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1.
Clin Cancer Res ; 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35507014

RESUMO

PURPOSE: Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy (NAT) in retrospective studies. EXPERIMENTAL DESIGN: To better define clinical outcomes and correlates of response, we analyzed the rate of pathological complete response (pCR) to NAT, survival outcomes, and genomic and transcriptomic profiles of the pre-treatment tumors in a prospective clinical trial (NCT02276443). 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide-based NAT. RESULTS: Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience a pCR (23% vs 40%; p=0.07), had shorter event-free survival (29.4 vs 32.2 months, p=0.15), metastasis-free survival (30.3 vs 32.4 months, p=0.22) and overall survival (32.6 vs 34.3 months, p=0.21). This heterogeneity is mirrored in the molecular profiling. Mutations in PI3KCA (23% vs 9%, p=0.07) and its pathway (41% vs 18%, p=0.02), were frequently observed and enriched in MpBCs. The gene expression profiles of each histologically defined subtype were distinguishable, and characterized by distinctive gene signatures. Among non-Mp TNBCs, 10% possessed a metaplastic-like gene expression signature and had pCR rates and survival outcomes similar to MpBC. CONCLUSIONS: Further investigations will determine if metaplastic-like tumors should be treated more similarly to MpBC in the clinic. The 23% pCR rate in this study suggests that patients with MpBC should be considered for NAT. To improve this rate, a pathway analysis predicted enrichment of HDAC and RTK/MAPK pathways in MpBC, which may serve as new targetable vulnerabilities.

2.
Hum Pathol ; 2022 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-35447141

RESUMO

AIMS: The aim of this study was to review the clinicopathologic characteristics of metastatic non-hematopoietic malignancies to the breast, in order to identify salient features for practicing pathologist that are useful in distinguishing metastatic lesions from primary breast neoplasms. METHODS AND RESULTS: A total of 238 cases were identified during the period from January 2005 to January 2015. Clinicopathologic features of these cases were retrospectively reviewed. Primary tumors included melanoma (99, 42%), serous carcinoma (35, 15%), neuroendocrine neoplasm (32, 13%), sarcoma (23, 10%), and adenocarcinoma from various organs (47, 20%), among others. Most metastases were unilateral (223, 94%) and unifocal (206, 87%), and were detected radiographically (167, 70%). Concurrent ipsilateral axillary metastasis occurred in 33 (14%) patients. Among 238 cases, 41 had metastatic disease to the breast concurrently or preceding the primary cancer diagnosis. Notable, in 39 (16%) cases, breast metastasis was the first clinical presentation of disease, and 16 (41%) of these cases were initially misdiagnosed as breast primaries. In contrast, with known history of non-mammary primary tumors, only 4 of 197 (2%) cases were misdiagnosed (p<0.0001). CONCLUSIONS: Metastatic tumors share many overlapping features with breast primary carcinomas. However, cases with a well-circumscribed tumor, lack of in situ component, ER/PR negativity, and unusual morphologic features should raise the consideration of metastatic disease. While clinical history is paramount for correct diagnosis, metastasis to the breast as the first clinical presentation is not uncommon.

3.
Semin Diagn Pathol ; 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35461734

RESUMO

Due to the high prevalence of breast cancer in the female, a metastasis from primary breast cancer is usually considered in the differential diagnosis of metastatic carcinoma in the female patient, even for those without a history of breast cancer, as some breast cancers are first diagnosed as metastases. Immunohistochemical analysis for breast cancer markers is the most common way to determine breast cancer origin besides clinical history and histology. In this review, we (1) summarize the commonly used and the newly identified breast cancer markers, including GCDFP-15, mammaglobin, GATA3, SOX10, and TRPS1; (2) point out the strengths and weaknesses of using these markers for breast cancers with luminal/epithelial or basal/myoepithelial differentiation; and (3) recommend diagnostic panels to differentiate breast carcinoma from carcinoma with similar morphology of other origins.

4.
Hum Pathol ; 2022 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-35417734

RESUMO

AIMS: Knowing the sensitivity and specificity of tissue-specific immunohistochemical markers is crucial for accurate determination of the primary tumor site. PAX8 has been used as a diagnostic marker for carcinomas of the gynecologic tract, kidney, and thyroid gland, and CDX2 has been used as a marker of gastrointestinal carcinoma. Neither is considered a marker for breast carcinoma (BC). However, we have encountered BCs that express PAX8 or CDX2, some of which caused diagnostic confusion. We investigated the immunohistochemical staining frequency of PAX8 and CDX2 in BC. METHODS AND RESULTS: We identified 237 BCs for which PAX8 staining results were reported (102 primary and 135 metastatic BCs); seven primary and four metastatic BCs (4.6%) were positive for PAX8, with various intensities and staining patterns. CDX2 staining results were reported for 271 BCs (78 primary and 193 metastatic); four primary and one metastatic BC (1.8%) were positive for CDX2, ranging from focal and weak to diffuse and strong. We also stained primary invasive BCs with PAX8 and CDX2 using tissue microarrays. None of 332 PAX8-stained cases was positive, while one of 143 CDX2-stained cases were positive. Four PAX8-positive and three CDX2-positive cases were stained with TRPS1, and all were positive for TRPS1. In addition, we reviewed the literature for PAX8 and CDX2 expression in BCs and found 5.5% PAX8-positive BCs (90/1625) in 17 studies and 0.8% CDX-2 positive BCs (7/909) in 20 studies. CONCLUSIONS: PAX8 and CDX2 are infrequently expressed in BC by immunohistochemistry, and in rare cases, the staining can be strong and diffuse. Additional diagnostic markers are necessary and helpful in distinguishing breast from other primary origins.

5.
Hum Pathol ; 2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35413381

RESUMO

A diagnostic dilemma can be encountered when primary triple-negative breast carcinoma (TNBC) without an in-situ component or metastatic TNBCs lose the currently used organ-specific marker such as GATA3, raising concerns about metastatic carcinoma from other sites. In the current study, we compared the newly identified breast marker TRPS1 with currently used breast markers GATA3 and SOX10 in whole-tissue sections from 315 cases of various subtypes of TNBC. TRPS1 was highly expressed in 100% of triple-negative primary and metastatic invasive lobular carcinomas, 99% of triple-negative primary and metastatic invasive breast carcinoma of no special type (IBC-NST) and 95% of metaplastic breast carcinomas. In contrast, GATA3 and SOX10 were expressed in 94% and 0% of invasive lobular carcinomas, 63% and 74% of IBC-NST, and 50% and 49% of metaplastic breast carcinomas, respectively. For special-type TNBCs, both TRPS1 and GATA3 were negative in acinic cell carcinomas, most cribriform adenoid cystic carcinomas and neuroendocrine carcinomas, but positive in secretory carcinomas. Triple-negative apocrine carcinoma was the only subtype of TNBC with positive GATA3 but negative TRPS1. These data indicate that TRPS1 is a highly sensitive marker for TNBCs with positivity not only in GATA3/SOX10-positive TNBCs but also in almost all GATA3/SOX10-negative TNBCs.

6.
Talanta ; 243: 123380, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35334434

RESUMO

Rapid and convenient preparation of covalent organic framework (COF) coated fibers is of great significance to solid-phase microextraction (SPME) technology. In this work, a novel chemical preparation strategy was established for rapid fabrication of ß-ketoenamine-linked COF coatings, in which clay-like starting materials of COFs were first wrapped on the fiber surface through self-viscosity and further fixed on the fiber in an oven via chemical bonding. Based on this strategy, four different COF (TpTph, TpPa-1, TpBD and TpTpb) coated fibers was fabricated within 1 h, which is very rapid compared to the recently reported research. Moreover, the strategy also demonstrates the good general applicability for COF fiber preparation. Subsequently, the TpTph coated fiber was used to develop a new SPME method for gas chromatography-tandem mass spectrometry (GC-MS/MS) of trace phthalic acid esters (PAEs) in environmental water. The developed analytical method compared to the previous SPME methods for PAEs based on other sorbents possesses low limits of detection (LODs, 0.02-0.08 ng L-1), and better or comparable precision (RSD ≤9.4%, n = 6), and relatively short extraction time. Furthermore, the trace PAEs (0.27-11.62 ng L-1) in the real water samples were successfully detected with recoveries of 82.2-117.5%. The above results indicates that the proposed fiber preparation strategy is reliable and opens a potential avenue for rapid and facile fabrication of COF coated fibers.


Assuntos
Estruturas Metalorgânicas , Ácidos Ftálicos , Ésteres/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Limite de Detecção , Estruturas Metalorgânicas/química , Ácidos Ftálicos/análise , Microextração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos
7.
Surg Pathol Clin ; 15(1): 77-93, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35236635

RESUMO

Most of the high-grade spindle cell lesions of the breast are malignant phyllodes tumors (MPTs), spindle cell carcinomas (SpCCs), and matrix-producing metaplastic breast carcinomas (MP-MBCs). MPTs have neoplastic spindle stromal cells and a classic leaf-like architecture with subepithelial stromal condensation. MPTs are often positive for CD34, CD117, and bcl-2 and are associated with MED12, TERT, and RARA mutations. SpCCs and MP-MBCs are high-grade metaplastic carcinomas, whereas neoplastic epithelial cells become spindled or show heterologous mesenchymal differentiation, respectively. The expression of epithelial markers must be evaluated to make a diagnosis. SAS, or rare metastatic spindle cell tumors, are seen in the breast, and clinical history is the best supporting evidence. Surgical resection is the standard of care.


Assuntos
Neoplasias da Mama , Carcinoma , Tumor Filoide , Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Carcinoma/diagnóstico , Carcinoma/genética , Feminino , Humanos , Imuno-Histoquímica , Tumor Filoide/diagnóstico , Tumor Filoide/genética
8.
Anal Chim Acta ; 1200: 339586, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35256131

RESUMO

In this work, a hollow zirconium-porphyrin-based metal-organic framework (HZ-PMOF) was prepared as a coating for solid-phase microextraction (SPME) fiber to determine two naphthols. HZ-PMOF coating provided good extraction performance for naphthols because of the rich forces including π-π interactions, hydrogen bonding, and electrostatic interaction between the materials and targets. Furthermore, due to the special shape of the hollow structure, HZ-PMOF coating showed time-saving SPME equilibrium time and higher extraction capacity than zirconium-porphyrin-based metal-organic framework (Z-PMOF) coating without hollow structure. Combining with gas chromatography-tandem mass spectrometry (GC-MS/MS), an analytical method of naphthols with low detection limit (1.0 ng L-1), wider linear range (3.0-1000.0 ng L-1) and good reproducibility (RSD ≤8.6%) was established. Subsequently, naphthols in water samples from five cities in China were successfully detected by this developed method with satisfactory recoveries (81.1%-117.9%) and precision (RSDs, 3.2-9.6%). The results indicated that the prepared HZ-PMOF-coated fiber has good application prospects, and would broaden the application of materials with special morphology in the field of pretreatment.


Assuntos
Estruturas Metalorgânicas , Porfirinas , Cromatografia Gasosa-Espectrometria de Massas , Limite de Detecção , Naftóis , Reprodutibilidade dos Testes , Microextração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Zircônio/química
9.
Hum Pathol ; 121: 73-80, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35063444

RESUMO

When a sarcomatous neoplasm is identified in the breast, distinguishing metaplastic carcinoma, malignant phyllodes tumor (MPT), and primary sarcoma is a diagnostic challenge, especially on small biopsies, as all these tumors may have overlapping morphological features, thoroughly grossing with histological examination and immunohistochemical staining being the standard approach to aid in classifying these lesions. Recently, we identified a highly sensitive and specific breast carcinoma marker TRPS1 with high expression in metaplastic breast carcinoma. In the current study, we tested TRPS1 in MPTs and primary sarcoma of the breast. We found TRPS1 was highly expressed (95%) within spindle cell, chondro-osseous, and/or liposarcomatous components of MPTs, in all breast primary chondrosarcomas and extraskeletal osteosarcomas, but not in other sarcomas of the breast. In extramammary sarcomas, TRPS1 was expressed in 28% of conventional chondrosarcomas and 56% of osteosarcomas of bone, but rarely in undifferentiated pleomorphic sarcomas (UPSs), liposarcomas, and angiosarcomas. In summary, MPTs may share similar genetic background with metaplastic carcinoma exhibiting TRPS1 expression, and TRPS1 may play a role in chondro-osseous differentiation because of its expression in chondro-osseous sarcomas from both breast and extramammary sites. Our findings suggest TRPS1 may be clinically useful in distinguishing MPT and metaplastic carcinoma from primary breast sarcoma except for tumors with chondro-osseous differentiation.


Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Carcinoma , Condrossarcoma , Osteossarcoma , Tumor Filoide , Sarcoma , Neoplasias de Tecidos Moles , Neoplasias Ósseas/genética , Neoplasias da Mama/patologia , Carcinoma/patologia , Condrossarcoma/genética , Feminino , Dedos/anormalidades , Doenças do Cabelo , Humanos , Síndrome de Langer-Giedion , Nariz/anormalidades , Tumor Filoide/patologia , Proteínas Repressoras , Sarcoma/patologia
10.
Clin Breast Cancer ; 22(2): e158-e166, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34187752

RESUMO

INTRODUCTION: Breast conservation surgery (BCS) is the treatment of choice for unifocal, early-stage breast cancer. The ability to offer BCS to a wider subset of patients, including those with multifocal/multicentric cancer as well as extensive ductal carcinoma in situ, has emerged over time, especially in those undergoing joint oncoplastic reconstruction and those treated with neoadjuvant therapy. However, localization techniques using multiple radioactive seeds for bracketing in this patient subset have not been validated. MATERIALS AND METHODS: A single-institution retrospective review was conducted of all patients with breast cancer who underwent BCS, guided by multiple bracketed iodine I 125 radioactive seeds between January 2014 and April 2017. RESULTS: Bracketing of breast cancer using 2 or more radioactive seeds was performed in 157 breasts in 156 patients. Negative margins were achieved in 124 of 157 (79%) breasts, including 33 cases (21%) that underwent targeted margin reexcision at the time of surgery after intraoperative, multidisciplinary margin assessment. Thirty-three cases (21%) resulted in close or positive margins, of which 11 (7%) and 10 (6.4%) underwent completion mastectomy or repeat lumpectomy, respectively. Twelve patients (7.6%) did not undergo reexcision. En bloc resection was successful in 134 of 157 (85.4%) lumpectomies. Eighty-nine percent of the procedures were coupled with oncoplastic reconstruction. CONCLUSION: Bracketing techniques using multiple radioactive seeds expands the indications for breast conservation therapy in patients who would have traditionally required mastectomy. Intraoperative margin assessment improves surgical and pathologic success. Larger defects created by multifocal resection are optimally managed in concert with oncoplastic reconstruction to minimize asymmetries and aesthetic defects.


Assuntos
Neoplasias da Mama/cirurgia , Estética , Margens de Excisão , Mastectomia Segmentar/métodos , Adulto , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
11.
Se Pu ; 39(12): 1281-1290, 2021 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-34811999

RESUMO

Plant hormones (PHs) are of significance in plant growth, as they regulate the various processes related to plant growth, development, and resistance. Sensitive and precise quantitative analysis of PHs is a bottleneck in plant science research. Currently, liquid chromatography-tandem mass spectrometry is used for the accurate and efficient detection of PHs. Sample pretreatment is an indispensable step in the chromatography-mass spectrometry analysis of PHs because it directly affects the sensitivity and accuracy of subsequent detection methods. Among various pretreatment methods for PHs, solid phase extraction (SPE) is the most widely used. Various new types of SPE, such as dispersive SPE, magnetic SPE, and solid phase microextraction, have been developed by modifying the extraction cartridge. The choice of adsorption material is the key factor in the abovementioned SPE methods, which has a decisive effect on the extraction, purification, and enrichment effects of the target substance in the sample pretreatment process. Carbon-based materials, including carbon nanotubes, graphene, carbon and nitrogen compounds, as well as organic frameworks, including metal organic frameworks and covalent organic materials, are suitable adsorption materials because of their designable structure, large specific surface area, and good stability. Molecularly imprinted polymers and supramolecular compounds show specific molecular recognition based on host-guest interactions, which can significantly improve the selectivity of sample pretreatment methods. In this paper, SPE-related technology and the abovementioned types of functionalized adsorption materials in the pretreatment of PHs prevalent in the past five years have been reviewed. The related development trends are also summarized.


Assuntos
Nanotubos de Carbono , Reguladores de Crescimento de Plantas , Adsorção , Extração em Fase Sólida , Microextração em Fase Sólida
12.
Front Pharmacol ; 12: 769647, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790132

RESUMO

Emerging evidences demonstrate that metabolic reprogramming is a hallmark of malignancies, including gastric cancer (GC). Abnormal expression of metabolic rate-limiting enzymes, as the executive medium of energy metabolism, drives the occurrence and development of cancer. However, a comprehensive model of metabolic rate-limiting enzymes associated with the development and progression of GC remains unclear. In this research, we identified a rate-limiting enzyme, sterol O-acyltransferase 1 (SOAT1), was highly expressed in cancerous tissues, which was associated with advanced tumor stage and lymph node metastasis, leading to the poor prognosis of GC. It was shown that knockdown of SOAT1 or pharmacological inhibition of SOAT1 by avasimibe could suppress GC cell proliferation, cholesterol ester synthesis, and lymphangiogenesis. However, overexpression of SOAT1 promoted these biological processes. Mechanistically, SOAT1 regulated the expression of cholesterol metabolism genes SREBP1 and SREBP2, which could induce lymphangiogenesis via increasing the expression of VEGF-C. In conclusion, our results indicated that SOAT1 promotes gastric cancer lymph node metastasis through lipid synthesis, which suggested that it may be a promising prognostic biomarker for guiding clinical management and treatment decisions.

13.
Anal Chim Acta ; 1181: 338886, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34556223

RESUMO

A facile and rapid strategy for preparation of covalent organic framework (COF) coated fibers at ambient temperature is urgently needed for solid-phase microextraction (SPME) technology. In this work, an in situ room-temperature rapid growth strategy was developed to high-efficiently fabricate imine-linked COF (TPB-DVA) coated fibers in as little as 30 min at room temperature, and the thickness of the coating reached 9 µm. The prepared TPB-DVA coated fiber offer high thermal and chemical stability, and outstanding service lifetime. Moreover, we generalize this strategy to other two imine-linked COF (TPB-DMTP and TFPB-TAPB) coated fibers and the fibers were fabricated at room temperature for 3 h and 12 h, respectively, which demonstrate the applicability of this strategy. Subsequently, a SPME-GC-MS/MS analytical method was developed for trace pyrethroids (PYs) detection, which exhibited high enhancement factors (EFs, 2700-13195), wide linear range (0.08-800 ng L-1), low limits of detection (LODs, 0.02-0.20 ng L-1), and good repeatability (RSD ≤ 8.5%, n = 6). Furthermore, the developed analytical method was applied to tea samples and trace PYs (1.31-4.32 ng L-1) were found with satisfactory recovery (80.2-119.8%). The above results demonstrated that the feasibility of the developed strategy for the facile and rapid fabrication of imine-linked COF coated fibers.


Assuntos
Estruturas Metalorgânicas , Piretrinas , Poluentes Químicos da Água , Iminas , Limite de Detecção , Microextração em Fase Sólida , Espectrometria de Massas em Tandem , Temperatura , Poluentes Químicos da Água/análise
14.
Hum Pathol ; 117: 51-59, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34363799

RESUMO

Human epidermal growth factor receptor 2 (HER2)-positive classic invasive lobular carcinoma (ILC) is a rare entity, and its specific pathological characteristics and clinical behavior are unclear. Therefore, we retrospectively investigated the clinicopathological features of HER2-positive classic ILC and described HER2-targeted neoadjuvant chemotherapy outcome. Fourteen HER2-positive classic ILC cases were identified, their clinicopathological data were collected, and their clinical management was investigated. In general, HER2 positivity is associated with higher grade carcinoma in ductal lesions; however, our 14 cases had typical morphologic features of classic ILC. We did not identify unique morphologic features in HER2-positive classic ILC with the clinicopathological parameters examined, including age, menopausal status, histological grade, and hormone receptor status. Four of six patients who received HER2-targeted neoadjuvant chemotherapy had a pathological complete or partial response. Based on our findings, clinicopathological features of classic ILC may not predict HER2 overexpression or amplification. HER2-targeted neoadjuvant chemotherapy was effective against some HER2-positive classic ILCs. Taken together, these results demonstrate that HER2 immunohistochemistry and fluorescence in situ hybridization should be considered for all ILC patients regardless of subtype.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Receptor ErbB-2 , Idoso , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Terapia Neoadjuvante/métodos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Resultado do Tratamento
15.
Talanta ; 233: 122542, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34215045

RESUMO

The tailor-prepare solid phase microextraction (SPME) coatings with stable and excellent properties to effectively extract analytes from sample matrix still remains a challenge. Herein, a nitrogen doped graphitic carbon networks (NG-CNTW) coated fiber was fabricated by direct carbonization of nanosized ZIF-67 crystals (nano-ZIF-67) that grown on stainless steel wire. The NG-CNTW coated fiber coupled with gas chromatography-tandem mass spectrometry (GC-MS/MS) was applied for enrichment and determination of pyrethroids. The NG-CNTW coating exhibited high surface area and hierarchical porous structures that facilitate diffusion and accessibility of target molecules. Simultaneously, the nitrogen doped and highly graphitic structures endow the coating with high adsorption affinity for aromatic compounds. Under optimum conditions, the SPME-GC-MS/MS method presented wide range of linearity performance (0.08-200.0 ng g-1), low limits of detection (0.02-0.5 ng g-1) and good repeatability (RSD < 9.6%) for 8 kinds of pyrethroids. Furthermore, the proposed method was successfully applied in the determination of pyrethroids in grape and cauliflower samples, as the results were in the range of 3.16-15.06 ng g-1and 2.08-9.29 ng g-1, respectively. This work not only provides a new method by fabricating carbon nanomaterial coatings in situ derived from MOFs, but also shows great potential of MOFs derivative materials in environmental analysis field.


Assuntos
Grafite , Praguicidas , Piretrinas , Poluentes Químicos da Água , Carbono , Cromatografia Gasosa-Espectrometria de Massas , Nitrogênio , Praguicidas/análise , Microextração em Fase Sólida , Espectrometria de Massas em Tandem , Poluentes Químicos da Água/análise
16.
Cell Death Dis ; 12(7): 707, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34267186

RESUMO

Both bench and bedside investigations have challenged the supportive role of Hedgehog (Hh) activity in the progression of colorectal cancers, thus raising a critical need to further deeply determine the contribution of Hh to the growth of colorectal cancer. Combining multiple complementary means, including in vitro and in vivo inflammatory colorectal cancer models, and pathological analysis of clinical colorectal cancer patients samples. We report that colorectal cancer cells hijack prostaglandin E2 (PGE2) to non-canonically promote Hh transcriptional factor Gli activity and Gli-dependent proliferation of colorectal cancer cells in a Smo-independent manner. Mechanistically, PGE2 activates c-Jun N-terminal kinase (JNK), which in turn enables Gli2 to evade ubiquitin-proteasomal degradation by phosphorylating Gli2 at Thr1546. This study not only presents evidence for understanding the contribution of Hh to colorectal cancers, but also provides a novel molecular portrait underlying how PGE2-activated JNK fine-tunes the evasion of Gli2 from ubiquitin-proteasomal degradation. Therefore, it proposes a rationale for the future evaluation of chemopreventive and selective therapeutic strategies for colorectal cancers by targeting PGE2-JNK-Gli signaling route.


Assuntos
Neoplasias Colorretais/enzimologia , Dinoprostona/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Nucleares/metabolismo , Proteína Gli2 com Dedos de Zinco/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ativação Enzimática , Genes APC , Humanos , Masculino , Camundongos Transgênicos , Proteínas Nucleares/genética , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , Proteólise , Transdução de Sinais , Ubiquitinação , Proteína Gli2 com Dedos de Zinco/genética
17.
Clin Cancer Res ; 27(19): 5365-5375, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34253579

RESUMO

PURPOSE: Increasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. EXPERIMENTAL DESIGN: We obtained pretreatment core-needle biopsies from 105 patients with stage I-III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT. RESULTS: The pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 µm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage. CONCLUSIONS: In patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.


Assuntos
Neoplasias de Mama Triplo Negativas , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Humanos , Linfócitos do Interstício Tumoral , Terapia Neoadjuvante , Fenótipo , Prognóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Microambiente Tumoral/genética
18.
Adv Mater ; 33(29): e2006836, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34096113

RESUMO

Macromolecular films are crucial functional materials widely used in the fields of mechanics, electronics, optoelectronics, and biology, due to their superior properties of chemical stability, small density, high flexibility, and solution-processing ability. Their electronic and mechanical properties, however, are typically much lower than those of crystalline materials, as the macromolecular films have no long-range structural ordering. The state-of-the-art for producing highly ordered macromolecular films is still facing a great challenge due to the complex interactions between adjacent macromolecules. Here, the growth of textured macromolecular films on a designed graphene/high-index copper (Cu) surface is demonstrated. This successful growth is driven by a patterned potential that originates from the different amounts of charge transfer between the graphene and Cu surfaces with, alternately, terraces and step edges. The textured films exhibit a remarkable improvement in remnant ferroelectric polarization and fracture strength. It is also demonstrated that this growth mechanism is universal for different macromolecules. As meter-scale graphene/high-index Cu substrates have recently become available, the results open a new regime for the production and applications of highly ordered macromolecular films with obvious merits of high production and low cost.

19.
Oncogene ; 40(28): 4686-4694, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34140640

RESUMO

Cancer-associated fibroblasts (CAFs) constitute a prominent component of the tumor microenvironment and play critical roles in cancer progression and drug resistance. Although recent studies indicate CAFs may consist of several CAF subtypes, the breadth of CAF heterogeneity and functional roles of CAF subtypes in cancer progression remain unclear. In this study, we implemented a cell-type deconvolutional approach to comprehensively characterize cell-type alternations across 18 cancer types from The Cancer Genome Atlas (TCGA). Pan-cancer survival analysis using deconvoluted CAF subtypes revealed myofibroblastic CAF (myCAF) composition as a poor prognostic factor in nine cancer types. Patients with higher myCAF compositions tend to have worse response to six antineoplastic drugs predicted by a lncRNA-based Elastic Net prediction model (LENP). In addition, integrative mutational analysis identified 14 and 413 genes associated with the differentiation degree of myCAF and inflammatory CAF (iCAF), respectively, with significant enrichment of genes involved in fibroblast and extracellular matrix (ECM)-related pathways. In summary, our findings systematically illustrated the complex roles of CAF subtypes in patient prognosis and drug response, and identified putative driver genes in CAF-subtype differentiation. These results provided novel therapeutic perspectives for targeting CAF subtypes in tumor microenvironment and arranging treatment scheme based on the CAF compositions in different cancer types.


Assuntos
Miofibroblastos , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Microambiente Tumoral
20.
Medicine (Baltimore) ; 100(23): e25888, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34114985

RESUMO

BACKGROUND: Circular RNAs (circRNAs) play an important role in many neurological diseases and can serve as biomarkers for these diseases. However, the information about circRNAs in Parkinson disease (PD) remained limited. In this study, we aimed to determine the circRNAs expression profile in PD patients and discuss the significance of circRNAs in the diagnosis of PD. METHODS AND RESULTS: Using RNA-sequencing in peripheral blood RNAs, we showed that a significant number of mRNAs or circRNAs were differentially expressed between PD patients and normal controls (NCs), which included 273 up-regulated and 493 down-regulated mRNAs, and 129 up-regulated and 282 down-regulated circRNAs, respectively. Functional analysis was performed using the Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analysis, and the results showed that the second most enriched KEGG pathway was PD. These data suggest that the levels of mRNAs and circRNAs in peripheral blood could be potentially used as biomarkers for PD. In addition, we correlated mRNAs and circRNAs by constructing a competing endogenous RNA (ceRNA) network in PD. The resulted-in ceRNA network included 10 differentially expressed mRNAs from PD pathway, 13 predicted miRNAs, and 10 differentially expressed circRNAs. CONCLUSION: Collectively, we first characterized the expression profiles of circRNAs and mRNAs in peripheral blood from PD patients and proposed their possible characters in the pathogenesis of PD. These results provided valuable insights into the clues underlying the pathogenesis of PD.


Assuntos
Doença de Parkinson , RNA Circular , RNA Mensageiro , Análise de Sequência de RNA/métodos , Biomarcadores/sangue , China/epidemiologia , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação Oxidativa , Doença de Parkinson/sangue , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , RNA Circular/sangue , RNA Circular/genética , RNA Mensageiro/sangue , RNA Mensageiro/genética
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