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2.
Ann Transl Med ; 7(20): 541, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31807523

RESUMO

Background: Gliomas are the most frequently occurring malignant brain cancers. Recently, isocitrate dehydrogenase (IDH) mutations, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and 1p/19q co-deletion have been suggested to indicate a favorable prognosis in gliomas. However, the clinical prognostic value of these genetic tests in human gliomas is not fully understood. Methods: We included glioma patients who accepted genetic testing including IDH, MGMT and 1p/19q at Xiangya Hospital, Central South University in China (Jan 2015 to Jun 2017) and further analyzed the effect of the above gene states in high-grade gliomas. Results: In 103 high-grade glioma patients, IDH mutation, MGMT promoter methylation, and 1p/19q co-deletion had better progression-free survival (PFS) than IDH wild-type (P=0.005), MGMT unmethylated promoter (P=0.002), and without 1p19q co-deletion (P=0.008), respectively. Additionally, we classified the above gliomas into 5 molecular groups, triple-positive, IDH mutation and MGMT methylation, methylation in MGMT only, mutation in IDH only, and triple-negative, according to characteristics of recruited patients. We found that triple-positive gliomas had better PFS than triple-negative cases in high-grade patients (P=0.016). Moreover, the IDH mutation and MGMT methylation groups had prolonged PFS compared to triple-negative (P=0.029). Conclusions: Our study reinforced the clinical value of biomarkers, including 1p/19q co-deletion, IDH mutation, and the most prominent MGMT methylation, as previously described in glioma prognosis. Further, triple-negative patients have poorer PFS, indicating that the states of these genes can be divided into subgroups as a potential prognostic marker for clinical treatment, which requires a larger, multicenter study to testify.

3.
HPB (Oxford) ; 2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31843444

RESUMO

BACKGROUND: To compare outcomes of patients with arterially hyperenhancing intrahepatic cholangiocarcinomas (ICC) and arterially hypoenhancing ICCs after partial hepatectomy in a cohort with an analysis of prognostic factors. METHODS: From June 2009 to October 2011, a prospective cohort of 68 patients with single resectable ICCs (≤5 cm in diameter) underwent gadolinium contrast-enhanced dynamic-phase magnetic resonance imaging and were treated with partial hepatectomy. Patients were divided into those with arterially hyperenhancing ICCs (n = 28) or arterially hypoenhancing ICCs (n = 40). Clinic-radiologic-pathologic results and survival of these patients were compared and statistically analyzed. RESULTS: The median overall survival (OS) time was significantly longer in the arterially hyperenhancing ICCs (56.8 vs. 37.0 months) (p = 0.044). At pathologic evaluation, arterially hyperenhancing ICCs showed significantly higher microvessel count (MVC) than arterially hypoenhancing ICCs (106.2 ± 47.5 vs. 46.9 ± 21.6/mm2, p = 0.001). Arterial enhancement of ICCs was found to be an independent prognostic factor for longer survival. CONCLUSION: The presence of arterially hyperenhancing ICCs is related to higher MVC and exhibit a better OS time than arterially hypoenhancing ICCs after partial hepatectomy.

4.
Sci Rep ; 9(1): 16058, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690770

RESUMO

Tremendous efforts have been made to explore biomarkers for classification and grading on gliomas. The goal of this study was to identify more molecular features that are associated with clinical outcomes by comparing the genomic profiles of primary and recurrent gliomas and determine potential recurrence leading factors that are significantly enriched in relapse tumors. Hybrid capture based next generation sequencing (NGS) analysis was performed on 64 primary and 17 recurrent glioma biopsies. Copy number variation (CNV) was more frequent in recurrent tumors and CDKN2A/B loss was significantly enriched. In addition, overall mutations in cell cycle pathway are more common in relapse tumors. The patterns of gene sets, including IDH1/TERT and IDH1/TP53 exhibited significant difference between the groups. Survival analysis uncovered the worse disease-free survival (DFS) and overall survival (OS) associated with altered copy number and excessive activation of CELL CYCLE pathway. High Tumor Mutation Burden (TMB) was also a biomarker with great potential for poor prognosis. The assessment of genomic characteristics in primary versus recurrent gliomas aids the discovery of potential predictive biomarkers. The prognostic value of TMB in gliomas was raised for the first time.

6.
Front Cell Dev Biol ; 7: 217, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632968

RESUMO

Background: LncRNAs have been shown to play essential roles in cancer therapeutic response. However, the detailed mechanism of lncRNAs in temozolomide (TMZ) resistance in glioblastoma (GBM) remain to be elucidated. Methods: To elucidate the mechanism maintaining TMZ resistance, we constructed two TMZ-resistant GBM cell lines (T98G-R/U118-R). LncRNAs from four public datasets were reanalyzed, and the candidate lncRNA ADAMTS9-AS2 was evaluated in TMZ-treated GBM patients and in vitro cell lines. Results: Reanalysis of lncRNA expression profiles identified ADAMTS9-AS2 as significantly overexpressed in TMZ-resistant GBM cells and as positively associated with the IC50 of TMZ in GBM cells. Overexpression of ADAMTS9-AS2 was also significantly associated with poor TMZ response and shorter progression-free survival (PFS) in TMZ-treated GBM patients. Knockdown of ADAMTS9-AS2 inhibited proliferation and attenuated the IC50 of TMZ, as well as mitigating invasion and migration in TMZ-resistant GBM cells. Subsequent investigations indicated that reduced expression of ADAMTS9-AS2 significantly suppressed expression of the FUS protein, which was predicted as a direct substrate of ADAMTS9-AS2. Expression trends of FUS were directly correlated with those of ADAMTS9-AS2, as shown by increasing concentrations and prolonged treatment with TMZ. RNA pull-down and RIP assays indicated that both endogenous and exogenous ADAMTS9-AS2 directly binds to the RRM and Znf_RanBP2 domains of FUS, consequently increasing FUS protein expression. Knockdown of ADAMTS9-AS2 reduced the half-life of FUS and decreased FUS protein stability via K48 ubiquitin degradation. Moreover, the E3 ubiquitin-protein ligase MDM2 interacts with and down regulates FUS, while the RRM and Znf_RanBP2 domains of FUS facilitate its binding with MDM2. ADAMTS9-AS2 decreased the interaction between MDM2 and FUS, which mediates FUS K48 ubiquitination. Additionally, knockdown of the ADAMTS9-AS2/FUS signaling axis significantly alleviated progression and metastasis in TMZ-resistant cells. Conclusion: ADAMTS9-AS2 possessed a novel function that promotes TMZ resistance via upregulating the FUS/MDM2 axis in GBM cells. The RRM or Znf_RanBP2 domains of FUS facilitate the combination of ADAMTS9-AS2 and FUS, competitively inhibiting MDM2-dependent FUS K48 ubiquitination and resulting in enhanced FUS stability and TMZ resistance. Our results suggest that the ADAMTS9-AS2/FUS/MDM2 axis may represent a suitable prognostic biomarker and a potential target in TMZ-resistant GBM therapy.

7.
Int J Low Extrem Wounds ; 18(4): 367-375, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31313614

RESUMO

The current Wagner and Texas classifications of diabetic foot ulcers (DFUs) are used worldwide to assess the extent of foot lesions, but wound treatment principles based on both the classification systems are lacking. We have summarized the STAGE principles of wound treatment for clinical practice based on the Wagner and Texas classification systems. The STAGE principles refer to the principles of surgical intervention during wound treatment of DFUs and emphasize that "based on anatomical layers, the management focuses on blood supply and includes layer-by-layer incision to the infected area, maintenance of effective wound drainage, and step-by-step treatment of the wound." During treatment, microcirculation improvement and microvascular angiogenesis (A) are essential for granulation tissue formation in the bone (skeleton, S) and tendons (T) and healing of the wound with reepithelialization (E). We defined the above mentioned steps as the STAGE principles, namely, layer-by-layer incision and step-by-step management (Phase A is essential for the treatments in Phases S-T and G-E). Ulcers or gangrene formed during Phases S-T or T should be treated according to the STAGE or TAGE principles, respectively. Similar treatment principles are applied in the other phases. However, treatments at each phase are not isolated and can be performed simultaneously. The STAGE principle can be combined with the tissue, infection, moisture, and wound edge (TIME) and TIME-H chronic wound treatment principles to eliminate the shortcomings of a single principle in wound management.

8.
Ann Surg Oncol ; 26(11): 3478-3488, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31187364

RESUMO

PURPOSE: Mucocele-like lesions of the breast identified on core biopsy are rare high-risk lesions associated with variable upgrade rates to carcinoma on excision. We aimed to identify the clinicoradiopathological features that can help optimize management of this lesion. METHODS: We evaluated 50 mucocele-like lesions identified on core biopsies from two institutions, including 36 with no atypia and 14 with limited atypia. Outcome data from excision or clinicoradiological follow-up were reviewed with core biopsy results. RESULTS: Radiological targets were calcifications in 74% of cases, calcifications with associated mass or density in 16%, and mass in 10%. One of the 16 excised lesions without atypia on core biopsy, which was a mass lesion, was upgraded to mucinous carcinoma on excision. Of the 12 excised lesions with limited atypia, none were upgraded on excision. Among the lesions not excised, 20 without atypia had a median follow-up of 61 months, and 2 with limited atypia had follow-up of 97 and 109 months. None of these 22 patients had new development of their lesions on follow-up. The upgrade rate was 2% in our entire cohort, 3% for lesions without atypia, and 0% for lesions with limited atypia. CONCLUSIONS: Clinicoradiological surveillance can be appropriate when a mucocele-like lesion without atypia is identified on core biopsy for a non-mass lesion with pathological-radiological concordance. For mucocele-like lesions with limited atypia, a nonsurgical approach could be considered if the atypia by itself does not warrant excision. The latter recommendation requires careful clinicopathological correlation and support from additional studies.

9.
Eur J Radiol ; 114: 167-174, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31005169

RESUMO

OBJECTIVE: Different molecular subtypes of triple-negative breast cancer (TNBC) have previously been identified through analysis of gene expression profiles. The luminal androgen receptor (LAR) subtype has been shown to have a lower rate of pathologic complete response to neoadjuvant chemotherapy than other TNBC subtypes. The purpose of this study was to determine if the imaging features of TNBCs differ by AR (androgen receptor) status, which is a surrogate immunohistochemical (IHC) marker for the chemoresistant LAR subtype of TNBC. MATERIALS AND METHODS: This sub-study was part of a clinical trial in patients with stage I-III TNBC who were prospectively monitored for response while receiving neoadjuvant systemic therapy (NAST) at a single comprehensive cancer center. This interim imaging analysis included 144 patients with known AR status measured by IHC. AR-positive (AR+) tumors were defined as those in which at least 10% of tumor cells had positive nuclear AR staining. Two experienced, fellowship-trained breast radiologists who were blinded to the IHC results retrospectively reviewed and reached consensus on all imaging studies for the index lesion (i.e., mammogram, ultrasound, and breast magnetic resonance imaging). The index lesion for each patient was reviewed and described according to the fifth edition of the Breast Imaging Reporting and Data System lexicon. Logistic regression modeling was used to identify imaging features predictive of AR status. p ≤ 0.05 was considered statistically significant. RESULTS: Univariate logistic regression models for AR status showed that AR+ TNBC was significantly associated with heterogeneously dense breast composition on mammography (p = 0.02), mass with calcifications (p = 0.05), irregular mass shape on mammography (p = 0.03), and irregular mass shape on sonography (p = 0.003). Multivariate logistic regression models for AR status showed that AR+ TNBC was significantly associated with heterogeneously dense breast composition on mammography (p = 0.01), high mass density on mammography (p = 0.003), and irregular mass shape on sonography (p = 0.0004). CONCLUSION: The imaging features of TNBCs differ by AR status. Multimodality breast imaging may help identify the LAR subtype of TNBC, which has been shown to be a subtype that is relatively resistant to neoadjuvant chemotherapy.


Assuntos
Mama/diagnóstico por imagem , Mama/metabolismo , Receptores Androgênicos/metabolismo , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Mamografia , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/patologia
10.
Sci Rep ; 9(1): 5967, 2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979930

RESUMO

This study aimed to explore the effects of radiochemotherapy on the neurocognitive function of patients with high-grade gliomas (HGG). The mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), event-related potential P300 (ERP-P300), and specific MRI parameters were compared, and the associations between specific MRI parameters and different doses of radiation were determined for before and up to 12 months after radiotherapy. There were no significant differences in MMSE, MoCA, or ERP-P300 before and after radiotherapy. Compared with pre-radiochemotherapy, fractional anisotropy (FA) in the contralateral hippocampus decreased at 6 and 9 months after radiotherapy. FA in the ipsilateral hippocampus before radiochemotherapy decreased compared with 6 months after radiotherapy. Compared to the end of radiotherapy, as well as 3- and 6-months post-radiotherapy, the regional cerebral blood volume (rCBV) in the genu of the corpus was significantly lower at 12 months post-radiotherapy. Some MRI parameters in different regions of the brain were negatively correlated with the mean and maximum dose. There was no significant effect of radiochemotherapy on the neurocognitive functioning of patients with HGGs found before radiochemotherapy until 12 months after radiotherapy. The radiation-induced FA decrease in the bilateral hippocampus preceded cognitive dysfunction, and DTI of the hippocampus may provide a useful biomarker for predicting radiation-induced neurocognitive impairment in patients with HGGs.

11.
Int J Low Extrem Wounds ; 18(2): 200-207, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968713

RESUMO

Diabetic foot gangrene with lower extremity ischemia can preclude amputation. However, wound treatment principles based on the Wagner classification system are lacking. We proposed the STAGE principle for the surgical management of diabetic foot wounds. The STAGE principle guides surgical intervention during the wound treatment of diabetic foot ulcers and emphasizes that "based on anatomical layers, the management focuses on blood supply and includes layer-by-layer incision to the infected area, maintenance of effective wound drainage, and step-by-step treatment of the wound." We applied the STAGE principle for the treatment of 7 patients with an ankle brachial index <0.5 and Wagner grade 4 diabetic foot gangrene. The average ankle brachial index was 0.42 (0.32-0.48; SD = 0.06), and male patients smoked an average of 1.28 packs/day (0.4-2; SD = 0.63). The average wound duration was 45.86 days (14-63 days; SD = 18.46). The average wound healing time was 8.86 months (5-13 months; SD = 2.36). The follow-up time was 37.71 months (3-84 months; SD = 25.04; median = 36 months). Patient 1 received endovascular interventional therapy twice for the lower extremity artery, and the wound healed. After 3 months of follow-up, the patient exhibited recurrence. After the third application of endovascular interventional therapy for the lower extremity artery, the blood supply was improved, and the wound healed after 1 month. In summary, the treatment of 7 cases of diabetic foot gangrene with severe lower extremity ischemia using the STAGE principle resulted in remarkable efficacy.


Assuntos
Amputação/métodos , Pé Diabético/cirurgia , Procedimentos Endovasculares/métodos , Gangrena/cirurgia , Isquemia/cirurgia , Guias de Prática Clínica como Assunto , Cicatrização/fisiologia , Idoso , China , Estudos de Coortes , Desbridamento/métodos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Pé Diabético/diagnóstico , Pé/cirurgia , Gangrena/diagnóstico , Humanos , Isquemia/fisiopatologia , Perna (Membro)/cirurgia , Salvamento de Membro , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Dedos do Pé/cirurgia , Resultado do Tratamento
12.
Eur Radiol ; 29(10): 5205-5216, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30915560

RESUMO

OBJECTIVES: To determine the sensitivity and positive predictive value (PPV) of gadobenate-enhanced MR imaging for the detection of liver metastases. METHODS: This systematic review and meta-analysis was conducted according to PRISMA guidelines. A comprehensive search (EMBASE, PubMed) was performed to identify relevant articles up to December 2017. Studies eligible for inclusion were performed using appropriate methodology with complete verification by means of histopathology, intraoperative observation and/or follow-up, and sufficient information to permit determination of true-positive (TP), false-negative (FN), and false-positive (FP) values. Sources of bias were assessed using the QUADAS-2 tool. An inverse variance-weighted random-effects model was used to obtain sensitivity and PPV estimates. Information was analyzed and presented using Cochran's Q statistic, funnel plots, and modified Deeks' analysis. RESULTS: Ten articles (256 patients, 562 metastases) were included. Sensitivity estimates for pre-contrast (unenhanced) imaging, gadobenate-enhanced dynamic imaging, and combined unenhanced, dynamic, and delayed hepatobiliary phase imaging for detecting liver metastases on a per-lesion basis were 77.8% (95% CI 71.4-84.3%, 7 assessments), 88.1% (95% CI, 84.0-92.2%, 13 assessments), and 95.1% (95% CI 93.1-97.1%, 15 assessments), respectively. The addition of hepatobiliary phase images significantly improved the detection of liver metastases. The overall PPV was 90.9% (95% CI 86.6-95.1%, 11 assessments). Deeks' funnel analysis revealed no association between sample size and sensitivity (ß = 0.02, p = 0.814) indicating no significant publication bias. CONCLUSIONS: Gadobenate-enhanced MR imaging has high sensitivity and PPV for the detection of liver metastases on a per-lesion basis. The sensitivity and PPV for detection is comparable to reported values for the pure liver-specific agent gadoxetate. KEY POINTS: • Gadobenate dimeglumine is a hepatobiliary MR contrast agent that permits acquisition of contrast-enhanced liver images during the immediate post-injection dynamic phase, like any extracellular agent, and in the delayed hepatobiliary phase, after specific uptake by the hepatocytes. • The hepatobiliary phase improves detection of liver metastases when compared either to pre-contrast unenhanced images alone or to pre-contrast + gadobenate-enhanced dynamic phase images. • The meta-analysis showed an overall sensitivity of 95.1% and PPV of 90.9% of gadobenate-enhanced MRI for the detection of metastases, when based on the evaluation of all available acquisitions.


Assuntos
Gadolínio DTPA/farmacologia , Neoplasias Hepáticas/diagnóstico , Fígado/patologia , Imagem por Ressonância Magnética/métodos , Adulto , Meios de Contraste/farmacologia , Feminino , Humanos , Aumento da Imagem/métodos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade
13.
Cell Biosci ; 9: 23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30886700

RESUMO

Background: Portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) is a sign of advanced stage disease, which is associated with poor prognosis. Liver resection (LR) may provide better prognosis in selected patients. In the present study, we aimed to assess information from HCC patients with PVTT who died within 3 months or 2 years after LR in order to identify preoperative factors correlated to short-term or long-term survival, by which inappropriate selection of patients for LR might be avoided in the future. Methods: A retrospective cohort study consisting of 487 consecutive cases of HCC patients with PVTT was performed from 2008 to 2010 at Eastern Hepatobiliary Surgery Hospital. Medical records, including laboratory values, imaging results and treatment information, were obtained from participants. Study endpoints were survival at 3 months and 2 years post-hepatectomy. Logistic regression analysis was utilized to determine the significant pre-operative factors influencing short-term or long-term survival. Results: In multivariable analysis, α-fetoprotein, total bilirubin and radiologic ascites were significantly associated with short-term survival, while α-fetoprotein level, clinical significant portal hypertension, extent of PVTT and tumor differentiation were factors significantly associated with long-term survival. Conclusions: The independent risk factors of poor short-term survival were the liver function-associated, such as factors radiologic ascites and total bilirubin, while tumor differentiation indicating the tumor biology was associated with longer-term survival. In addition, α-fetoprotein was a risk factor associated with both short-term and longer-term survivals.

14.
Leuk Res ; 79: 34-37, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30831481

RESUMO

Hemorrhage is the typical manifestation of APL-related coagulopathy while thrombosis is infrequently reported. In a retrospective analysis with 33 patients with hyperleukocytic APL, we found 6 out of 33 hyperleukocytic APL patients presented with thrombosis rather than hemorrhage. A notable feature in these high-risk APL patients with thrombosis is that there were no significant abnormalities in fibrinogen (FIB), prothrombin time (PT) and activated partial thromboplastin time (APTT). Compared with the normal ranges, both the high-risk APL patients with thrombosis and the high-risk APL patients with hemorrhage had a significant increase in fibrinogen degradation product (FDP) and d-dimer levels. However, the group with hemorrhage had noticeably higher plasma levels of FDP and d-dimer than the group with thrombosis. To find a close relationship between coagulation markers and the onset of thrombotic events in patients with high-risk APL, the potential effects of FDP/FIB and d-dimer/FIB ratios as risk markers were investigated. We demonstrated that FDP/FIB and d-dimer/FIB ratios in the patients with high-risk APL with thrombosis showed higher ratios than the normal range but significantly lower ratios than the patients with high-risk APL-related hemorrhage. Our data demonstrated that the alteration in FDP/FIB and d-dimer/FIB ratios have more significant relevance than the levels of FIB, FDP or d-dimer as potential factors for predicting thrombosis and may help with designing more appropriately risk-adapted treatment protocols or personalized therapy.


Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/diagnóstico , Trombose/diagnóstico , Adolescente , Adulto , Idoso , Testes de Coagulação Sanguínea/métodos , Criança , Pré-Escolar , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinogênio/metabolismo , Humanos , Leucemia Promielocítica Aguda/complicações , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Trombose/sangue , Trombose/etiologia , Adulto Jovem
15.
Biomed Res Int ; 2019: 5138175, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31930124

RESUMO

Bisphosphonates (BPs) have been extensively used for management of bone diseases with pathologically high resorption. Despite the great clinical benefits, a severe complication known as medication-related osteonecrosis of the jaw (MRONJ) has been reported. It is found that most of the reported MRONJ cases were limited in the jawbones/craniofacial bones instead of long bones. The present study aims to investigate the differential bone response to surgical procedures between jawbones and long bones exposed to BPs. Forty-eight skeletal mature Sprague Dawley female rats were administered oncologic dose of zoledronic acid (ZA) or normal saline for 4 weeks and then subjected to tooth extraction on the mandible and maxilla, and a bone defect creation on the femur. After surgical procedures, ZA or saline treatment were continued until sacrifice at week 2, week 4, and week 8, post-operatively. The samples were subjected to micro-computerized tomography (micro-CT) and histological assessment. Osteonecrosis was only found in jawbones in ZA-treated rats. ZA-treated rats showed significantly higher bone mineral density with greater bone volume in all surgical sites than that in the controls. The length of exposure of ZA did not seem to affect trabecular microstructure, and it only showed higher bone volume and BMD with longer healing time which is expected in the healing process.

16.
Phys Chem Chem Phys ; 20(46): 29091-29104, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30457605

RESUMO

Upon excitation at 308 nm, 4-biphenyl carbonyl azide (4-BpCON3) shows unusually fast decay of transient absorption associated with the first excited singlet state, with time constants of several ps in MeOH, acetonitrile, and CHCl3. In cyclohexane and cyclohexene, the lifetimes are ca. 0.3 ps, which is in stark contrast to the lifetimes of hundreds of ps in the case of 2-naphthoyl azide. Furthermore, photolysis at 266 and 308 nm brought about the same yields of nitrene and isocyanate products. To understand these findings, we also applied ultrafast transient absorption spectroscopy to the structurally related molecule, fluorene-2-carbonyl azide (F2CON3), in which the two phenyl rings are fixed in a plane by a methylene group. Both carbonyl azides (biphenyl and fluorenyl) have very short lived excited states in different solvents, indicating that the twisting of phenyl rings is not the reason for the fast decay. Theoretical studies using time dependent density functional theory (TDDFT), especially with PBE0 and CAM-B3LYP functionals, suggest that excited-state potential energy surface crossings lead to the efficient and fast decomposition of carbonyl azides upon photoexcitation. Especially, the decay of the Franck-Condon state to the S1 state with π(CON3)-π*(N3') transition character, where -N3 is in a bent conformation (∠NNN = ca. 125°), is the key step. Finally, a model is presented to explain solvent dependence, different decaying rates, and other experimental findings.

17.
Biol Open ; 7(7)2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30012552

RESUMO

Patients taking glucocorticoid or glucocorticoid-like drugs for an extended period of time may develop osteoporosis, termed glucocorticoid-induced osteoporosis (GIOP). GIOP is the most common form of secondary osteoporosis, but the mechanism underlying its development is unclear. In the present study, we used prednisolone to treat zebrafish larvae to investigate GIOP. Our RNA deep-sequencing (RNA-seq) results show that prednisolone affects genes known to act in the extracellular region. Therefore the extracellular region, extracellular matrix, and collagen trimer might be involved in glucocorticoid-induced osteoporosis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the focal adhesion signaling pathway is the most enriched signaling pathway in terms of differentially expressed genes (DEGs). In this pathway, integrin subunit alpha 10 (itga10) and integrin subunit beta like 1 (itgbl1), genes encoding two adapter proteins, were down-regulated in the prednisolone-treated larvae. Further experiments showed that prednisolone contributes to GIOP by down-regulating itga10 and itgbl1.

18.
Adv Exp Med Biol ; 1068: 119-133, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29943300

RESUMO

Hematological malignancies (HM) are a heterogeneous group of life-threatening hematological diseases. The heterogeneity and clonal evolution of HM subpopulations are the main obstacles for precise diagnoses, risk stratification, and even targeted therapies. Standard bulk-sample genomic examinations average total mutations from multiple subpopulations and conceal the clonal diversity that may play a significant role in HM progression. Therefore, the development of novel methods that detect intra-tumor heterogeneity is critical for the discovery of novel potential therapeutic targets. The recently developed single cell sequencing (SCS) technologies can analyse genetic polymorphisms at a single cell level. SCS requires the precise isolation of single cells and amplification of their genetic material. It allows the analysis of genomic, transcriptomic, and epigenomic information in single cancer cells. SCS may also be able to monitor minimal residual disease (MRD) of HM by sequencing circulating tumor cells (CTCs) from peripheral blood. Functional heterogeneity and clonal evolution exist in acute leukemia, multiple myeloma (MM) and chronic myeloid leukemia (CML) subpopulations and have prognostic value. In this thesis, we provide an overview of SCS technologies in HM and discuss the heterogeneous genetic variation and clonal structure among subpopulations of HM. Furthermore, we aimed to shed light on the clinical applications of SCS technologies, including the development of new targeted therapies for drug-resistant or recurrent HM.


Assuntos
Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Animais , Evolução Clonal , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Humanos , Células Neoplásicas Circulantes/química , Células Neoplásicas Circulantes/metabolismo , Análise de Célula Única
19.
J Phys Chem B ; 122(25): 6483-6490, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29860828

RESUMO

Oxamate and pyruvate are isoelectronic molecules. They both quench tryptophan fluorescence with Stern-Volmer constants of 16 and 20 M-1, respectively, which are comparable to that of arcrylamide, a commonly used probe for protein structure. On the other hand, it is well known that neither the carboxylate group of these molecules nor the amide group is a good quencher. To find the mechanism of the quenching by oxamate and pyruvate, density functional theory computations with a polarizable continuum model, solvation based on density, and explicit waters, were performed. Results indicate that both molecules can be an electron acceptor via photoinduced electron transfer. There are two requirements. First, the carboxylate and amide moieties must be in direct contact to bring about noticeable quenching. The conjugation between the amide (or the keto) group and the carboxylate group leads to a lower π* orbital, which is the lowest unoccupied molecular orbital (LUMO), and can then accept an electron from the excited tryptophan. Second, since oxamate and pyruvate ions have high electron density, hydrogen bonds with waters, which can be simulated by an explicit water model, are essential. Their LUMO energies are strongly influenced by water in aqueous solution. The above findings demonstrate how tryptophan fluorescence gets quenched in aqueous solution. The findings may be important in dealing with those problems where frontier orbitals are considered, especially with molecules having high electron density.


Assuntos
Ácido Oxâmico/química , Ácido Pirúvico/química , Triptofano/química , Transporte de Elétrons , Ligações de Hidrogênio , Teoria Quântica , Espectrometria de Fluorescência , Água/química
20.
Pathol Res Pract ; 214(7): 1024-1030, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29724530

RESUMO

Hepatocellular carcinoma (HCC) is one of the biggest challenges that human beings faced with in 21st century. Previous researches have revealed that miRNAs can serve as regulators in various cancers. MiR-876-5p, a member of miRNA family, has been studied in lung cancer for its anti-oncogenic function. However, the exact function of it is not reported in HCC. Our study aims to find out the effects of miR-876-5p expression on HCC progression. Two HCC cells were chosen to do functional assays after miR-876-5p expression was detected in cell lines by qRT-PCR. HepG2 cell was transfected with miR-876-5p mimics, whereas LM3 cell was transfected with miR-876-5p inhibitors. Next, cell activities of these two indicated cells were analyzed by means of MTT assay, colony forming assay, transwell migration assay and western blot analysis. Consequently, we found that miR-876-5p could inhibit both cell proliferation and metastasis. Moreover, we found out a target gene (DNMT3A) of miR-876-5p by performing bioinformatics analysis, dual luciferase reporter assay and biotin-avidin pull-down assay. Finally, rescue assays were carried out in HepG2 cells. We found that DNMT3A could reverse miR-876-5p mimics-induced inhibition. Therefore, we concluded that miR-876-5p suppressed hepatocellular carcinoma progression by targeting DNMT3A.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , DNA (Citosina-5-)-Metiltransferases/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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