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1.
Artigo em Inglês | MEDLINE | ID: mdl-32169932

RESUMO

OBJECTIVES: Patients with type 2 diabetes have a higher risk of colorectal cancer (CRC), but whether Chinese herbal medicines (CHMs) can reduce this risk is unknown. This study investigated the effect that CHMs have on CRC risk in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This cohort study used the Taiwanese National Health Insurance Research Database to identify 54 744 patients, newly diagnosed with type 2 diabetes, aged 20-70 years, who were receiving treatment between 1998 and 2007. From this sample, we randomly selected 14 940 CHMs users and 14 940 non-CHMs users, using propensity scores matching. All were followed through 2012 to record CRC incidence. Cox proportional hazards regression was used to compute the hazard ratio (HR) of CRC by CHMs use. RESULTS: During follow-up, 235 CHMs users and 375 non-CHMs users developed CRC, incidence rates of 1.73% and 2.47% per 1000 person-years, respectively. CHM users had a significantly reduced risk of CRC compared with non-CHM users (adjusted HR=0.71; 95% CI 0.60 to 0.84). The greatest effect was in those receiving CHMs for more than 1 year. Huang-Qin, Xue-Fu-Zhu-Yu-Tang, Shu-Jing-Huo-Xue-Tang, Liu-Wei-Di-Huang-Wan, Ji-Sheng-Shen-Qi-Wan, Gan-Lu-Yin, Shao-Yao-Gan-Cao-Tang and Ban-Xia-Xie-Xin-Tang were significantly associated with lower risk of CRC. CONCLUSION: Integrating CHMs into the clinical management of patients with type 2 diabetes may be beneficial in reducing the risk of CRC.

2.
mBio ; 11(2)2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127444

RESUMO

Anti-galactose-α-1,3-galactose (anti-α-Gal) antibody is naturally expressed at a high level in humans. It constitutes about 1% of immunoglobulins found in human blood. Here, we designed a live attenuated influenza virus vaccine that can generate α-Gal epitopes in infected cells in order to facilitate opsonization of infected cells, thereby enhancing vaccine-induced immune responses. In the presence of normal human sera, cells infected with this mutant can enhance phagocytosis of human macrophages and cytotoxicity of NK cells in vitro Using a knockout mouse strain that allows expression of anti-α-Gal antibody in vivo, we showed that this strategy can increase vaccine immunogenicity and the breadth of protection. This vaccine can induce 100% protection against a lethal heterosubtypic group 1 (H5) or group 2 (mouse-adapted H3) influenza virus challenge in the mouse model. In contrast, its heterosubtypic protective effect in wild-type or knockout mice that do not have anti-α-Gal antibody expression is only partial, demonstrating that the enhanced vaccine-induced protection requires anti-α-Gal antibody upon vaccination. Anti-α-Gal-expressing knockout mice immunized with this vaccine produce robust humoral and cell-mediated responses upon a lethal virus challenge. This vaccine can stimulate CD11blo/- pulmonary dendritic cells, which are known to be crucial for clearance of influenza virus. Our approach provides a novel strategy for developing next-generation influenza virus vaccines.IMPORTANCE Influenza A viruses have multiple HA subtypes that are antigenically diverse. Classical influenza virus vaccines are subtype specific, and they cannot induce satisfactory heterosubtypic immunity against multiple influenza virus subtypes. Here, we developed a live attenuated H1N1 influenza virus vaccine that allows the expression of α-Gal epitopes by infected cells. Anti-α-Gal antibody is naturally produced by humans. In the presence of this antibody, human cells infected with this experimental vaccine virus can enhance several antibody-mediated immune responses in vitro Importantly, mice expressing anti-α-Gal antibody in vivo can be fully protected by this H1N1 vaccine against a lethal H5 or H3 virus challenge. Our work demonstrates a new strategy for using a single influenza virus strain to induce broadly cross-reactive immune responses against different influenza virus subtypes.

3.
Can J Cardiol ; 36(2): 159-169, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32036861

RESUMO

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32086201

RESUMO

Magnetic resonance imaging (MRI) is widely used for screening, diagnosis, image-guided therapy, and scientific research. A significant advantage of MRI over other imaging modalities such as computed tomography (CT) and nuclear imaging is that it clearly shows soft tissues in multi-contrasts. Compared with other medical image super-resolution methods that are in a single contrast, multi-contrast super-resolution studies can synergize multiple contrast images to achieve better super-resolution results. In this paper, we propose a one-level nonprogressive neural network for low up-sampling multi-contrast super-resolution and a two-level progressive network for high upsampling multi-contrast super-resolution. The proposed networks integrate multi-contrast information in a high-level feature space and optimize the imaging performance by minimizing a composite loss function, which includes mean-squared-error, adversarial loss, perceptual loss, and textural loss. Our experimental results demonstrate that 1) the proposed networks can produce MRI super-resolution images with good image quality and outperform other multi-contrast super-resolution methods in terms of structural similarity and peak signal-to-noise ratio; 2) combining multi-contrast information in a high-level feature space leads to a signicantly improved result than a combination in the lowlevel pixel space; and 3) the progressive network produces a better super-resolution image quality than the non-progressive network, even if the original low-resolution images were highly down-sampled.

5.
J Neurooncol ; 146(2): 285-292, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31894518

RESUMO

PURPOSE: Patients with high rates of developing new brain metastases have an increased likelihood of dying of neurologic death. It is unclear, however, whether this risk is affected by treatment choice following failure of primary stereotactic radiosurgery (SRS). METHODS: From July 2000 to March 2017, 440 patients with brain metastasis were treated with SRS and progressed to have a distant brain failure (DBF). Eighty-seven patients were treated within the immunotherapy era. Brain metastasis velocity (BMV) was calculated for each patient. In general, the institutional philosophy for use of salvage SRS vs whole brain radiotherapy (WBRT) was to postpone the use of WBRT for as long as possible and to treat with salvage SRS when feasible. No further treatment was reserved for patients with poor life expectancy and who were not expected to benefit from salvage treatment. RESULTS: Two hundred and eighty-five patients were treated with repeat SRS, 91 patients were treated with salvage WBRT, and 64 patients received no salvage radiation therapy. One-year cumulative incidence of neurologic death after salvage SRS vs WBRT was 15% vs 23% for the low- (p = 0.06), 30% vs 37% for the intermediate- (p < 0.01), and 31% vs 48% (p < 0.01) for the high-BMV group. Salvage WBRT was associated with increased incidence of neurologic death on multivariate analysis (HR 1.64, 95% CI 1.13-2.39, p = 0.01) when compared to repeat SRS. One-year cumulative incidence of neurologic death for patients treated within the immunotherapy era was 9%, 38%, and 38% for low-, intermediate-, and high-BMV groups, respectively (p = 0.01). CONCLUSION: Intermediate and high risk BMV groups are predictive of neurologic death. The association between BMV and neurologic death remains strong for patients treated within the immunotherapy era.

6.
Cardiovasc Intervent Radiol ; 43(4): 572-586, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31897617

RESUMO

PURPOSE: Multiple studies have demonstrated adjuvant transcatheter arterial chemoembolization (aTACE) after resection improved outcomes compared to resection alone for patients with hepatocellular carcinoma (HCC). Unlike pre-operative TACE which targets a lesion, aTACE is administered in the proximal hepatic artery to destroy cancer cells within the remaining liver. This systematic review and meta-analysis aims to quantify this survival and disease-free survival (DFS) benefit. METHODS: A search of five databases was performed from inception to 20 August 2019. RESULTS: A total of 26 studies (six randomized controlled trials) involving 7817 patients were included. Patients treated with resection plus aTACE had significantly better 1-year survival (OR, 2.53 [95% CI, 1.70-3.76, p < 0.001) and 1-year DFS (OR, 1.91 [95% CI, 1.60-2.28, p < 0.001) compared to resection alone. The survival benefit remained significant for 2- to 5-year survival (OR 2.39, 1.83, 2.12, 1.87, respectively) and 2- to 4-year DFS (OR 1.85, 1.24, 1.67, respectively). Subgroup analysis showed significant survival benefit with aTACE in microvascular invasion (MVI)-positive HCC, portal venous tumour thrombus (PVTT) that does not involve the main trunk, PVTT-negative, satellite nodules, with and without resection margin < 1 cm. No mortalities were reported with aTACE. CONCLUSION: Post-operative aTACE is safe and improves overall and disease-free survival, with the greatest benefit in MVI-positive patients. The current evidence weakly supports the use of adjuvant TACE for patients without PVTT, with PVTT that does not involve the main trunk, with and without a resection margin < 1 cm, and patients with satellite nodules. LEVEL OF EVIDENCE: Level 1.

7.
Thyroid ; 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31910112

RESUMO

Background: A population-based reference interval (RI) of thyroid hormones in pregnancy using a standardized methodology is crucial for clinicians to make accurate diagnoses and important for the comparison of test results obtained from different analytic platforms. Methods: We enrolled 600 healthy Chinese women to obtain longitudinal serum samples across gestation, after exclusion of subjects with antibodies to thyroid peroxidase, thyroglobulin or thyrotropin receptor. Gestational age-specific RIs were constructed by using polynomial regression equations with MLwiN. Results: Free thyroxine (fT4) levels rose to a peak at the 7th-8th gestational weeks and then declined gradually till 28th week, while thyrotropin (TSH) level decreased from early pregnancy to a nadir at the 9th week. The data support the recent notion by the American Thyroid Association to raise the TSH upper RI to 4.0 mIU/L. We also demonstrate that thyroid hormone reference ranges are not affected in a mildly iodine-deficient population and by including women with the presence of antibodies against thyroid peroxidase and thyroglobulin who are otherwise healthy. Conclusions: The study highlights a methodology in constructing gestational age-specific thyroid function test RIs on different analytic platforms to provide a better interpretation and comparison of results obtained across different platforms.

8.
J Diabetes Investig ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31912653

RESUMO

AIMS/INTRODUCTION: Women with gestational diabetes mellitus are at increased risk for type 2 diabetes. We characterized the association between maternal glycemia during pregnancy with long-term outcomes. METHODS AND METHODS: In this prospective nested case-cohort study, participants were recalled for follow up with detailed evaluation including oral glucose tolerance test at 8, 15 and 22 years. Logistic regression was used to estimate the risk of developing impaired glucose tolerance/type 2 diabetes and metabolic syndrome at follow up. The association between maternal glycemia at pregnancy and follow up was evaluated by linear regression. We also charted trajectory of ß-cell function during follow up. RESULTS: The analysis included 121 women with a mean follow-up period of 22.5 years, and a mean age of 50.3 years. Gestational diabetes was associated with an adjusted odds ratio of 2.48 (95% confidence interval 1.03-5.99) for combined diabetes/impaired glucose tolerance at follow up (P = 0.04). Women with a pre-pregnancy body mass index ≥23 had an odds ratio of 5.43 (95% confidence interval 1.87-15.72) for metabolic syndrome at follow up, compared with those with body mass index <23 (P = 0.002). Both fasting and 2-h glucose during pregnancy were strongly associated with glycemic indices at follow up (P-value <0.001-0.016). Gestational diabetes was associated with impaired ß-cell function that remained relatively stable after the index pregnancy. CONCLUSIONS: Chinese women with a history of gestational diabetes have a high prevalence of impaired glucose tolerance/type 2 diabetes at 22-year follow up. Glucose levels during mid-pregnancy are strongly associated with those of middle age.

9.
Radiother Oncol ; 142: 168-174, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31526671

RESUMO

INTRODUCTION: Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radiosurgery (SRS). We have previously risk stratified patients into high, intermediate, and low-risk BMV groups, which correlates with overall survival (OS). We sought to externally validate BMV in a multi-institutional setting. METHODS: Patients from nine academic centers were treated with upfront SRS; the validation cohort consisted of data from eight institutions not previously used to define BMV. Patients were classified by BMV into low (<4 BMV), intermediate (4-13 BMV), and high-risk groups (>13 BMV). Time-to-event outcomes were estimated using the Kaplan-Meier method. Cox proportional hazards methods were used to estimate the effect of BMV and salvage modality on OS. RESULTS: Of 2829 patients, 2092 patients were included in the validation dataset. Of these, 921 (44.0%) experienced distant brain failure (DBF). Median OS from initial SRS was 11.2 mo. Median OS for BMV < 4, BMV 4-13, and BMV > 13 were 12.5 mo, 7.0 mo, and 4.6 mo (p < 0.0001). After multivariate regression modeling, melanoma histology (ß: 10.10, SE: 1.89, p < 0.0001) and number of initial brain metastases (ß: 1.52, SE: 0.34, p < 0.0001) remained predictive of BMV (adjusted R2 = 0.06). CONCLUSIONS: This multi-institutional dataset validates BMV as a predictor of OS following initial SRS. BMV is being utilized in upcoming multi-institutional randomized controlled trials as a stratification variable for salvage whole brain radiation versus salvage SRS after DBF.

10.
Oncogene ; 39(1): 64-78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31462709

RESUMO

Mechanisms for breast cancer metastasis remain unclear. Whether truncated glioma-associated oncogene homolog 1 (TGLI1), a transcription factor known to promote angiogenesis, migration and invasion, plays any role in metastasis of any tumor type has never been investigated. In this study, results of two mouse models of breast cancer metastasis showed that ectopic expression of TGLI1, but not GLI1, promoted preferential metastasis to the brain. Conversely, selective TGLI1 knockdown using antisense oligonucleotides led to decreased breast cancer brain metastasis (BCBM) in vivo. Immunohistochemical staining showed that TGLI1, but not GLI1, was increased in lymph node metastases compared to matched primary tumors, and that TGLI1 was expressed at higher levels in BCBM specimens compared to primary tumors. TGLI1 activation is associated with a shortened time to develop BCBM and enriched in HER2-enriched and triple-negative breast cancers. Radioresistant BCBM cell lines and specimens expressed higher levels of TGLI1, but not GLI1, than radiosensitive counterparts. Since cancer stem cells (CSCs) are radioresistant and metastasis-initiating cells, we examined TGLI1 for its involvement in breast CSCs and found TGLI1 to transcriptionally activate stemness genes CD44, Nanog, Sox2, and OCT4 leading to CSC renewal, and TGLI1 outcompetes with GLI1 for binding to target promoters. We next examined whether astrocyte-priming underlies TGLI1-mediated brain tropism and found that TGLI1-positive CSCs strongly activated and interacted with astrocytes in vitro and in vivo. These findings demonstrate, for the first time, that TGLI1 mediates breast cancer metastasis to the brain, in part, through promoting metastasis-initiating CSCs and activating astrocytes in BCBM microenvironment.

11.
Pharmacol Ther ; 206: 107428, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31626870

RESUMO

Glucocorticoids (GC) in all its various forms and formulations are likely one of the most commonly used pharmacologic agents in medicine. Their use can be profoundly therapeutic but are also associated with a myriad of acute and chronic side effects. It is fairly well-accepted in the medical community that GC can be life-saving when used in critically ill patients with severe exacerbations of asthma and chronic obstructive pulmonary disease, HIV-associated pneumocystosis, and systemic vasculitides. However, the adjunctive role of GC is much more controversial in acute respiratory distress syndrome (ARDS), septic shock, community-acquired pneumonia, and several other serious medical conditions. Despite such controversies, GC should at least be considered for patients with fulminant manifestations of the following conditions as there is equipoise to indicate that GC may improve outcome with acceptable risks: (i) severe ARDS with refractory hypoxemia despite one to two weeks of state-of-the-art management, (ii) recalcitrant, vasopressor-dependent septic shock, (iii) non-influenza, severe community-acquired pneumonia, and (iv) severe alcoholic hepatitis. The bases for these controversies is likely due to both host factors (e.g., differences in GC resistance and susceptibility to adverse effects) and different phenotypes of any one disease state; e.g., different pathogenesis and pathogens under the rubric of "sepsis." Elucidation of better biomarkers to determine the underlying pathogenic phenotype will significantly advance our understanding and prediction of which critically ill patients will benefit from GC and who would experience a deleterious effect from its use.

12.
Med Phys ; 47(3): 1139-1150, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31885094

RESUMO

PURPOSE: Pseudoprogression (PsP) occurs in 20-30% of patients with glioblastoma multiforme (GBM) after receiving the standard treatment. PsP exhibits similarities in shape and intensity to the true tumor progression (TTP) of GBM on the follow-up magnetic resonance imaging (MRI). These similarities pose challenges to the differentiation of these types of progression and hence the selection of the appropriate clinical treatment strategy. METHODS: To address this challenge, we introduced a novel feature learning method based on deep convolutional generative adversarial network (DCGAN) and AlexNet, termed DC-AL GAN, to discriminate between PsP and TTP in MRI images. Due to the adversarial relationship between the generator and the discriminator of DCGAN, high-level discriminative features of PsP and TTP can be derived for the discriminator with AlexNet. We also constructed a multifeature selection module to concatenate features from different layers, contributing to more powerful features used for effectively discriminating between PsP and TTP. Finally, these discriminative features from the discriminator are used for classification by a support vector machine (SVM). Tenfold cross-validation (CV) and the area under the receiver operating characteristic (AUC) were applied to evaluate the performance of this developed algorithm. RESULTS: The accuracy and AUC of DC-AL GAN for discriminating PsP and TTP after tenfold CV were 0.920 and 0.947. We also assessed the effects of different indicators (such as sensitivity and specificity) for features extracted from different layers to obtain a model with the best classification performance. CONCLUSIONS: The proposed model DC-AL GAN is capable of learning discriminative representations from GBM datasets, and it achieves desirable PsP and TTP classification performance superior to other state-of-the-art methods. Therefore, the developed model would be useful in the diagnosis of PsP and TTP for GBM.

13.
Bioorg Med Chem Lett ; 30(3): 126840, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31864800

RESUMO

Toll-like receptors (TLRs) are a type of pattern recognition receptors (PRRs), which are activated by recognizing pathogen-associated molecular patterns (PAMPs). The activation of TLRs initiates innate immune responses and subsequently leads to adaptive immune responses. TLR agonists are effective immuomodulators in vaccine adjuvants for infectious diseases and cancer immunotherapy. In exploring hydrophilic small molecules of TLR7 ligands using the cell-targeted property of a vaccine adjuvant, we conjugated 1V209, a small TLR7 ligand molecule, with various low or middle molecular weight sugar molecules that work as carriers. The sugar-conjugated 1V209 derivatives showed increased water solubility and higher immunostimulatory activity in both mouse and human cells compared to unmodified 1V209. The improved immunostimulatory potency of sugar-conjugates was attenuated by an inhibitor of endocytic process, cytochalasin D, suggesting that conjugation of sugar moieties may enhance the uptake of TLR7 ligand into the endosomal compartment. Collectively our results support that sugar-conjugated TLR7 ligands are applicable to novel drugs for cancer and vaccine therapy.

14.
Br J Radiol ; 93(1108): 20190866, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31860329

RESUMO

OBJECTIVE: This systematic review and meta-analysis investigated risk factors for pneumothorax following CT-guided percutaneous transthoracic lung biopsy. METHODS: A systematic search of nine literature databases between inception to September 2019 for eligible studies was performed. RESULTS: 36 articles were included with 23,104 patients. The overall pooled incidence for pneumothorax was 25.9% and chest drain insertion was 6.9%. Pneumothorax risk was significantly reduced in the lateral decubitus position where the biopsied lung was dependent compared to a prone or supine position [odds ratio (OR):3.15]. In contrast, pneumothorax rates were significantly increased in the lateral decubitus position where the biopsied lung was non-dependent compared to supine (OR:2.28) or prone position (OR:3.20). Other risk factors for pneumothorax included puncture site up compared to down through a purpose-built biopsy window in the CT table (OR:4.79), larger calibre guide/needles (≤18G vs >18G: OR 1.55), fissure crossed (OR:3.75), bulla crossed (OR:6.13), multiple pleural punctures (>1 vs 1: OR:2.43), multiple non-coaxial tissue sample (>1 vs 1: OR 1.99), emphysematous lungs (OR:3.33), smaller lesions (<4 cm vs 4 cm: OR:2.09), lesions without pleural contact (OR:1.73) and deeper lesions (≥3 cm vs <3cm: OR:2.38). CONCLUSION: This meta-analysis quantifies factors that alter pneumothorax rates, particularly with patient positioning, when planning and performing a CT-guided lung biopsy to reduce pneumothorax rates. ADVANCES IN KNOWLEDGE: Positioning patients in lateral decubitus with the biopsied lung dependent, puncture site down with a biopsy window in the CT table, using smaller calibre needles and using coaxial technique if multiple samples are needed are associated with a reduced incidence of pneumothorax.


Assuntos
Biópsia Guiada por Imagem/efeitos adversos , Pulmão/patologia , Pneumotórax/etiologia , Tomografia Computadorizada por Raios X , Humanos , Incidência , Agulhas/efeitos adversos , Posicionamento do Paciente/métodos , Punções/efeitos adversos , Radiografia Intervencionista/efeitos adversos , Fatores de Risco
15.
J Autoimmun ; : 102362, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31787479

RESUMO

Dendritic cells (DCs) play key roles in regulating T cell proliferation and differentiation, and epigenetic modification involves in this process. In the periphery, programmed death ligand-1 (PD-L1) expressed on antigen-presenting cells interacts with programmed death-1 (PD-1) on T cells to negatively regulate T cell responses. In this study, we investigate whether DNA demethylation in DCs, downmodulates CD4+ T cell activation, to halt progression of experimental autoimmune encephalomyelitis (EAE). These results showed that during the development of bone marrow-derived DCs (BMDCs), DNA hypomethylation by 0.1 µM and 1 µM 5-aza-2'-deoxycytidine (5-aza) upregulated PD-L1, but not CD40, CD80, or CD86, with surprising downregulation of PD-L2. In co-culture, 5-aza-treated BMDCs, as well as CD11c+ cells from 5-aza-treated EAE mice, inhibited EAE CD4+ T cell proliferation and cytokine secretion. Additionally, in vivo 5-aza pretreatment arrested disease progression, inflammatory cell infiltration, and CNS demyelination, in EAE mice. Compared to DCs from vehicle control-treated EAE rodents, DCs from 5-aza-treated EAE mice upregulated PD-L1, in correlation with hypomethylation of the Cd274 promoter. Furthermore, antibody-mediated blockage of PD-L1 rescued EAE progression from 5-aza treatment, in vivo, while also disinhibiting EAE CD4+ T cell proliferation, by 5-aza-treated DCs, in vitro. Consequently, we conclude that PD-L1 is upregulated via DNA hypomethylation in DCs, resulting in downregulation of autoimmune effector T cell functions, thereby halting progression of EAE.

16.
Eur Radiol Exp ; 3(1): 49, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31853685

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) guidelines recommend ultrasound screening in high-risk patients. However, in some patients, ultrasound image quality is suboptimal due to factors such as hepatic steatosis, cirrhosis, and confounding lesions. Our aim was to investigate an abbreviated non-contrast magnetic resonance imaging (aNC-MRI) protocol as a potential alternative screening method. METHODS: A retrospective study was performed using consecutive liver MRI studies performed over 3 years, with set exclusion criteria. The unenhanced T2-weighted, T1-weighted Dixon, and diffusion-weighted sequences were extracted from MRI studies with a known diagnosis. Each anonymised aNC-MRI study was read by three radiologists who stratified each study into either return to 6 monthly screening or investigate with a full contrast-enhanced MRI study. RESULTS: A total of 188 patients were assessed; 28 of them had 42 malignant lesions, classified as Liver Imaging Reporting and Data System 4, 5, or M. On a per-patient basis, aNC-MRI had a negative predictive value (NPV) of 97% (95% confidence interval [CI] 95-98%), not significantly different in patients with steatosis (99%, 95% CI 93-100%) and no steatosis (97%, 95% CI 94-98%). Per-patient sensitivity and specificity were 85% (95% CI 75-91%) and 93% (95% CI 90-95%). CONCLUSION: Our aNC-MRI HCC screening protocol demonstrated high specificity (93%) and NPV (97%), with a sensitivity (85%) comparable to that of ultrasound and gadoxetic acid contrast-enhanced MRI. This screening method was robust to hepatic steatosis and may be considered an alternative in the case of suboptimal ultrasound image quality.

17.
J Med Imaging Radiat Oncol ; 63(6): 802-811, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31709778

RESUMO

INTRODUCTION: This study investigates the outcomes and safety of 70-150 µm and 100-300 µm doxorubicin drug-eluting bead transarterial chemoembolisation (DEB-TACE) in patients with unresectable hepatocellular carcinoma (HCC). METHODS: Retrospective, cohort study of 51 patients treated with DEB-TACE for unresectable HCC was studied: 23 with 100-300 µm particles and 28 with 70-150 µm particles. Overall, survival (OS), progression-free survival (PFS), tumour response and prognostic factors were assessed. RESULTS: The median OS of the entire cohort was 30 months. The median OS and median PFS for 70-150 µm particles were not reached, whilst for the 100-300 µm group, it was 29.2 months and 15.0 months, respectively. The 6-month, 1-year and 2-year OS for 70-150 µm was 96%, 86% and 85% versus the 100-300 µm particles size of 83%, 64% and 44%, respectively. At 1-month follow-up, patients treated with 70-150 µm had significantly better mRECIST tumour response compared to 100-300 µm (complete response 38.5% vs. 19%; partial response 57.7% vs. 42.9%; stable disease 0% vs. 4.8%; progressive disease 3.8% vs. 33.3%, P = 0.027). Patients treated with 100-300 µm DEBs were significantly more likely to have progressive disease on 1-month follow-up imaging compared those treated with 70-150 µm DEB sizes (odds ratio 7.15, P = 0.007). The 30-day mortality rate was similar between the two groups (3.6% for 70-150 µm vs. 4.3% for 100-300 µm). Multivariate analysis demonstrated entire cohort OS was significantly associated with BCLC stage (aHR: 10.5, P = 0.002), albumin (aHR: 15.0, P = 0.02) and ALP (aHR 62, P = 0.001). CONCLUSIONS: DEB-TACE with 70-150 µm particles demonstrates improved 1-month objective tumour response compared to 100-300 µm, whilst having a similar safety profile. Elevated ALP, lower albumin and higher BCLC stage were significantly associated with poorer survival outcomes.

18.
F1000Res ; 8: 1612, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31723423

RESUMO

Familial hypocalciuric hypercalcaemia (FHH) is a genetic disorder of altered calcium homeostasis. Mutations in the CASR, GNA11 and AP2S1 genes have been reported to cause FHH. We report a Hong Kong Chinese kindred with FHH type 3 (FHH3) caused by mutations in AP2S1. The proband, a 51-year-old woman with hypercalcaemia, was initially diagnosed to have primary hyperparathyroidism but repeated parathyroidectomy failed to normalize her plasma calcium concentrations. Later, FHH was suspected and yet no mutations were identified in the CASR gene which causes FHH type 1 (FHH1), the most common form of FHH. Genetic testing of AP2S1 revealed a heterozygous c.43C>T (p.Arg15Cys) mutation, confirming the diagnosis of FHH3. The elder brother and niece of the proband, who both have hypercalcaemia, were found to harbour the same mutation. To our knowledge, this is the first Chinese kindred of FHH3 reported in the English literature.

20.
Cancers (Basel) ; 11(10)2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31569404

RESUMO

MicroRNAs (miRNAs) have been shown to play a crucial role in the progression of human cancers, including urothelial carcinoma (UC), the sixth-most common cancer in the world. Among them, miR-34a has been implicated in the regulation of cancer stem cells (CSCs); however, its role in UC has yet to be fully elucidated. In this study, bioinformatics and experimental analysis confirmed that miR-34a targets CD44 (a CSC surface marker) and c-Myc (a well-known cell cycle regulator) in UC. We found that, surprisingly, most UC cell lines and patient samples did express miR-34a, although epigenetic silencing by promoter hypermethylation of miR-34a expression was observed only in UMUC3 cells, and a subset of patient samples. Importantly, overexpression of c-Myc, a frequently amplified oncogene in UC, was shown to upregulate CD44 expression through a competing endogenous RNA (ceRNA) mechanism, such that overexpression of the c-Myc 3'UTR upregulated CD44, and vice versa. Importantly, we observed a positive correlation between the expression of c-Myc and CD44 in clinical samples obtained from UC patients. Moreover, overexpression of a dominant-negative p53 mutant downregulated miR-34a, but upregulated c-Myc and CD44, in UC cell lines. Functionally, the ectopic expression of miR-34a was shown to significantly suppress CD44 expression, and subsequently, suppression of cell growth and invasion capability, while also reducing chemoresistance. In conclusion, it appears that aberrant promoter methylation, and c-Myc-mediated ceRNA mechanisms, may attenuate the function of miR-34a, in UC. The tumor suppressive role of miR-34a in controlling CSC phenotypes in UC deserves further investigation.

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