Ubiquitination in Scleroderma Fibrosis and Its Treatment

Scleroderma (systemic sclerosis, SSc) is a highly heterogeneous rheumatic disease, and uncontrolled fibrosis in visceral organs is the major cause of death in patients. The transforming growth factor-β (TGF-β) and WNT/β-catenin signaling pathways, along with signal transducer and activator of transcription 3 (STAT3), play crucial roles in this fibrotic process. Currently, no therapy is available that effectively arrests or reverses the progression of fibrosis in patients with SSc. Ubiquitination is an important post-translational modification that controls many critical cellular functions. Dysregulated ubiquitination events have been observed in patients with systemic lupus erythematosus, rheumatoid arthritis and fibrotic diseases. Inhibitors targeting the ubiquitination pathway have considerable potential for the treatment of rheumatic diseases. However, very few studies have examined the role and mechanism of ubiquitination in patients with SSc. In this review, we will summarize the molecular mechanisms of ubiquitination in patients with SSc and explore the potential targets for treatment

Safety and Efficacy of Exclusive Enteral Nutrition for Percutaneously Undrainable Abdominal Abscesses in Crohn’s Disease

Background. The percutaneously undrainable abdominal abscesses in Crohn’s disease (CD) are not uncommon. The treatment protocol is still under debate. This study was conducted to assess the safety and efficacy of exclusive enteral nutrition (EEN) for percutaneously undrainable abscesses in CD. Methods. A consecutive cohort of 83 CD patients with percutaneously undrainable abdominal abscesses between January 2011 and June 2015 was retrospectively analyzed. They were divided into the EEN group and the non-EEN group. Results. The cumulative surgical rate was significantly lower in the EEN group than in the non-EEN group (P=0.001). Fifteen percent patients treated with EEN avoided surgery. EEN (P=0.002) was associated with a decreased need for surgery. Previous abdominal surgery (P=0.009) and abscess diameter > 3 cm (P=0.022) were associated with an increased need for operation. EEN increased the albumin level, while decreased ESR and CRP significantly for patients requiring surgery. The risk of postoperative intra-abdominal septic complications (P=0.036) was significantly lower in the EEN group compared with the non-EEN group. Conclusions. EEN is feasible in CD patients presenting with percutaneously undrainable abdominal abscesses. It is associated with a reduction in surgical rate, optimized preoperative condition, and improved postoperative outcomes in these specific groups of patients

Mask TextSpotter: An End-to-End Trainable Neural Network for Spotting Text with Arbitrary Shapes

Recently, models based on deep neural networks have dominated the fields of scene text detection and recognition. In this paper, we investigate the problem of scene text spotting, which aims at simultaneous text detection and recognition in natural images. An end-to-end trainable neural network model for scene text spotting is proposed. The proposed model, named as Mask TextSpotter, is inspired by the newly published work Mask R-CNN. Different from previous methods that also accomplish text spotting with end-to-end trainable deep neural networks, Mask TextSpotter takes advantage of simple and smooth end-to-end learning procedure, in which precise text detection and recognition are acquired via semantic segmentation. Moreover, it is superior to previous methods in handling text instances of irregular shapes, for example, curved text. Experiments on ICDAR2013, ICDAR2015 and Total-Text demonstrate that the proposed method achieves state-of-the-art results in both scene text detection and end-to-end text recognition tasks.Comment: To appear in ECCV 201

TFEB Probably Involved in Midazolam-Disturbed Lysosomal Homeostasis and Its Induced β-Amyloid Accumulation

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, and β-amyloid (Aβ) plays a leading role in the pathogenesis of AD. The transcription factor EB (TFEB), a main regulating factor of autophagy and lysosome biosynthesis, is involved in the pathogenesis of AD by regulating autophagy-lysosomal pathways. To date, the choice of anesthetics during surgery in patients with neurodegenerative diseases and evaluation of the effects and underlying mechanisms in these patients have rarely been reported. In this study, the HEK293-APP cells overexpressing APP and Hela cells were used. The cells were treated with midazolam at different concentrations and at different times, then lysosomes were stained by lysotracker and their morphology was observed under a fluorescence microscope. The number and size of lysosomes were analyzed using the ImageJ software. The levels of TFEB in the nucleus and APP-cleaved intracellular proteins were detected by nuclear separation and Western Blot. Finally, ELISA was used to detect the levels of Aβ40 and Aβ42 in the cells after drug treatment. We found that 30 μM midazolam decreased the number of lysosomes and increased its size in HEK293 and HeLa cells. However, 15 μM midazolam transiently disturbed lysosomal homeostasis at 24 h and recovered it at 36 h. Notably, there was no significant difference in the extent to which lysosomal homeostasis was disturbed between treatments of different concentrations of midazolam at 24 h. In addition, 30 μM midazolam prevents the transport of TFEB to the nucleus in either normal or starved cells. Finally, the intracellular C-terminal fragment β (CTFβ), CTFα, Aβ40 and Aβ42 levels were all significantly elevated in 30 μM midazolam-treated HKE293-APP cells. Collectively, the inhibition of TFEB transport to the nucleus may be involved in midazolam-disturbed lysosomal homeostasis and its induced Aβ accumulation in vitro. The results indicated the risk of accelerating the pathogenesis of AD by midazolam and suggested that TFEB might be a candidate target for reduction of midazolam-dependent neurotoxicity

Impact of clinicopathological factors on extended endocrine therapy decision making in estrogen receptor–positive breast cancer

PurposeIn our study, we aim to analyze the impact of clinicopathological factors on the recommendation of extended endocrine therapy (EET) in patients with ER+ breast cancer and to retrospectively validate the value of CTS5 in EET decision making.Patients and methodsThe retrospective analysis was performed in patients with ER+ breast cancer who have finished 4.5–5 years of adjuvant endocrine therapy and undergone MDT discussion from October 2017 to November 2019. Multivariate logistic regression was used to identify the independent factors for treatment recommendation. CTS5 was calculated for retrospective validation of the EET decision making.ResultsTwo hundred thirty-five patients were received; 4.5–5 years of adjuvant endocrine therapy were included in the study. Multivariate analysis suggested that age (OR 0.460, 95% CI 0.219–0.965, p = 0.04), pN (OR 39.350, 95% CI 9.831–157.341, P < 0.001), and receipt of chemotherapy (OR 3.478, 95% CI 1.336–9.055, p = 0.011) were independent predictors for the recommendation of EET. In the previously selective estrogen receptor modulator (SERM)–treated subgroup, pN and receipt of chemotherapy were independent predictors for the recommendation of EET. In the previously AI-treated subgroup, age, pN, and receipt of chemotherapy were independent predictors. Adverse events did not affect the recommendation in patients previously treated with adjuvant endocrine treatment nor in the previously SERM or AI-treated subgroups. CTS5 (OR 21.887, 95% CI 2.846–168.309, p = 0.003) remained an independent predictor for the recommendation of EET.ConclusionsOur study indicated that age, lymph nodal status, and receipt of chemotherapy were independent predictors for the recommendation of EET. The application of the CTS5 on EET decision making might be valuable among ER+ breast cancer patients

Origin and anatomy of two different types of mass-transport complexes: a 3D seismic case study from the northern South China Sea margin

Integration of 2D and 3D seismic data from the Qiongdongnan Basin along the northwestern South China Sea margin has enabled the seismic stratigraphy, seismic geomorphology and emplacement mechanisms of eight separate, previously undocumented, mass-transport complexes (MTCs) to be characterized. These eight MTCs can be grouped into two types:. (1) Localized detached MTCs, which are confined to submarine canyons and cover hundreds of km, consist of a few tens of km remobilized sediments and show long striations at their base. They resulted from small-scale mass-wasting processes induced by regional tectonic events and gravitational instabilities on canyon margins.(2) Regional attached MTCs, which occur within semi-confined or unconfined settings and are distributed roughly perpendicular to the strike of the regional slope. Attached MTCs occupy hundreds to thousands of km and are composed of tens to hundreds of km of remobilized sediments. They contain headwall escarpments, translated blocks, remnant blocks, pressure ridges, and basal striations and cat-claw grooves. They were created by large-scale mass-wasting processes triggered by high sedimentation rates, slope oversteepening by shelf-edge deltas, and seismicity.Our results show that MTCs may act as both lateral and top seals for underlying hydrocarbon reservoirs and could create MTC-related stratigraphic traps that represent potential drilling targets on continental margins, helping to identify MTC-related hydrocarbon traps

Natrium Benzoate Alleviates Neuronal Apoptosis via the DJ-1-Related Anti-oxidative Stress Pathway Involving Akt Phosphorylation in a Rat Model of Traumatic Spinal Cord Injury

This study aimed to explore the neuroprotective effects and mechanisms of natrium benzoate (NaB) and DJ-1 in attenuating reactive oxygen species (ROS)-induced neuronal apoptosis in traumatic spinal cord injury (t-SCI) in rats. T-SCI was induced by clip compression. The protein expression and neuronal apoptosis was evaluated by Western blotting, double immunofluorescence staining and transmission electron microscope (TEM). ROS level, spinal cord water content (SCWC) and Evans blue (EB) extravasation was also examined. Locomotor function was evaluated by Basso, Beattie, and Bresnahan (BBB) and inclined plane test (IPT) scores. We found that DJ-1 is expressed in spinal cord neurons and increased after t-SCI. At 24 h post-injury, the levels of DJ-1, p-Akt, SOD2, ROS, p-p38 MAPK/p38 MAPK ratio, and CC-3 increased, while the Bcl-2/Bax ratio decreased. NaB upregulated DJ-1, p-Akt, and SOD2, decreased ROS, p-p38 MAPK/p38 MAPK ratio, and CC-3, and increased the Bcl-2/Bax ratio, which were reversed by DJ-1 siRNA. The proportion of CC-3- and TUNEL-positive neurons also increased after t-SCI and was reduced by NaB. These effects were reversed by MK2206. Moreover, the level of oxDJ-1 increased after t-SCI, which was decreased by DJ-1 siRNA, NaB or the combination of them. NaB also reduced mitochondrial vacuolization, SCWC and EB extravasation, and improved locomotor function assessed by the BBB and IPT scores. In conclusion, NaB increased DJ-1, and thus reduced ROS and ROS-induced neuronal apoptosis by promoting Akt phosphorylation in t-SCI rats. NaB shows potential as a therapeutic agent for t-SCI, with DJ-1 as its main target