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1.
J Oral Implantol ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32068860

RESUMO

This study aims to elucidate the biomechanical effects of combined loading of maxillary anterior and posterior implants using the sliding method on en-mass retraction of the anterior teeth and to quantify the loading ratio (LR) of anterior and posterior implants to achieve controlled retraction of the maxillary anterior teeth. A three-dimensional finite element model of the maxilla-upper dentition appliance was constructed. Implants were placed on the distal (A) and mesial (B) sides of the lateral incisors as well as on the mesial (C) side of the first molar and different amounts of force were loaded between the implants using 2 or 5 mm traction hooks. The labio-lingual movement of the anterior teeth was recorded and the relationship between the LR of the implants and the movement of the central incisors was evaluated. With 2 mm traction hooks, the central incisors exhibited a translation tendency during retraction at lower A/C and B/C LR and labial or lingual crown inclination at higher values. With 5 mm traction hooks, the central incisors, lateral incisors, and canine teeth exhibited a labial crown inclination. The results of this study suggest that 2 mm traction hooks can cause labial crown inclination, translation tendency during retraction, or lingual crown inclination of the central incisors due to alterations in the LR of the anterior and posterior implants. The central incisors only exhibited labial crown inclination during combined loading of the anterior and posterior implants when 5 mm traction hooks were used.

2.
Cell Death Differ ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051546

RESUMO

Rab5 is a master regulator for endosome biogenesis and transport while its in vivo physiological function remains elusive. Here, we find that Rab5a is upregulated in several in vivo and in vitro myogenesis models. By generating myogenic Rab5a-deficient mice, we uncover the essential roles of Rab5a in regulating skeletal muscle regeneration. We further reveal that Rab5a promotes myoblast differentiation and directly interacts with insulin receptor substrate 1 (IRS1), an essential scaffold protein for propagating IGF signaling. Rab5a interacts with IRS1 in a GTP-dependent manner and this interaction is enhanced upon IGF-1 activation and myogenic differentiation. We subsequently identify that the arginine 207 and 222 of IRS1 and tyrosine 82, 89, and 90 of Rab5a are the critical amino acid residues for mediating the association. Mechanistically, Rab5a modulates IRS1 activation by coordinating the association between IRS1 and the IGF receptor (IGFR) and regulating the intracellular membrane targeting of IRS1. Both myogenesis-induced and IGF-evoked AKT-mTOR signaling are dependent on Rab5a. Myogenic deletion of Rab5a also reduces the activation of AKT-mTOR signaling during skeletal muscle regeneration. Taken together, our study uncovers the physiological function of Rab5a in regulating muscle regeneration and delineates the novel role of Rab5a as a critical switch controlling AKT-mTOR signaling by activating IRS1.

3.
J Natl Cancer Inst ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32016387

RESUMO

BACKGROUND: To forecast survival and enhance treatment decisions for patients with colorectal cancer liver metastases (mCRC) by using on-treatment radiomics signature to predict tumor sensitiveness to FOLFIRI±cetuximab. METHODS: We retrospectively analyzed 667 mCRC patients treated with FOLFIRI alone [F] or in combination with cetuximab [FC]. CT quality was classified as high (HQ) or standard (SD). Four datasets were created using the nomenclature [treatment]-[quality]. Patients were randomly assigned (2:1) to training or validation sets: FCHQ: 78:38, FCSD: 124:62, FHQ: 78:51, FSD: 158:78. Four tumor imaging biomarkers measured quantitative radiomics changes between standard of care CT scans at baseline and 8 weeks. Using machine learning, the performance of the signature to classify tumors as treatment-sensitive or treatment-insensitive was trained and validated using ROC curves. Hazard Ratio (HR) and Cox Regression models evaluated association with overall survival (OS). RESULTS: The signature (AUC[95CI]) used temporal decrease in tumor spatial heterogeneity plus boundary infiltration to successfully predict sensitivity to anti-EGFR therapy (FCHQ: 0.80 [0.69-0.94], FCSD: 0.72 [0.59-0.83]) but failed with chemotherapy (FHQ: 0.59 [0.44-0.72], FSD: 0.55 [0.43-0.66]). In cetuximab-containing sets, radiomics signature outperformed existing biomarkers (KRAS-mutational status, and tumor shrinkage by RECIST 1.1) for detection of treatment-sensitivity and was strongly associated with OS (two-sided P < 0.005). CONCLUSIONS: Radiomics response signature can serve as an intermediate surrogate marker of overall survival. The signature outperformed known biomarkers in providing an early prediction of treatment-sensitivity and could be used to guide cetuximab treatment continuation decisions.

4.
Nat Commun ; 11(1): 739, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029730

RESUMO

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous disease with features that vary by ethnicity. A systematic characterization of the genomic landscape of Chinese ccRCC is lacking, and features of ccRCC associated with tumor thrombus (ccRCC-TT) remain poorly understood. Here, we applied whole-exome sequencing on 110 normal-tumor pairs and 42 normal-tumor-thrombus triples, and transcriptome sequencing on 61 tumor-normal pairs and 30 primary-thrombus pairs from 152 Chinese patients with ccRCC. Our analysis reveals that a mutational signature associated with aristolochic acid (AA) exposure is widespread in Chinese ccRCC. Tumors from patients with ccRCC-TT show a higher mutational burden and genomic instability; in addition, mutations in BAP1 and SETD2 are highly enriched in patients with ccRCC-TT. Moreover, patients with/without TT show distinct molecular characteristics. We reported the integrative genomic sequencing of Chinese ccRCC and identified the features associated with tumor thrombus, which may facilitate ccRCC diagnosis, prognosis and treatment.

6.
Eur J Radiol ; 125: 108850, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32070870

RESUMO

PURPOSE: The clinical adoption of quantitative imaging biomarkers (radiomics) has established the need for high quality contrast-enhancement in medical images. We aimed to develop a machine-learning algorithm for Quality Control of Contrast-Enhancement on CT-scan (CECT-QC). METHOD: Multicenter data from four independent cohorts [A, B, C, D] of patients with measurable liver lesions were analyzed retrospectively (patients:time-points; 503:3397): [A] dynamic CTs from primary liver cancer (60:2359); [B] triphasic CTs from primary liver cancer (31:93); [C] triphasic CTs from hepatocellular carcinoma (121:363); [D] portal venous phase CTs of liver metastasis from colorectal cancer (291:582). Patients from cohort A were randomized to training-set (48:1884) and test-set (12:475). A random forest classifier was trained and tested to identify five contrast-enhancement phases. The input was the mean intensity of the abdominal aorta and the portal vein measured on a single abdominal CT scan image at a single time-point. The output to be predicted was: non-contrast [NCP], early-arterial [E-AP], optimal-arterial [O-AP], optimal-portal [O-PVP], and late-portal [L-PVP]. Clinical utility was assessed in cohorts B, C, and D. RESULTS: The CECT-QC algorithm showed performances of 98 %, 90 %, and 84 % for predicting NCP, O-AP, and O-PVP, respectively. O-PVP was reached in half of patients and was associated with a peak in liver malignancy density. Contrast-enhancement quality significantly influenced radiomics features deciphering the phenotype of liver neoplasms. CONCLUSIONS: A single CT-image can be used to differentiate five contrast-enhancement phases for radiomics-based precision medicine in the most common liver neoplasms occurring in patients with or without liver cirrhosis.

7.
Cell Death Differ ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31965061

RESUMO

DNA double-strand breaks (DSBs) pose a serious threat to genomic stability. Paradoxically, hundreds of programed DSBs are generated by SPO11 in meiotic prophase, which are exclusively repaired by homologous recombination (HR) to promote obligate crossover between homologous chromosomes. In somatic cells, MRE11-RAD50-NBS1 (MRN) complex-dependent DNA end resection is a prerequisite for HR repair, especially for DSBs that are covalently linked with proteins or chemicals. Interestingly, all meiotic DSBs are linked with SPO11 after being generated. Although MRN complex's function in meiotic DSB repair has been established in lower organisms, the role of MRN complex in mammalian meiotic DSB repair is not clear. Here, we show that MRN complex is essential for repairing meiotic SPO11-linked DSBs in male mice. In male germ cells, conditional inactivation of NBS1, a key component of MRN complex, causes dramatic reduction of DNA end resection and defective HR repair in meiotic prophase. NBS1 loss severely disrupts chromosome synapsis, generates abnormal chromosome structures, and eventually leads to meiotic arrest and male infertility in mice. Unlike in somatic cells, the recruitment of NBS1 to SPO11-linked DSB sites is MDC1-independent but requires other phosphorylated proteins. Collectively, our study not only reveals the significance of MRN complex in repairing meiotic DSBs but also discovers a unique mechanism that recruits MRN complex to SPO11-linked DSB sites.

8.
J Neurosurg ; : 1-10, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31899871

RESUMO

OBJECTIVE: Cushing's disease (CD) involves brain impairments caused by excessive cortisol. Whether these impairments are reversible in remitted CD after surgery has long been controversial due to a lack of high-quality longitudinal studies. In this study the authors aimed to assess the reversibility of whole-brain changes in remitted CD after transsphenoidal surgery (TSS), and its correlations with clinical and hormonal parameters, in the largest longitudinal study cohort to date for CD patient brain analysis. METHODS: Fifty patients with pathologically diagnosed CD and 36 matched healthy controls (HCs) were enrolled in a tertiary comprehensive hospital and national pituitary disease registry center in China. 3-T MRI studies were analyzed using an artificial intelligence-assisted web-based autosegmentation tool to quantify 3D brain volumes. Clinical parameters as well as levels of serum cortisol, adrenocorticotrophic hormone (ACTH), and 24-hour urinary free cortisol were collected for the correlation analysis. All CD patients underwent TSS and 46 patients achieved remission. All clinical, hormonal, and MRI parameters were reevaluated at the 3-month follow-up after surgery. RESULTS: Widespread brain volume loss was observed in active CD patients compared with HCs, including total gray matter (p = 0.003, with false discovery rate [FDR] correction) and the frontal, parietal, occipital, and temporal lobes; insula; cingulate lobe; and enlargement of lateral and third ventricles (p < 0.05, corrected with FDR). All affected brain regions improved significantly after TSS (p < 0.05, corrected with FDR). In patients with remitted CD, total gray matter and most brain regions (except the frontal and temporal lobes) showed full recovery of volume, with volumes that did not differ from those of HCs (p > 0.05, corrected with FDR). ACTH and serum cortisol changes were negatively correlated with brain volume changes during recovery (p < 0.05). CONCLUSIONS: This study demonstrates the rapid reversal of total gray matter loss in remitted CD. The combination of full recovery areas and partial recovery areas after TSS is consistent with the incomplete recovery of memory and cognitive function observed in CD patients in clinical practice. Correlation analyses suggest that ACTH and serum cortisol levels are reliable serum biomarkers of brain recovery for clinical use after surgery.

9.
Ophthalmologica ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31905362

RESUMO

OBJECTIVE: To investigate the effectiveness and safety of intravitreal injection of conbercept (IVC) as the initial treatment for exudative circumscribed choroidal haemangioma (CCH). METHODS: Forty-two eyes of 42 patients received three monthly IVC (0.5mg/0.05ml) as the initial treatment. Three months later, patients were assessed for further treatment including observation, re-injection of conbercept, laser photocoagulation (lesion was 3000µm away from macular fovea) or photodynamic therapy (PDT, lesion under macular fovea). Anatomical and functional responses including best corrected visual acuity (BCVA), central foveal thickness (CFT), and tumor size were analyzed. RESULTS: 23 patients (54.76%) were sensitive to the monotherapy of IVC. 14 patients (33.33%) were insensitive to IVC and underwent rescue laser photocoagulation, 5 patients (11.90%) underwent rescue PDT due to insensitiveness to IVC treatment at Month 3. For subgroup analysis, although no statistical difference was found for BCVA at any follow-up time-point compared with the baseline, an increasing tendency of BCVA was found in IVC group (P>0.05). The mean CFT decreased significantly from 427.13±214.74µm at the baseline to 259.83±61.68µm at Month 6 in the IVC group (P<0.05). No influence was found on tumor size in IVC group. CONCLUSION: IVC as the initial treatment might be a treatment option for exudative CCH.

10.
J Mol Cell Cardiol ; 139: 1-13, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31958462

RESUMO

OBJECTIVE: Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are related to in-stent-restenosis (ISR) following percutaneous coronary intervention (PCI). Osteoprotegerin (OPG) has been implicated in various vascular diseases. However, the effects of OPG on ISR and the underlying mechanism remained elusive. We here investigated the association between OPG and ISR, and to demonstrate the role and potential mechanisms of OPG in neointimal hyperplasia. APPROACH AND RESULTS: From 2962 patients who received coronary angiography and follow-up coronary angiography at approximately one year, 291 patients were diagnosed with ISR, and another 291 gender- and age- matched patients without ISR were selected as controls. Serum OPG levels were significantly increased in patients with ISR. Multivariable logistic regression analysis indicated that OPG level was independently associated with the increased risk of ISR. In a mouse femoral artery wire injury model, upregulated OPG was evidenced in vascular tissue after injury. OPG deletion attenuated the vascular injury-induced neointimal hyperplasia and related gene expression in mice. OPG promoted neointimal hyperplasia and human aortic smooth muscle cell (hASMC) proliferation and migration through activation of yes-associated protein (YAP), a major downstream effector of the Hippo signaling pathway, whereas knockdown or inhibition of YAP in hASMCs blunted OPG-induced above effects. Moreover, we found that OPG, as a ligand for integrin αVß3, mediated phosphorylation of focal adhesion kinase (FAK) and actin cytoskeleton reorganization, resulting in YAP dephosphorylation in hASMCs. OPG-dependent YAP and VSMC activation was prevented by treatment with αVß3-blocking antibodies and inhibitors of FAK and actin stress fibers. CONCLUSIONS: Increased serum OPG levels are associated with increased risk of ISR following PCI and OPG could promote neointimal hyperplasia in response to injury through integrin αVß3 mediated FAK and YAP activation, indicating OPG/YAP inhibition might serve as an attractive novel target for the prevention of ISR after PCI.

11.
Nurse Educ Today ; 87: 104342, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31978634

RESUMO

OBJECTIVES: The purpose of this study was to determine whether frequency of participation in activities offered in a student response system was associated with students' final course grades in four different nursing courses and to explore whether that effect was dependent on the specific pedagogical context of each course. DESIGN: An observational approach with a predictive model was used to examine the effect of a student's frequency of responses to prompts in a student response system (Nearpod) on final grade. SETTING: This investigation was carried out in four high-enrollment nursing courses in a large Midwestern university in the United States. PARTICIPANTS: Students who participated in this study were enrolled in one of four core nursing courses: Pathophysiology, Health Assessment, Nursing Care of the Adult at the undergraduate level, and Pathophysiology at the graduate level. METHODS: Multiple regression analysis was conducted to examine the association between a student's frequency of Nearpod use and their final grade. RESULTS: The regression model explained 25.42% of the variance in final grade when controlling for course differences. The key finding from this study is that the more a student responded to prompts in Nearpod, the more likely they were to earn a higher final grade, but this effect was statistically significant only in undergraduate Pathophysiology. CONCLUSIONS: The positive association between more frequent Nearpod use and higher final grade appears to be dependent on contextual factors. These factors may include consistent use of Nearpod in class, detailed feedback and elaboration on student responses, and required participation in Nearpod activities.

12.
Retina ; 40(1): 33-40, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30300265

RESUMO

PURPOSE: To compare the efficiency of releasable scleral buckling (RSB) and pars plana vitrectomy (PPV) in the treatment of phakic patients with primary rhegmatogenous retinal detachment. METHODS: The current study was a prospective randomized clinical trial. One hundred and ten eyes from 110 patients with primary rhegmatogenous retinal detachment and proliferative vitreoretinopathy of Grade B or less were included in this study. The patients were randomly allocated into an RSB group and a PPV group. The functional and anatomical success was compared between groups. RESULTS: The primary anatomical success rate (PPV 41/43 [95.35%] and RSB 38/41 [92.68%]) and final anatomical success rate (PPV and RSB 100%) showed a nonsignificant difference. The best-corrected visual acuity, intraocular pressure, and complications were not different between the groups. However, the incidence of cataract progression was higher in the PPV group (26 of 43 [60.47%]) than in the RSB group (4 of 41 [9.76%]) at the 12-month follow-up. The subfoveal choroidal thickness increased significantly in the RSB group 3 months after surgery, but no longer differed at the postoperative 6-month and 12-month follow-ups. The axial length had increased significantly 1 month after surgery, but the difference was no longer significant at 3 months, 6 months, and 12 months. CONCLUSION: The RSB and PPV procedures have the same effects on the functional and anatomical success for patients with phakic primary rhegmatogenous retinal detachment. Nevertheless, based on the few cases of intraocular complications and cataract progression, we believe that the RSB technique should be preferentially recommended.

13.
Perspect Psychiatr Care ; 56(1): 14-19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30746711

RESUMO

PURPOSE: The purpose of this project was to evaluate a long-acting injectable (LAI) antipsychotics program regarding the quality of care and outcomes of individuals with schizophrenia. DESIGN AND METHODS: Observational design with retrospective chart review and survey was utilized in an outpatient clinic. FINDINGS: Individuals on LAIs receive the quality of care by exhibiting favorable knowledge about LAIs, positive attitude toward medications, and satisfaction with care. They take higher dosages of medications than those who take oral antipsychotics and report decreases in hospitalizations/emergency room visits after LAIs. PRACTICE IMPLICATIONS: Reducing reservations about LAIs may provide awareness of the positive effects of treatment leading to viable management options and patient satisfaction.

14.
J Hazard Mater ; 385: 121586, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31759759

RESUMO

Microplastics (MPs) have become global environmental concern. However, the effects of environmental concentrations of MPs, singly or in combination with organic pollutants, on the early development of marine fish remain unclear. In this study, fertilized eggs of marine medaka (Oryzias melastigma) were exposed to polystyrene MPs (0, 2, 20, 200 µg/L) and/or phenanthrene (Phe, 50 µg/L) for 28 days. The results revealed that MPs were accumulated on the chorion and ingested by larvae from 2 days post-hatching. High levels of MPs (20 and 200 µg/L) decreased the hatchability, delayed the hatching time, and suppressed the growth, whereas Phe inhibited hatching and caused malformations in larvae. The presence of MPs at 20 and 200 µg/L did not alter the toxicity of Phe. By contrast, combined exposure to 2 µg/L MPs and Phe increased the hatchability by 25.8%, decreased malformation and mortality rates, and restored Phe-induced abnormal expressions of cardiac development-related genes. The reduced early developmental toxicity could be attributed to the decreased bioavailability and bioaccumulation of Phe by the low level of MPs. These findings contradicted the view that MPs would aggravate the toxicity of organic pollutants, and future studies are warranted to elucidate the ecological risks of marine MPs.

15.
J Clin Invest ; 130(1): 438-450, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31815740

RESUMO

An excess of fecal bile acids (BAs) is thought to be one of the mechanisms for diarrhea-predominant irritable bowel syndrome (IBS-D). However, the factors causing excessive BA excretion remain incompletely studied. Given the importance of gut microbiota in BA metabolism, we hypothesized that gut dysbiosis might contribute to excessive BA excretion in IBS-D. By performing BA-related metabolic and metagenomic analyses in 290 IBS-D patients and 89 healthy volunteers, we found that 24.5% of IBS-D patients exhibited excessive excretion of total BAs and alteration of BA-transforming bacteria in feces. Notably, the increase in Clostridia bacteria (e.g., C. scindens) was positively associated with the levels of fecal BAs and serum 7α-hydroxy-4-cholesten-3-one (C4), but negatively correlated with serum fibroblast growth factor 19 (FGF19) concentration. Furthermore, colonization with Clostridia-rich IBS-D fecal microbiota or C. scindens individually enhanced serum C4 and hepatic conjugated BAs but reduced ileal FGF19 expression in mice. Inhibition of Clostridium species with vancomycin yielded opposite results. Clostridia-derived BAs suppressed the intestinal FGF19 expression in vitro and in vivo. In conclusion, this study demonstrates that the Clostridia-rich microbiota contributes to excessive BA excretion in IBS-D patients, which provides a mechanistic hypothesis with testable clinical implications.

16.
J Anim Physiol Anim Nutr (Berl) ; 104(1): 237-244, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31808203

RESUMO

Two experiments were conducted to investigate the kinetics of phosphorus (P) absorption and expressions of type IIb sodium-dependent phosphate cotransporter (NaP-IIb), inorganic phosphate transporters 1 and 2 (PiT-1 and PiT-2) in primary cultured duodenal epithelial cells of chick embryos. In experiment 1, the P absorptions across duodenal epithelial cell monolayers at different incubation time points (0, 10, 20, 40, 60, 80, 100 and 120 min) were compared. In experiment 2, the kinetics of P absorption was performed at 40 min after incubation of duodenal epithelial cells with the media containing 0, 0.75, 1.5, 3.0, 6.0, 12.0, 24.0 and 48.0 mmol P/L as KH2 PO4 , and the mRNA and protein expression levels of NaP-IIb, PiT-1 and PiT-2 in duodenal epithelial cells with the media containing 0, 6.0 and 48.0 mmol P/L were determined at 87 min after incubation. The results from experiment 1 showed that the P absorption increased linearly (p < .0001) from 0 to 80 min and the fastest increase occurred at 40 min; the asymptotic model was shown to have the best fit degree, and the optimal incubation time for saturable P absorption was determined to be 87 min. The kinetic curves of P absorption from experiment 2 demonstrated that P absorption was a mixed process of a non-saturable diffusion plus a saturable carrier-mediated transport across the duodenal epithelial cells. The high P concentration (48.0 mmol/L) decreased (p < .05) NaP-IIb and PiT-1 mRNA and protein levels and increased (p < .0001) PiT-2 mRNA level. These results indicated that the P absorption across primary cultured duodenal epithelial cell monolayers of chick embryos was a mixed process of a non-saturable diffusion plus a saturable carrier-mediated transport and could be restricted by reducing the NaP-IIb and PiT-1 expressions while increasing the PiT-2 expression at a high P concentration.

17.
Mar Pollut Bull ; 150: 110601, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31706722

RESUMO

Endocrine-disrupting pollutants in marine environments have aroused great concern for their adverse effects on the reproduction of marine organisms. This study aimed to seek promising biomarkers for estrogenic/androgenic chemicals. First, two possible male-specific genes, SRY-box containing gene 9a2 (sox9a2) and gonadal soma-derived factor (gsdf), were cloned from marine medaka (Oryzias melastigma). Then the responses of sox9a2, gsdf, choriogenin (chgH and chgL), vitellogenin (vtg1 and vtg2), and cytochrome P450 aromatase (cyp19a and cyp19b) were investigated after exposure to 17α-ethynylestradiol (EE2) and 17ß-trenbolone (TB) at 2, 10, and 50 ng/L. The results showed that gsdf was specifically expressed in the testes and easily induced in the ovaries after TB exposure, indicating that gsdf was a potential biomarker of environmental androgens. ChgL was a useful biomarker of weak estrogen pollution for its high sensitivity to low levels of EE2. In addition, both EE2 and TB exposure damaged gonadal structures and inhibited gonadal development.

18.
Acad Radiol ; 27(2): e10-e18, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31151901

RESUMO

OBJECTIVES: To develop a deep learning-based algorithm to automatically identify optimal portal venous phase timing (PVP-timing) so that image analysis techniques can be accurately performed on post contrast studies. METHODS: 681 CT-scans (training: 479 CT-scans; validation: 202 CT-scans) from a multicenter clinical trial in patients with liver metastases from colorectal cancer were retrospectively analyzed for algorithm development and validation. An additional external validation was performed on a cohort of 228 CT-scans from gastroenteropancreatic neuroendocrine cancer patients. Image acquisition was performed according to each centers' standard CT protocol for single portal venous phase, portal venous acquisition. The reference gold standard for the classification of PVP-timing as either optimal or nonoptimal was based on experienced radiologists' consensus opinion. The algorithm performed automated localization (on axial slices) of the portal vein and aorta upon which a novel dual input Convolutional Neural Network calculated a probability of the optimal PVP-timing. RESULTS: The algorithm automatically computed a PVP-timing score in 3 seconds and reached area under the curve of 0.837 (95% CI: 0.765, 0.890) in validation set and 0.844 (95% CI: 0.786, 0.889) in external validation set. CONCLUSION: A fully automated, deep-learning derived PVP-timing algorithm was developed to classify scans' contrast-enhancement timing and identify scans with optimal PVP-timing. The rapid identification of such scans will aid in the analysis of quantitative (radiomics) features used to characterize tumors and changes in enhancement with treatment in a multitude of settings including quantitative response criteria such as Choi and MASS which rely on reproducible measurement of enhancement.

19.
Neurosci Bull ; 36(1): 66-76, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30859414

RESUMO

Accumulating evidence suggests that the circadian rhythm plays a critical role in mood regulation, and circadian disturbances are often found in patients with major depressive disorder (MDD). The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is involved in mediating entrainment of the circadian system. Furthermore, the MAPK/ERK signaling pathway has been shown to be involved in the pathogenesis of MDD and the rapid onset of action of antidepressant therapies, both pharmaceutical and non-pharmaceutical. This review provides an overview of the involvement of the MAPK/ERK pathway in modulating the circadian system in the rapid action of antidepressant therapies. This pathway holds much promise for the development of novel, rapid-onset-of-action therapeutics for MDD.

20.
Mol Psychiatry ; 25(2): 339-350, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31427752

RESUMO

Predicting antidepressant treatment response has been a clinical challenge for major depressive disorder (MDD). The inflammation hypothesis of depression suggests that cytokines play a key role in the pathophysiology of MDD and alterations in peripheral cytokine levels are associated with antidepressant treatment outcome. Present meta-analysis aimed to examine the association between baseline peripheral cytokine levels and the response to antidepressant treatment and to evaluate whether changes of cytokine levels were associated with the response to antidepressant treatment in patients with MDD. Human-based studies published in any language in peer-reviewed journals were systematically searched from the PubMed, Embase and Web of Science databases, from inception up to October 2018. The search terms included cytokine, depressive disorder and antidepressant and their synonyms. Case-control or case-case studies reporting on levels of IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, CRP, TNF-α, IFN-γ, GM-CSF, MIP-1α, and Eotaxin-1 in patients with MDD based on validated depression scales both before and after antidepressant treatment were included. Of 7408 identified records, 44 studies met inclusion. Standardized mean differences in each cytokine were evaluated, and random-effects meta-analyses were performed. MDD patients who responded to antidepressant treatment had lower baseline IL-8 levels than the nonresponders (Hedge's g = -0.28; 95%CI, -0.43 to -0.13; P = 0.0003; FDR = 0.004). Antidepressant treatment significantly decreased levels of TNF-α (Hedge's g = 0.60; 95%CI, 0.26-0.94; P = 0.0006; FDR = 0.004) only in responders, and responders showed significantly more decreased TNF-α levels compared with nonresponders (P = 0.046). These findings suggested that alterations in peripheral cytokine levels were associated with antidepressant treatment outcomes in MDD. Further investigations are warranted to elucidate sources of heterogeneity and examine the potentiality of using inflammatory cytokines as novel predictive markers for the pharmacological treatment of MDD.

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