Ki-67 is an established marker of cell proliferation, and the Ki-67 index correlates with the clinical course of several cancer types, including bladder cancer (BC). However, the clinicopathological ...and prognostic significance of Ki-67 in bladder cancer remains unclear. Therefore, we performed a systematic review and meta-analysis to clarify this relationship.
A comprehensive literature search for relevant studies published up to February 1, 2016, was performed using PubMed, Cochrane Library, Embase and ISI Web of Knowledge. The effects of Ki-67 expression on survival outcome in patients with BC and BC subtypes were evaluated. Furthermore, the relationship between Ki-67 expression and the clinicopathological features of BC were assessed.
Thirty-one studies with 5147 bladder cancer patients were selected for evaluation. Ki-67 expression was significantly associated with shorter recurrence-free (HR 1.69, 95% CI: 1.33-2.14), progression-free (HR 1.89, 95% CI: 1.43-2.51), overall (HR 2.03, 95% CI: 1.31-3.16), and cancer-specific (HR 1.69, 95% CI: 1.47-1.95) survival. Moreover, whereas high expression was more common in high tumor stage, recurrence status, tumor size, there was no correlation between high Ki-67 expression and age, gender, smoking habits, and tumor number. Importantly, analysis of the different subgroups of BC suggested that significant correlations between high Ki-67 expression and survival outcome (recurrence-free/progression-free/overall/cancer-specific survival) are present only in European-American patients.
The present results indicate that over-expression of Ki-67 is distinctly correlated with poor patient survival. Ki-67 may serve as a valuable biomarker for prognosis in BC patients, particularly in non-Asian BC patients. The results suggest no significant association between Ki-67 expression and BC prognosis in Asian patients. Further efforts are needed to fully clarify this relationship.
The stress state and its dynamic background of East Asia, especially that during the late Mesozoic, remain controversial. We analyze the structural evolution of the Bohai Bay Basin (BBB) and it ...relationship with the regional tectonic history of East Asia. In particular, we focus on the central BBB NW-trending faults that have received little attention due to their inconspicuous structural features. Here we show that the erratic inversion of these NW-trending faults records episodic crustal deformation that is crucial for better understanding the regional tectonism. We find that these faults experienced alternating phases of shortening, stretching and shearing deformation. They initiated as reverse faults during the Late Triassic and reversed to normal faults during the Early Cretaceous. The pre-existing faults determined the development of NW-trending basins, which are synchronous with the peak destruction period of the North China Craton (NCC). The Late Cretaceous marks a stage of regional shortening without magmatism, which we propose to reflect a previously unrecognized period of flat-slab subduction of the Izanagi Plate. During the Early Paleogene (65–40 Ma), the reactivation of the NW-trending faults, likely due to the rollback of the oceanic slab, caused intensive rifting of the basin. During the Late Paleogene (40–23 Ma), they transformed to transtensional faulting due to the north-south oblique stretching from the parallel dextral strike-slip bounding faults. From Neogene, the basin entering its post-rift stage was characterized by the conjugate NE- and NW-trending strike-slip fault systems, likely in response to E-W regional compression.
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•Erratic NW-trending faults record the East Asia alternating deformation of extension, compression and shearing.•Late Cretaceous basin inversion and magmatic lull indicate flat-slab subduction of the Izanagi Plate.•Pre-existing faults and evolving subduction processes contribute to the erratic East Asian tectonics.
Subduction of young seafloors straddling mid-ocean ridges (MOR) is an inevitable consequence of plate tectonics. Surprisingly, this process correlates globally with prolonged back-arc extension when ...the MOR is largely trench-parallel. We investigate the underlying mechanism by analyzing the East China Sea Basin (ECSB) whose Cenozoic tectonic history consists of three syn-rift stages with the rift center progressively migrating oceanward. Global geodynamic models satisfying the past subduction history and present-day mantle structures successfully reproduce the lithospheric stress states of the evolving ECSB. We show that segmented removal of the Mesozoic Izanagi slab due to subduction of the young seafloor initiated Paleocene rifting within the western ECSB. Detachment of the former slab facilitated a strong landward mantle wind driven by the large pressure gradient across the slab. The resulting mantle traction pushed the thickened upper plate landward while entraining the young seafloors behind to slowly subduct, a process causing long-lasting Eocene extension of the central ECSB. The waning mantle wind after 30 Ma reduced basal traction and upper plate extension. A final phase of ECSB extension since the late Miocene formed the Okinawa Trough, when the subducting plate became old enough to trigger slab retreat. A similar dynamic scenario is also predicted in other circum-Pacific margins. We conclude that this enduring back-arc extension during MOR subduction represents an important mechanism for continental evolution during the closure of major ocean basins.
•Trench-parallel MOR subduction correlates with back-arc extension globally.•Slab tearing proceeds MOR subduction and generates enduring strong basal traction.•Realistic geodynamic models reproduce extension along major convergent margins.
Alzheimer’s disease (AD) displays a long asymptomatic stage before dementia. We characterize AD stage-associated molecular networks by profiling 14,513 proteins and 34,173 phosphosites in the human ...brain with mass spectrometry, highlighting 173 protein changes in 17 pathways. The altered proteins are validated in two independent cohorts, showing partial RNA dependency. Comparisons of brain tissue and cerebrospinal fluid proteomes reveal biomarker candidates. Combining with 5xFAD mouse analysis, we determine 15 Aβ-correlated proteins (e.g., MDK, NTN1, SMOC1, SLIT2, and HTRA1). 5xFAD shows a proteomic signature similar to symptomatic AD but exhibits activation of autophagy and interferon response and lacks human-specific deleterious events, such as downregulation of neurotrophic factors and synaptic proteins. Multi-omics integration prioritizes AD-related molecules and pathways, including amyloid cascade, inflammation, complement, WNT signaling, TGF-β and BMP signaling, lipid metabolism, iron homeostasis, and membrane transport. Some Aβ-correlated proteins are colocalized with amyloid plaques. Thus, the multilayer omics approach identifies protein networks during AD progression.
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•Deep profiling of proteome and phosphoproteome in AD progression•Validation of protein alterations in two independent AD cohorts•Identification of Aβ-induced protein changes in AD and the 5xFAD mouse model•Prioritization of proteins and pathways in AD by multi-omics integration
By mass spectrometry-based proteomics and integrated multi-omics, Bai et al. reveal novel proteins and molecular networks during Alzheimer’s disease progression and validate the proteins in 5xFAD mice. Further comparisons of brain tissue and cerebrospinal fluid proteomes identify biomarker candidates.
Models of extensional fault systems are predominantly based on examples where extension is approximately orthogonal to rift boundaries and deformation can be regarded as plane strain. In contrast, ...extensional faults in transtensional or strike-slip settings present complex geometric and kinematic features due to rotational deformation, and distinct rift and post-rift phases may be difficult to separate. Well-constrained 3D seismic data from the Bohai Bay Basin, East China reveal the growth history and transtensional reactivation of a basin-bounding fault (Chengbei Fault). During the syn-rift phase, the Chengbei Fault reached its near-final length within ∼24 Ma via the propagation and linkage of six initial fault segments, accompanied by the accumulation of 26% of its total displacement; in the following ∼18.7 Ma of the Paleogene, it accumulated the remaining 74% of displacement without an obvious increase in fault length. Following a phase of relative quiescence in the early Neogene, the Chengbei Fault was reactivated at ∼12 Ma, associated with the enhanced activity of a continental-scale strike-slip fault. At least 17 fault segments developed quickly and linked vertically to the lower fault system of the Chengbei Fault. The plan-view en-echelon and horse-tail configuration, and the flower structure seen in section views of the fault system, indicate that the post-rift activity of Chengbei Fault has had both dip-slip and strike-slip components. A calculation of the rotational deformation using fault heaves and orientations indicates that the tectonic reactivation occurred in a strike-slip-dominated transtensional setting accompanied by an increasing extension component with time. In basins affected by strike slip, kinematic analyses that consider rotational deformation can provide more detailed and convincing information on the tectonic setting.
•We record normal fault growth and reactivation in the Bohai Bay Basin, China.•Syn-rift fault growth follows lengthening and throw accumulation stages.•Post-rift reactivation causes development of oblique-slip fault systems.•Fault orientations and heaves are used to calculate post-rift rotational strains.•Results of rotational strains suggest post-rift reactivation occur in transtension.
Multiplexed isobaric labeling methods, such as tandem mass tags (TMT), remarkably improve the throughput of quantitative mass spectrometry. Here, we present a 27-plex TMT method coupled with ...two-dimensional liquid chromatography (LC/LC) for extensive peptide fractionation and high-resolution tandem mass spectrometry (MS/MS) for peptide quantification and then apply the method to profile the complex human brain proteome of Alzheimer’s disease (AD). The 27-plex method combines multiplexed capacities of the 11-plex and the 16-plex TMT, as the peptides labeled by the two TMT sets display different mass and hydrophobicity, which can be well separated in LC-MS/MS. We first systematically optimized the protocol for the newly developed 16-plex TMT, including labeling reaction, desalting, and MS conditions, and then directly compared the 11-plex and 16-plex methods by analyzing the same human AD samples. Both methods yielded similar proteome coverage, analyzing >100 000 peptides in >10 000 human proteins. Furthermore, the 11-plex and 16-plex samples were mixed for a 27-plex assay, resulting in more than 8000 protein measurements within the same MS time. The 27-plex results are highly consistent with those of the individual 11-plex and 16-plex TMT analyses. We also used these proteomics data sets to compare the AD brain with the nondementia controls, discovering major AD-related proteins and revealing numerous novel protein alterations enriched in the pathways of amyloidosis, immunity, mitochondrial, and synaptic functions. Overall, our data strongly demonstrate that this new 27-plex strategy is highly feasible for routine large-scale proteomic analysis.
Recognition of microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) triggers the first line of inducible defence against invading pathogens
. Receptor-like ...cytoplasmic kinases (RLCKs) are convergent regulators that associate with multiple PRRs in plants
. The mechanisms that underlie the activation of RLCKs are unclear. Here we show that when MAMPs are detected, the RLCK BOTRYTIS-INDUCED KINASE 1 (BIK1) is monoubiquitinated following phosphorylation, then released from the flagellin receptor FLAGELLIN SENSING 2 (FLS2)-BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1 (BAK1) complex, and internalized dynamically into endocytic compartments. The Arabidopsis E3 ubiquitin ligases RING-H2 FINGER A3A (RHA3A) and RHA3B mediate the monoubiquitination of BIK1, which is essential for the subsequent release of BIK1 from the FLS2-BAK1 complex and activation of immune signalling. Ligand-induced monoubiquitination and endosomal puncta of BIK1 exhibit spatial and temporal dynamics that are distinct from those of the PRR FLS2. Our study reveals the intertwined regulation of PRR-RLCK complex activation by protein phosphorylation and ubiquitination, and shows that ligand-induced monoubiquitination contributes to the release of BIK1 family RLCKs from the PRR complex and activation of PRR signalling.
Detailed geometric and kinematic analyses of a large multi-stage normal fault in the Jiyang Depression, eastern China, have been conducted using high-quality 3D seismic data. The Xiakou fault is a ...serrated fault zone consisting of four connected segments that alternately appear NE trending and EW trending. There are two tension stages, namely, the Ek stage (65 Ma) and Es4-Ed stage (50–23.5 Ma). The evolution process can be divided into four stages under the control of the regional geological background. In the Ek stage (65 Ma), only the NE-trending segments are active. The whole Xiakou fault zone is in the isolated fault growth stage. As the regional stress transformed from NW-SE to nearly S–N, the NE-trending segments in the Es4 stage (50 Ma) continued their activities and EW-trending faults started to develop. Soft connections were formed between the NE-trending segments. The Es3 stage (42 Ma) experienced intense SN-trending extension, and hard connections were formed in the Xiakou fault zone. The segmented faults in different directions became connected, forming a serrated fault zone that alternately appears NE-trending and EW-trending. Es2-Ed (38–23.5 Ma) is the stage of strike-slip transformation. Horsetail and strike-slip duplex structures developed in different positions. Local tension or extrusion of different fold segments occurred, which reflects the superposition effect of strike slip against an extension background. Hence, the spatial and temporal differences in the development and evolution of the Xiakou fault zone have important controlling effects on the distribution of the settlement depocentres and the source channels in this area.
•The Xiakou fault experienced isolated fault growth, soft connectivity, hard connectivity and slip transformation.•We discuss the influence of multi-stage fault formation on geomorphology and sedimentation.•Different strike fault segments have different effects on hydrocarbon migration.
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