We further demonstrate that the viral oncogene Tax represses HLTF transcription via the Enhancer of zeste homolog 2 methyltransferase of the Polycomb repressive complex 2. The Tax protein also directly interacts with HLTF and induces its proteasomal degradation. RNA interference and gene transduction in HTLV-1-infected T cells derived from patients indicate that HLTF is a restriction factor. Restoring the normal levels of HLTF expression induces the dispersal of the Golgi apparatus and overproduction of secretory granules. By synergizing with Tax-mediated NF-κB activation, physiologically relevant levels of HLTF intensify the autophagic flux. Increased vesicular trafficking leads to an enlargement of the lysosomes and the production of large vacuoles containing viral particles. HLTF induction in HTLV-1-infected cells significantly increases the percentage of defective virions. In conclusion, HLTF-mediated activation of the autophagic flux blunts the infectious replication cycle of HTLV-1, revealing an original mode of viral restriction.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia de Células T , Humanos , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Productos del Gen tax/genética , Productos del Gen tax/metabolismo , Linfocitos T/metabolismo , FN-kappa B/metabolismo , Proteínas de Unión al ADN
6.
Semin Radiat Oncol ; 33(3): 262-278, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37331781

RESUMEN

Recent breakthroughs in circulating tumor DNA (ctDNA) technologies present a compelling opportunity to combine this emerging liquid biopsy approach with the field of radiogenomics, the study of how tumor genomics correlate with radiotherapy response and radiotoxicity. Canonically, ctDNA levels reflect metastatic tumor burden, although newer ultrasensitive technologies can be used after curative-intent radiotherapy of localized disease to assess ctDNA for minimal residual disease (MRD) detection or for post-treatment surveillance. Furthermore, several studies have demonstrated the potential utility of ctDNA analysis across various cancer types managed with radiotherapy or chemoradiotherapy, including sarcoma and cancers of the head and neck, lung, colon, rectum, bladder, and prostate . Additionally, because peripheral blood mononuclear cells are routinely collected alongside ctDNA to filter out mutations associated with clonal hematopoiesis, these cells are also available for single nucleotide polymorphism analysis and could potentially be used to detect patients at high risk for radiotoxicity. Lastly, future ctDNA assays will be utilized to better assess locoregional MRD in order to more precisely guide adjuvant radiotherapy after surgery in cases of localized disease, and guide ablative radiotherapy in cases of oligometastatic disease.


Asunto(s)
ADN Tumoral Circulante , Neoplasias , Oncología por Radiación , Masculino , Humanos , ADN Tumoral Circulante/genética , Leucocitos Mononucleares , Neoplasias/genética , Neoplasias/radioterapia , Biopsia Líquida , Biomarcadores de Tumor/genética , Neoplasia Residual/radioterapia
7.
J Immunother Cancer ; 11(6)2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37349125

RESUMEN

Liquid biopsies using cell-free circulating tumor DNA (ctDNA) are being used frequently in both research and clinical settings. ctDNA can be used to identify actionable mutations to personalize systemic therapy, detect post-treatment minimal residual disease (MRD), and predict responses to immunotherapy. ctDNA can also be isolated from a range of different biofluids, with the possibility of detecting locoregional MRD with increased sensitivity if sampling more proximally than blood plasma. However, ctDNA detection remains challenging in early-stage and post-treatment MRD settings where ctDNA levels are minuscule giving a high risk for false negative results, which is balanced with the risk of false positive results from clonal hematopoiesis. To address these challenges, researchers have developed ever-more elegant approaches to lower the limit of detection (LOD) of ctDNA assays toward the part-per-million range and boost assay sensitivity and specificity by reducing sources of low-level technical and biological noise, and by harnessing specific genomic and epigenomic features of ctDNA. In this review, we highlight a range of modern assays for ctDNA analysis, including advancements made to improve the signal-to-noise ratio. We further highlight the challenge of detecting ultra-rare tumor-associated variants, overcoming which will improve the sensitivity of post-treatment MRD detection and open a new frontier of personalized adjuvant treatment decision-making.


Asunto(s)
ADN Tumoral Circulante , Humanos , ADN Tumoral Circulante/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Genómica
8.
ACS Appl Mater Interfaces ; 15(15): 18598-18607, 2023 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-37015072

RESUMEN

Traditional cold chain systems of collection, transportation, and storage of biofluid specimens for eventual analysis pose a huge financial and environmental burden. These systems are impractical in pre-hospital and resource-limited settings, where refrigeration and electricity are not reliable or even available. Here, we develop an innovative technology using metal-organic frameworks (MOFs), a novel class of organic-inorganic hybrids with high thermal stability, as encapsulates for preserving the integrity of protein biomarkers in biofluids under ambient or non-refrigerated storage conditions. We encapsulate prostate-specific antigen (PSA) in whole patient plasma using hydrophilic zeolitic imidazolate framework-90 (ZIF-90) for preservation at 40 °C for 4 weeks and eventual on-demand reconstitution for antibody-based assays with recovery above 95% compared to storage at -20 °C. Without ZIF-90 encapsulation, only 10-30% of the PSA immunoactivity remained. Furthermore, we demonstrate encapsulation of multiple cancer biomarker proteins in whole patient plasma using ZIF-8 or ZIF-90 encapsulants for eventual on-demand reconstitution and analysis after 1 week at 40 °C. Overall, MOF encapsulation of patient biofluids is important as climate change may be affecting the stability and increase costs of maintaining biospecimen cold chain custody for the collection, transportation, and storage of biospecimens prior to analysis or for biobanking regardless of any countries' affluence.


Asunto(s)
Estructuras Metalorgánicas , Humanos , Masculino , Antígeno Prostático Específico , Bancos de Muestras Biológicas
9.
J Med Chem ; 66(4): 3058-3072, 2023 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-36763536

RESUMEN

Transient soluble oligomers of amyloid-ß (Aß) are considered among the most toxic species in Alzheimer's disease (AD). Soluble Aß oligomers accumulate early prior to insoluble plaque formation and cognitive impairment. The cyclic d,l-α-peptide CP-2 (1) self-assembles into nanotubes and demonstrates promising anti-amyloidogenic activity likely by a mechanism involving engagement of soluble oligomers. Systematic replacement of the residues in peptide 1 with aza-amino acid counterparts was performed to explore the effects of hydrogen bonding on propensity to mitigate Aß aggregation and toxicity. Certain azapeptides exhibited improved ability to engage, alter the secondary structure, and inhibit aggregation of Aß. Moreover, certain azapeptides disassembled preformed Aß fibrils and protected cells from Aß-mediated toxicity. Substitution of the l-norleucine3 and d-serine6 residues in peptide 1 with aza-norleucine and aza-homoserine provided, respectively, nontoxic [azaNle3]-1 (4) and [azaHse6]-1 (7), that significantly abated symptoms in a transgenic Caenorhabditis elegans AD model by decreasing Aß oligomer levels.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Nanotubos de Péptidos , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/química , Fragmentos de Péptidos/química , Estructura Secundaria de Proteína , Caenorhabditis elegans , Modelos Animales de Enfermedad
10.
NPJ Precis Oncol ; 7(1): 6, 2023 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-36658307

RESUMEN

Circulating tumor DNA (ctDNA) sensitivity remains subpar for molecular residual disease (MRD) detection in bladder cancer patients. To remedy this problem, we focused on the biofluid most proximal to the disease, urine, and analyzed urine tumor DNA in 74 localized bladder cancer patients. We integrated ultra-low-pass whole genome sequencing (ULP-WGS) with urine cancer personalized profiling by deep sequencing (uCAPP-Seq) to achieve sensitive MRD detection and predict overall survival. Variant allele frequency, inferred tumor mutational burden, and copy number-derived tumor fraction levels in urine cell-free DNA (cfDNA) significantly predicted pathologic complete response status, far better than plasma ctDNA was able to. A random forest model incorporating these urine cfDNA-derived factors with leave-one-out cross-validation was 87% sensitive for predicting residual disease in reference to gold-standard surgical pathology. Both progression-free survival (HR = 3.00, p = 0.01) and overall survival (HR = 4.81, p = 0.009) were dramatically worse by Kaplan-Meier analysis for patients predicted by the model to have MRD, which was corroborated by Cox regression analysis. Additional survival analyses performed on muscle-invasive, neoadjuvant chemotherapy, and held-out validation subgroups corroborated these findings. In summary, we profiled urine samples from 74 patients with localized bladder cancer and used urine cfDNA multi-omics to detect MRD sensitively and predict survival accurately.

11.
Proc Natl Acad Sci U S A ; 119(49): e2210766119, 2022 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-36442093

RESUMEN

Transient soluble oligomers of amyloid-ß (Aß) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer's disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1) self-assemble into cross ß-sheet nanotubes, react with early Aß species (1-3 mers), and inhibit Aß aggregation and toxicity in stoichiometric concentrations, in vitro. Employing a semicarbazide as an aza-glycine residue with an extra hydrogen-bond donor to tune nanotube assembly and amyloid engagement, [azaGly6]-1 inhibited Aß aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly6]-1 and Aß42 residues F19 and F20, which are pivotal for early dimerization and aggregation. In an AD mouse model, brain positron emission tomography (PET) imaging using stable 64Cu-labeled (aza)peptide tracers gave unprecedented early amyloid detection in 44-d presymptomatic animals. No tracer accumulation was detected in the cortex and hippocampus of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the thalamus, from where Aß oligomers may spread to other brain parts with disease progression. Compared with standard 11C-labeled Pittsburgh compound-B (11C-PIB), which binds specifically fibrillar Aß plaques, 64Cu-labeled (aza)peptide gave superior contrast and uptake in young mouse brain correlating with Aß oligomer levels. Effectively crossing the blood-brain barrier (BBB), peptide 1 and [azaGly6]-1 reduced Aß oligomer levels, prolonged lifespan of AD transgenic Caenorhabditis elegans, and abated memory and behavioral deficits in nematode and murine AD models. Cyclic (aza)peptides offer novel promise for early AD diagnosis and therapy.


Asunto(s)
Enfermedad de Alzheimer , Amiloidosis , Animales , Ratones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Diagnóstico Precoz , Péptidos beta-Amiloides , Placa Amiloide , Proteínas Amiloidogénicas
13.
Mol Diagn Ther ; 25(6): 757-774, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34725800

RESUMEN

The detection of circulating tumor DNA via liquid biopsy has become an important diagnostic test for patients with cancer. While certain commercial liquid biopsy platforms designed to detect circulating tumor DNA have been approved to guide clinical decisions in advanced solid tumors, the clinical utility of these assays for detecting minimal residual disease after curative-intent treatment of nonmetastatic disease is currently limited. Predicting disease response and relapse has considerable potential for increasing the effective implementation of neoadjuvant and adjuvant therapies. As a result, many companies are rapidly investing in the development of liquid biopsy platforms to detect circulating tumor DNA in the minimal residual disease setting. In this review, we discuss the development and clinical implementation of commercial liquid biopsy platforms for circulating tumor DNA minimal residual disease detection of solid tumors. Here, we aim to highlight the technological features that enable highly sensitive detection of tumor-derived genomic alterations, the factors that differentiate these commercial platforms, and the ongoing trials that seek to increase clinical implementation of liquid biopsies using circulating tumor DNA-based minimal residual disease detection.


Asunto(s)
ADN Tumoral Circulante , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Genómica , Humanos , Biopsia Líquida , Recurrencia Local de Neoplasia , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética
14.
PLoS Med ; 18(8): e1003732, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34464379

RESUMEN

BACKGROUND: The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. METHODS AND FINDINGS: We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4-38.9; p = 0.02) compared to utDNA MRD-negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point. CONCLUSIONS: utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.


Asunto(s)
Biomarcadores de Tumor/análisis , Cistectomía/estadística & datos numéricos , ADN de Neoplasias/análisis , Neoplasia Residual/diagnóstico , Neoplasias de la Vejiga Urinaria/diagnóstico , Orina/química , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Missouri , Invasividad Neoplásica/patología , Neoplasia Residual/etiología , Supervivencia sin Progresión , Neoplasias de la Vejiga Urinaria/etiología
15.
Org Lett ; 23(9): 3491-3495, 2021 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-33886343

RESUMEN

Fifteen N-aminoimidazolone (Nai) dipeptides having a variety of 5-position side-chain groups were synthesized by regioselective proline-catalyzed reactions of azopeptide and aldehyde components followed by acid-mediated dehydration of an aza-aspartate semialdehyde intermediate. The introduction of 5-aryl-Nai dipeptides into cluster of differentiation 36 receptor (CD36) peptide ligands has provided insight into the conformation responsible for binding affinity and anti-inflammatory activity.


Asunto(s)
Compuestos Azo/química , Dipéptidos/química , Imidazoles/química , Péptidos/química , Prolina/química , Fenómenos Biológicos , Catálisis , Ligandos , Conformación Molecular , Estructura Molecular
18.
JCO Precis Oncol ; 4: 680-713, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32903952

RESUMEN

PURPOSE: Cell-free DNA (cfDNA) and circulating tumor cell (CTC) based liquid biopsies have emerged as potential tools to predict responses to androgen receptor (AR)-directed therapy in metastatic prostate cancer. However, due to complex mechanisms and incomplete understanding of genomic events involved in metastatic prostate cancer resistance, current assays (e.g. CTC AR-V7) demonstrate low sensitivity and remain underutilized. The recent discovery of AR enhancer amplification in >80% of metastatic patients and its association with disease resistance presents an opportunity to improve upon current assays. We hypothesized that tracking AR/enhancer genomic alterations in plasma cfDNA would detect resistance with high sensitivity and specificity. METHODS: We developed a targeted sequencing and analysis method as part of a new assay called Enhancer and neighboring loci of Androgen Receptor Sequencing (EnhanceAR-Seq). We applied EnhanceAR-Seq to plasma collected from 40 patients with metastatic prostate cancer treated with AR-directed therapy to monitor AR/enhancer genomic alterations and correlate these events with therapy resistance, progression-free survival (PFS) and overall survival (OS). RESULTS: EnhanceAR-Seq identified genomic alterations in the AR/enhancer locus in 45% of cases, including a 40% rate of AR enhancer amplification. Patients with AR/enhancer alterations had significantly worse PFS and OS than those without (6-month PFS: 30% vs. 71%, P=0.0002; 6-month OS: 59% vs. 100%, P=0.0015). AR/enhancer alterations in plasma cfDNA detected 18 of 23 resistant cases (78%) and outperformed the CTC AR-V7 assay which was also run on a subset of patients. CONCLUSION: cfDNA-based AR locus alterations, including of the enhancer, are strongly associated with resistance to AR-directed therapy and significantly worse survival. cfDNA analysis using EnhanceAR-Seq may enable more precise risk stratification and personalized therapeutic approaches for metastatic prostate cancer.

19.
Proc Natl Acad Sci U S A ; 117(12): 6831-6835, 2020 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-32152102

RESUMEN

Glutamate is the major excitatory neurotransmitter in the brain, and photochemical release of glutamate (or uncaging) is a chemical technique widely used by biologists to interrogate its physiology. A basic prerequisite of these optical probes is bio-inertness before photolysis. However, all caged glutamates are known to have strong antagonism toward receptors of γ-aminobutyric acid, the major inhibitory transmitter. We have developed a caged glutamate probe that is inert toward these receptors at concentrations that are effective for photolysis with violet light. Pharmacological tests in vitro revealed that attachment of a fifth-generation (G5) dendrimer (i.e., cloaking) to the widely used 4-methoxy-7-nitro-indolinyl(MNI)-Glu probe prevented such off-target effects while not changing the photochemical properties of MNI-Glu significantly. G5-MNI-Glu was used with optofluidic delivery to stimulate dopamine neurons of the ventral tegmental area of freely moving mice in a conditioned place-preference protocol so as to mediate Pavlovian conditioning.


Asunto(s)
Glutamatos/farmacología , Indoles/farmacología , Aprendizaje/fisiología , Microfluídica , Neuronas/fisiología , Neurotransmisores/farmacología , Animales , Aprendizaje/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Neuroquímica , Neuronas/efectos de los fármacos , Fotoquímica , Fotólisis , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
20.
Clin Exp Med ; 18(2): 221-227, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29076004

RESUMEN

In acute lymphoblastic leukemia (ALL), limited data are available on mTOR gene expression in clinical samples and its role in predicting response to induction chemotherapy. mRNA expression of mTOR gene was determined quantitatively by real-time PCR in 50 ALL patients (30 B-ALL and 20 T-ALL) and correlated with clinical outcome after induction chemotherapy. Expression level of mTOR was upregulated in more than 50% of cases of ALL. In T-ALL, high expression of mTOR was commonly seen, more in adults than children (82 vs. 55% cases), while in B-ALL it was same (~ 63% cases) in both adults and children. Mean fold change of mTOR expression was significantly higher in non-responders compared to responders of both adult B-ALL (7.4 vs. 2.7, p = 0.05) and T-ALL (13.9 vs. 2.4, p = 0.001). Similar results were seen in pediatric non-responders when compared to responders of both B-ALL (14.5 vs. 2.5, p = 0.006) and T-ALL (24.2 vs. 1.7, p = 0.002). Interestingly, we have observed that mTOR expression was two times higher in non-responders of children compared to adults in both B-ALL (14.5 vs. 7.4, p = 0.05) and T-ALL (24.2 vs. 13.9, p = 0.01). Multivariate analysis with other known prognostic factors revealed that mTOR expression independently predicts clinical response to induction chemotherapy in ALL. This study demonstrates that high mTOR expression is associated with poor clinical outcome in ALL and can serve as a potential target for novel therapeutic strategies.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Serina-Treonina Quinasas TOR/genética , Regulación hacia Arriba , Adulto , Niño , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Quimioterapia de Inducción , Masculino , Pronóstico , Resultado del Tratamiento
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