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1.
Oxid Med Cell Longev ; 2020: 7353618, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32047579

RESUMO

Cisplatin chemotherapy causes myelosuppression and often limits treatment duration and dose escalation in patients. Novel approaches to circumvent or lessen myelotoxicity may improve clinical outcome and quality of life in these patients. Chlorella sorokiniana (CS) is a freshwater unicellular green alga and exhibits encouraging efficacy in immunomodulation and anticancer in preclinical studies. However, the efficacy of CS on chemoprotection remains unclear. We report here, for the first time, that CS extract (CSE) could protect normal myeloid cells and PBMCs from cisplatin toxicity. Also, cisplatin-induced apoptosis in HL-60 cells was rescued through reservation of mitochondrial function, inhibition of cytochrome c release to cytosol, and suppression of caspase and PARP activation. Intriguingly, cotreatment of CSE attenuated cisplatin-evoked hypocellularity of bone marrow in mice. Furthermore, we observed the enhancement of CSF-GM activity in bone marrow and spleen in mice administered CSE and cisplatin, along with increased CD11b levels in spleen. In conclusion, we uncovered a novel mechanism of CSE on myeloprotection, whereby potentially supports the use of CSE as a chemoprotector against cisplatin-induced bone marrow toxicity. Further clinical investigation of CSE in combination with cisplatin is warranted.

2.
Radiat Oncol ; 15(1): 33, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054487

RESUMO

BACKGROUND: The development of radiation pneumonitis (RP) after Stereotactic Body Radiotherapy (SBRT) is known to be associated with many different factors, although historical analyses of RP have commonly utilized heterogeneous fractionation schemes and methods of reporting. This study aims to correlate dosimetric values and their association with the development of Symptomatic RP according to recent reporting standards as recommended by the American Association of Physicists in Medicine. METHODS: We performed a single-institution retrospective review for patients who received SBRT to the lung from 2010 to 2017. Inclusion criteria required near-homogeneous tumoricidal (α/ß = 10 Gy) biological effective dose (BED10) of 100-105 Gy (e.g., 50/5, 48/4, 60/8), one or two synchronously treated lesions, and at least 6 months of follow up or documented evidence of pneumonitis. Symptomatic RP was determined clinically by treating radiation oncologists, requiring radiographic evidence and the administration of steroids. Dosimetric parameters and patient factors were recorded. Lung volumes subtracted gross tumor volume(s). Wilcoxon Rank Sums tests were used for nonparametric comparison of dosimetric data between patients with and without RP; p-values were Bonferroni adjusted when applicable. Logistic regressions were conducted to predict probabilities of symptomatic RP using univariable models for each radiation dosimetric parameter. RESULTS: The final cohort included 103 treated lesions in 93 patients, eight of whom developed symptomatic RP (n = 8; 8.6%). The use of total mean lung dose (MLD) > 6 Gy alone captured five of the eight patients who developed symptomatic RP, while V20 > 10% captured two patients, both of whom demonstrated a MLD > 6 Gy. The remaining three patients who developed symptomatic RP without exceeding either metric were noted to have imaging evidence of moderate interstitial lung disease, inflammation of the lungs from recent concurrent chemoradiation therapy to the contralateral lung, or unique peri-tumoral inflammatory appearance at baseline before treatment. CONCLUSIONS: This study is the largest dosimetric analysis of symptomatic RP in the literature, of which we are aware, that utilizes near-homogenous tumoricidal BED fractionation schemes. Mean lung dose and V20 are the most consistently reported of the various dosimetric parameters associated with symptomatic RP. MLD should be considered alongside V20 in the treatment planning process. TRIAL REGISTRATION: Retrospectively registered on IRB 398-17-EP.

3.
Chemosphere ; 249: 126095, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32044608

RESUMO

A microbial electrolysis cell (MEC) has been developing for enhanced absorbent regeneration in a chemical absorption-biological reduction integrated process for NO removal. In this work, the kinetics of electron transfer involved in the biocathodes along Fe(III)EDTA and Fe(II)EDTA-NO reduction was analyzed simultaneously. A modified Nernst-Monod kinetics considering the Faraday efficiency was applied to describe the electron transfer kinetics of Fe(III)EDTA reduction. The effects of substrate concentration, biocathodic potential on current density predicted by the model have been validated by the experimental results. Furthermore, extended from the kinetics of Fe(III)EDTA reduction, the electron transfer kinetics of Fe(II)EDTA-NO reduction was developed with a semi-experimental method, while both direct electrochemical and bioelectrochemical processes were taken into consideration at the same time. It was revealed that the developed model could simulate the electron transfer kinetics well. This work could not only help advance the biocathodic reduction ability and the utilization efficiency of electric power, but also provide insights into the industrial scale-up and application of the system.

4.
Invest New Drugs ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020437

RESUMO

In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120-300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment-related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%-47% (22%-54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967.

5.
Ann Thorac Surg ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32032573

RESUMO

BACKGROUND: Thoracoscopic resection of small pulmonary nodules can be challenging, which highlights the importance of preoperative localization. We report our experience with electromagnetic navigation (EMN)-guided localization. METHODS: The clinical, radiographic, surgical, and pathological data of patients who underwent EMN-guided preoperative localization for pulmonary tumors smaller than 2 cm were reviewed. Successful localization was defined as successful identification of target lesions during the thoracoscopic procedure without palpation. RESULTS: A total of 30 patients with 35 nodules were included. Thirty-one transthoracic and five transbronchial approaches were performed. One patient received both approaches for the same tumor. Three patients received both approaches for localization of multiple targets. The median nodule size was 1.0 (interquartile range (IQR): 0.8-1.2) cm, and the median distance from the pleural surface was 1.1 (IQR: 0.6-2.0) cm. Dye was the most commonly used (n = 18) marker for localization, followed by microcoils (n =15). In nodules located with microcoils, the median distance between the microcoil and nodule was 1 (IQR: 0-3) mm. There were no localization procedure-related complications. Successful localization was achieved in 27 of 30 (90.0%) patients and 32 of 35 (91.4%) nodules. The pathological diagnosis was primary pulmonary malignancy in 29 nodules and secondary pulmonary malignancy in 6 nodules. CONCLUSIONS: We reported our experience with EMN-guided transbronchial and transthoracic preoperative localization of small, malignant pulmonary tumors. This technique is feasible and appears to be a viable option for preoperative localization of pulmonary nodules that may be difficult to locate thoracoscopically.

6.
Neurosurgery ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31960049

RESUMO

BACKGROUND: Preganglionic cervical root transection (PCRT) is the most severe type of brachial plexus injury. In some cases, surgical procedures must be postponed for ≥3 wk until electromyographic confirmation. However, research works have previously shown that treating PCRT after a 3-wk delay fails to result in functional recovery. OBJECTIVE: To assess whether the immunosuppressive drug sirolimus, by promoting neuroprotection in the acute phase of PCRT, could enable functional recovery in cases of delayed repair. METHODS: First, rats received a left 6th to 8th cervical root transection, after which half were administered sirolimus for 1 wk. Markers of microglia, astrocytes, neurons, and autophagy were assessed at days 7 and 21. Second, animals with the same injury received nerve grafts, along with acidic fibroblast growth factor and fibrin glue, 3 wk postinjury. Sirolimus was administered to half of them for the first week. Mechanical sensation, grasping power, spinal cord morphology, functional neuron survival, nerve fiber regeneration, and somatosensory-evoked potentials (SSEPs) were assessed 1 and 23 wk postinjury. RESULTS: Sirolimus was shown to attenuate microglial and astrocytic proliferation and enhance neuronal autophagy and survival; only rats treated with sirolimus underwent significant sensory and motor function recovery. In addition, rats who achieved functional recovery were shown to have abundant nerve fibers and neurons in the dorsal root entry zone, dorsal root ganglion, and ventral horn, as well as to have SSEPs reappearance. CONCLUSION: Sirolimus-induced neuroprotection in the acute stage of PCRT enables functional recovery, even if surgical repair is performed after a 3-wk delay.

7.
Science ; 367(6473): 76-79, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31896714

RESUMO

Rotation around a specific bond after photoexcitation is central to vision and emerging opportunities in optogenetics, super-resolution microscopy, and photoactive molecular devices. Competing roles for steric and electrostatic effects that govern bond-specific photoisomerization have been widely discussed, the latter originating from chromophore charge transfer upon excitation. We systematically altered the electrostatic properties of the green fluorescent protein chromophore in a photoswitchable variant, Dronpa2, using amber suppression to introduce electron-donating and electron-withdrawing groups to the phenolate ring. Through analysis of the absorption (color), fluorescence quantum yield, and energy barriers to ground- and excited-state isomerization, we evaluate the contributions of sterics and electrostatics quantitatively and demonstrate how electrostatic effects bias the pathway of chromophore photoisomerization, leading to a generalized framework to guide protein design.

8.
Cerebellum ; 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31900856

RESUMO

Alzheimer's disease (AD) is a disease with dysfunctional brain network. Previous studies found the cerebellar volume changes over the course of AD disease progression; however, whether cerebellar volume change contributes to the cognitive decline in AD, or its earlier disease stage (i.e., mild cognitive impairment [MCI]) remains unclear. In ADNI, cognitive function was assessed using Alzheimer's Disease Assessment Scale-Cognitive Behavior section (ADAS-Cog). We used linear regression and linear mixed effects models to examine whether cerebellar volume is associated with either baseline cognition or with cognitive changes over time in MCI or in AD. We used logistic regression to assess the relationship between cerebellar volume and disease progression to MCI and AD. We found that cerebellar volume is associated with cognition in patients with MCI, after adjusting for age, gender, education, hippocampal volume, and APOE4 status. Consistently, cerebellar volume is associated with increased odds of the disease stages of MCI and AD when compared to controls. However, cerebellar volume is not associated with cognitive changes over time in either MCI or AD. In summary, cerebellar volume may contribute to cognition level in MCI, but not in AD, indicating that the cerebellar network might modulate the cognitive function in the early stage of the disease. The cerebellum may be a potential target for neuromodulation in treating MCI.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31970439

RESUMO

In oropharyngeal squamous cell carcinoma (OPSCC), the relationships between immune responses, carcinogens, and prognoses are not clarified yet. Here, we retrospectively reviewed the pathology samples of 46 OPSCC patients, and used p16 to determine their human papillomavirus (HPV) status. The Cancer Genome Atlas (TCGA) database was also analyzed for further comparison. The immunofluorescence staining of proinflammatory cytokines showed that high interferon gamma (IFNγ; T helper 1; Th1), low interleukin 4 (IL4; T helper 2; Th2), low thymic stromal lymphopoietin (TSLP; Th2), and low transforming growth factor beta (TGFß; T regulatory; Treg) expressions were good prognostic factors for OPSCC. p16-positive OPSCC showed higher Th1, lower Th2/Treg proinflammatory cytokine expressions, and a better prognosis than p16-negative OPSCC. In smokers alone, although p16-positive OPSCC smokers showed weaker Th2/Treg predominant cytokine expressions than p16-negative OPSCC smokers, the prognoses of both groups were equally poor. As for p16-positive OPSCC patients alone, p16-positive nonsmokers showed a significantly better prognosis than p16-positive smokers, but the immune responses of both groups were all weakly Th2/Treg predominant. Overall, higher Th1 and lower Th2/Treg proinflammatory cytokine expressions are associated with a better prognosis for OPSCC. HPV may be related to increased Th1, decreased Th2/Treg responses, and a good prognosis, while smoking may be related to increased Th2/Treg, decreased Th1 responses, and a poor prognosis in OPSCC. The impact of smoking on immune deviation may be weaker than that of HPV, but the impact of smoking on prognosis may be stronger than that of HPV in OPSCC.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31940520

RESUMO

Datastream analysis aims at extracting discriminative information for classification from continuously incoming samples. It is extremely challenging to detect novel data while incrementally updating the model efficiently and stably, especially for high-dimensional and/or large-scale data streams. This paper proposes an efficient framework for novelty detection and incremental learning for unlabeled chunk data streams. First, an accurate factorization-free kernel discriminative analysis (FKDA-X) is put forward through solving a linear system in the kernel space. FKDA-X produces a Reproducing Kernel Hilbert Space (RKHS), in which unlabeled chunk data can be detected and classified by multiple known-classes in a single decision model with a deterministic classification boundary. Moreover, based on FKDA-X, two optimal methods FKDA-CX and FKDA-C are proposed. FKDA-CX uses the micro-cluster centers of original data as the input to achieve excellent performance in novelty detection. FKDA-C and incremental FKDA-C (IFKDA-C) using the class centers of original data as their input have extremely fast speed in online learning. Theoretical analysis and experimental validation on under-sampled and large-scale real-world datasets demonstrate that the proposed algorithms make it possible to learn unlabeled chunk data streams with significantly lower computational costs and comparable accuracies than the state-of-the-art approaches.

11.
J Hazard Mater ; 387: 121717, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31767505

RESUMO

Composite beads are packed in the anode chamber of a microbial fuel cell (MFC), providing more area for microbial attachment and growth, increasing the efficiency of removal of toluene from toluene-contaminated groundwater. The composite beads were fabricated by integrating carbon coke (CC) with a relatively large specific surface area to which microorganisms easily adhere with conductive carbon black (CCB), which has low electrical resistance. Since the advantages of both are complementary, the power generation of MFC is improved. The single layer-packed anode MFC (SP-MFC) completely degraded 200 mg L-1 of toluene - 2.3 times faster than the non-packed anode MFC (NP-MFC). The high power density (44.9 mW m-3) and oxidation peak (1 mA), with low internal resistance (207 Ω) revealed that SP effectively improved the power generation efficiency. A composition ratio (CRCCB:CC) of composite beads of one to two yielded the best performance with a removal efficiency of 100 % - 76 % faster than CC. The closed circuit voltage of CR1:2 MFC reached 340 mV, which was 16 times that of CC; the power density and oxidation peak reached 103 mW m-3 and 1.38 mA, respectively. Therefore, CR1:2 effectively increased the overall removal efficiency and power generation of the MFC.

12.
J Adv Nurs ; 76(2): 514-525, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31657485

RESUMO

AIM: To investigate the long-term psychological reactions and resilient process of the young survivors after a large-scale burn disaster of the Formosa Color Dust Explosion in Taiwan. DESIGN: Longitudinal study with follow-up interviews using standardized questionnaire during November 2015-June 2018. METHODS: The burn survivors received structured assessment in the four-wave interviews including the five-item Brief Symptom Rating Scale, nine-item Concise Mental Health Checklist, and two-item Patient Health Questionnaire for depressive symptoms and suicide risk assessment. Post-traumatic psychological symptoms were assessed through the four-item Startle, Physiological Arousal, Anger, and Numbness Scale, and six-item Impact of Event Scale. FINDINGS: The response rates were 65.1%, 74.2%, 76.9%, and 78.5% across the four-wave interviews among 484 burn survivors. The participants were mean-aged 23.1 years with just over half having 40% or more burn wounds in total body surface area. The respondents at each wave were similar in gender, age, and per cent of total body surface area burned. In the first 2 years of recovery, the respondents showed resilience in coping with stress of trauma under family and social support. While there was a decreasing trend of psychological symptoms over the first 2 years, hypnotic use and alcohol consumption remained at about 10% in the final interview, which were accompanied by psychological symptom recurrence. CONCLUSION: Young burn survivors recovered both psychologically and physically under supportive care and personal resilience in 2 years after the burn event, yet post-traumatic mental distress and coping efforts after 2 years during community reintegration should be detected and managed. Early prevention and detection of mental health deterioration is needed even after 2 years of burn disasters. IMPACT: The study demonstrated post-burn longitudinal changes on psychological reactions. Nursing staffs may help young burn survivors identify mental distress and stress management needs in the long-term psychological adaptation process.

13.
Chemosphere ; 243: 125304, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31715296

RESUMO

This work presents a white rot fungus-microbial fuel cell (WRF-MFC) that uses WRF that is grown at its cathode. Adding Cu2+ to the fungi-containing solid medium stimulated WRF-secreting laccase, which catalyzed the redox reaction in the MFC and thereby promoting the generation of electricity. Adding 12.5 mg L-1 Cu2+ to a G. lucidum-containing medium provided the greatest laccase stimulation and increased the laccase activity by a factor of 1.6. Adding 12.5 mg L-1 Cu2+ to the WRF chamber of WRF-MFC increased its decolorization of Acid Orange 7 (AO-7) and increased its power density to 223 mW m-2, which was 1.77 times that of an MFC without WRF. The enhancement of decolorization and electricity generation improved the performance of the WRF-MFC, indicating that a laccase-catalyzed cathode has great potential effectiveness in microbial fuel cells.

14.
Proteomics Clin Appl ; 14(1): e1900024, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31520560

RESUMO

OBJECTIVE: Mesenchymal stem cells (MSCs) hold great therapeutic potential in morbidities associated with preterm birth. However, the molecular expressions of MSCs in preterm birth infants are not systematically evaluated. In this study, the dual-omics analyses of umbilical-cord (UC)-derived MSCs to identify the dysregulated cellular functions are presented. MATERIALS AND METHODS: The UC-MSCs are collected from ten full-term and eight preterm birth infants for microarray and iTRAQ-based proteome profiling. RESULTS: The integrative analysis of dual-omics data discovered 5615 commonly identified genes/proteins of which 29 genes/proteins show consistent up- or downregulation in preterm birth. The Gene Ontology analysis reveals that dysregulation of mitochondrial translation and cellular response to oxidative stress are mainly enriched in 290 differential expression proteins (DEPs) while the 412 differential expression genes (DEGs) are majorly involved in single-organism biosynthetic process, cellular response to stress, and mitotic cell cycle in preterm birth. Besides, a 13-protein module involving CUL2 and CUL3 is identified, which plays an important role in cullin-RING-based ubiquitin ligase complex, as potential mechanism for preterm birth. CONCLUSION: The dual-omics data not only provide new insights to the molecular mechanism but also identify panel of candidate markers associated with preterm birth.

15.
Med Mycol ; 58(2): 248-259, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31100153

RESUMO

Histone modifications play a crucial role in eukaryotic gene regulation. The Spt-Ada-Gcn5-acetyltransferase (SAGA) complex controls histone acetylation, with Gcn5 (GcnE) acting as the acetyltransferase. In the Aspergillus species, GcnE has been shown to regulate asexual development and secondary metabolism. Apart from this, GcnE is required for pathogenicity in plant fungal pathogen A. flavus; however, the role of GcnE in the pathogenicity of human pathogenic fungus A. fumigatus is unknown. In this study, we uncovered the key roles of GcnE in A. fumigatus conidiation, stress responses, and biofilm formation. We observed that deletion of gcnE resulted in aberrant conidiation in which conidiophores displayed abnormal phialide formation. In addition, the ΔgcnE mutant grew slightly faster under limited nitrogen sources (1 mM of ammonium or nitrate) compared to the wild type. The ΔgcnE mutant exhibited increased susceptibility to cell wall-perturbing agents, H2O2 and menadione but enhanced tolerance to LiCl. Furthermore, we showed that GcnE is involved in biofilm formation, and overexpression of adherence-related genes such as somA or uge3 partially rescued biofilm formation defects in the ΔgcnE mutant background. Interestingly, GcnE was not required for virulence in a neutropenic murine model of invasive aspergillosis. These results suggest that GcnE is critical for conidiation and biofilm formation but not virulence in A. fumigatus.

16.
J Biomed Mater Res B Appl Biomater ; 108(2): 538-554, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31087780

RESUMO

Indocyanine green (ICG) provides an advantage in the imaging of deep tumors as it can reach deeper location without being absorbed in the upper layers of biological tissues in the wavelengths, which named "therapeutic window" in the tissue engineering. Unfortunately, rapid elimination and short-term stability in aqueous media limited its use as a fluorescence probe for the early detection of cancerous tissue. In this study, stabilization of ICG was performed by encapsulating ICG molecules into the biodegradable polymer composited with poly(l-lactic acid) and poly(ε-caprolactone) via a simple one-step multiaxial electrospinning method. Different types of coaxial and triaxial structure groups were performed and compared with single polymer only groups. Confocal microscopy was used to image the encapsulated ICG (1 mg/mL) within electrospun nanofibers and in vitro ICG uptake by MIA PaCa-2 pancreatic cancer cells. Stability of encapsulated ICG is demonstrated by the in vitro sustainable release profile in PBS (pH = 4 and 7) up to 21 days. These results suggest the potential of the ability of internalization and accommodation of ICG into the pancreatic cell cytoplasm from in vitro implanted ICG-encapsulated multiaxial nanofiber mats. ICG-encapsulated multilayer nanofibers may be promising for the local sustained delivery system to eliminate loss of dosage caused by direct injection of ICG-loaded nanoparticles in systemic administration.

17.
IEEE Trans Cybern ; 50(3): 1292-1305, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31180879

RESUMO

Deep multitask learning for face analysis has received increasing attentions. From literature, most existing methods focus on optimizing a main task by jointly learning several auxiliary tasks. It is challenging to consider the performance of each task in a multitask framework due to the following reasons: 1) different face tasks usually rely on different levels of semantic features; 2) each task has different learning convergence rate, which could affect the whole performance when joint training; and 3) multitask model needs rich label information for efficient training, but existing facial datasets provide limited annotations. To address these issues, we propose a task-oriented feature-fused network (TFN) for simultaneously solving face detection, landmark localization, and attribute analysis. In this network, a task-oriented feature-fused block is designed to learn task-specific feature combinations; then, an alternative multitask training scheme is presented to optimize each task with considering of their different learning capacities. We also present a large-scale face dataset called JFA in support of proposed method, which provides multivariate labels, including face bounding box, 68 facial landmarks, and 3 attribute labels (i.e., apparent age, gender, and ethnicity). The experimental results suggest that the TFN outperforms several multitask models on the JFA dataset. Furthermore, our approach achieves competitive performances on WIDER FACE and 300W dataset, and obtains state-of-the-art results for gender recognition on the MORPH II dataset.

18.
J Pathol ; 250(1): 55-66, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31579932

RESUMO

Peritoneal fibrosis remains a problem in kidney failure patients treated with peritoneal dialysis. Severe peritoneal fibrosis with encapsulation or encapsulating peritoneal sclerosis is devastating and life-threatening. Although submesothelial fibroblasts as the major precursor of scar-producing myofibroblasts in animal models and M2 macrophage (Mϕ)-derived chemokines in peritoneal effluents of patients before diagnosis of encapsulating peritoneal sclerosis have been identified, attenuation of peritoneal fibrosis is an unmet medical need partly because the mechanism for cross talk between Mϕs and fibroblasts remains unclear. We use a sodium hypochlorite-induced mouse model akin to clinical encapsulated peritoneal sclerosis to study how the peritoneal Mϕs activate fibroblasts and fibrosis. Sodium hypochlorite induces the disappearance of CD11bhigh F4/80high resident Mϕs but accumulation of CD11bint F4/80int inflammatory Mϕs (InfMϕs) through recruiting blood monocytes and activating local cell proliferation. InfMϕs switch to express chemokine (C-C motif) ligand 17 (CCL17), CCL22, and arginase-1 from day 2 after hypochlorite injury. More than 75% of InfMϕs undergo genetic recombination by Csf1r-driven Cre recombinase, providing the possibility to reduce myofibroblasts and fibrosis by diphtheria toxin-induced Mϕ ablation from day 2 after injury. Furthermore, administration of antibody against CCL17 can reduce Mϕs, myofibroblasts, fibrosis, and improve peritoneal function after injury. Mechanistically, CCL17 stimulates migration and collagen production of submesothelial fibroblasts in culture. By breeding mice that are induced to express red fluorescent protein in Mϕs and green fluorescence protein (GFP) in Col1a1-expressing cells, we confirmed that Mϕs do not produce collagen in peritoneum before and after injury. However, small numbers of fibrocytes are found in fibrotic peritoneum of chimeric mice with bone marrow from Col1a1-GFP reporter mice, but they do not contribute to myofibroblasts. These data demonstrate that InfMϕs switch to pro-fibrotic phenotype and activate peritoneal fibroblasts through CCL17 after injury. CCL17 blockade in patients with peritoneal fibrosis may provide a novel therapy. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

19.
Mol Cell Endocrinol ; 499: 110595, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563469

RESUMO

The pentose phosphate pathway (PPP) plays an important role in the biosynthesis of ribonucleotide precursor and NADPH. Cancer cells frequently increase the flux of glucose into the PPP to support the anabolic demands and regulate oxidative stress. Consistently, metabolomic analyses indicate an upregulation of the PPP in thyroid cancer. In the present study, we found that the combination of glucose-6-phosphate dehydrogenase (G6PD) and transketolase inhibitors (6-aminonicotinamide and oxythiamine) exerted an additive or synergistic effect on cell growth inhibition in thyroid cancer cells. Targeting PPP significantly increased cellular reactive oxygen species (ROS) and induced endoplasmic reticulum (ER) stress and apoptosis. Suppressed cell viability could be partially rescued with treatment with the ROS scavenger or apoptosis inhibitor but not ER-stress inhibitor. Taken together, dual PPP blockade leads to pharmacologic additivity or synergism and causes ROS-mediated apoptosis in thyroid cancer cells.

20.
Neurotherapeutics ; 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823156

RESUMO

Despite Alzheimer's disease (AD) being the most common neurodegenerative disorder worldwide, no FDA-approved disease-modifying treatments have been approved for this condition since 2003. Neuronal-type alpha7 nicotinic acetylcholine receptors (α7nAChRs) play an essential role in cognitive functions, binding with extracellular ß-amyloid (Aß plaques) and inhibiting Aß-induced neurotoxicity. α7nAChRs are impaired early in the course of AD; drugs targeting α7nAChRs are being hotly pursued as a treatment of AD. Encenicline, a partial selective agonist of α7nAChR and modulator of acetylcholine, failed in phase III trials because of gastrointestinal side effects. We, therefore, evaluated the efficacy of galantamine, a positive allosteric modulator at α7nAChRs and an acetylcholinesterase inhibitor, that has been used since 2000 as first-line treatment of mild-to-moderate dementia. This study highlights an important new benefit with galantamine. We found that galantamine inhibits Aß1-42-induced apoptosis by activating the JNK signaling pathway, thus enhancing α7nAChR expression, and also inhibits the Akt pathway, which further increases autophagosome biogenesis and autophagy. These effects can be reproduced by α7nAChR overexpression in the absence of galantamine. Importantly, the α7 subunit protein sequence of α7nAChRs contains 3 LC3-interacting regions; our immunoprecipitation data show that α7 binds with the autophagosomal marker protein LC3. This is the first report to provide evidence showing that the cell surface receptor α7nAChR acts as a cargo carrier for LC3 binding for Aß1-42 sequestration to autophagosomes, suggesting a novel mechanism for the neuroprotective efficacy of galantamine in AD.

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