Spindle apparatus coiled-coil protein 1 (SPDL1) serves as a novel prognostic biomarker in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) has a poor prognosis, an ineffective diagnosis, and a high degree of aggressiveness. Therefore, novel therapeutic targets for TNBC urgently need to be identified. METHODS: Through a series of bioinformatics analyses, including analysis of differential gene expression, protein-protein interaction (PPI) network, univariate cox regression, immune infiltration, pathway enrichment, etc, as well as auxiliary immunohistochemistry (IHC) and protein quantitativae analysis, to explore prognostic marker for TNBC. RESULTS: In TNBC tissues, we found that SPDL1 (CCDC99) was considerably overexpressed at both the mRNA and protein levels compared to that in normal and non-TNBC tissues. Additionally, we found that SPDL1-high expression was strongly linked to poor prognosis in TNBC patients. Excessive SPDL1 expression was positively correlated with tumor growth and strongly linked to the cell cycle, DNA replication, and the p53 signaling pathway. In addition, CIBERSORT analysis revealed that SPDL1 can affect the tumor immune microenvironment (TME) in TNBC, encourage the development of TNBC and act as a potential prognostic biomarker for TNBC. Patients with SPDL1-high expression were more sensitive to AZD8055. Notably, we discovered that SPDL1 is highly expressed in the majority of malignancies and may have an impact on the pancancer prognosis. CONCLUSIONS: SPDL1 can serve as a novel prognostic marker for TNBC and pancancer patients.

Operational and Intervention Effects of Targeted Tuina in Lumbar Intervertebral Disc Degeneration Model Rabbits.

Tui Na or massage therapy alleviates symptoms related to intervertebral disc degeneration (IDD). However, precise, repeatable, standardized instructions for Tuina manipulation are lacking. This study establishes IDD model rabbits induced by fibrous ring puncture, creates targeted Tuina stimulation protocols at the acupuncture points in the lumbar region, and describes in detail the operation methods and requirements of kneading, pointing, and flicking. New Zealand male white rabbits (n = 15) were selected and randomly divided into a blank group, a model group, and a Tuina group. The rabbits in the model group and the Tuina group were molded by fibrous ring puncture; the rabbits in the model group were only immobilized on the operating table without treatment. In contrast, the Tuina group used the "8N/10N, 30 cycles/min" prescription for kneading, pointing, and flicking to perform the intervention, using tactile sensory aids to monitor and regulate the intensity of the Tuina operation. Imaging diagnosis and pathological tests were used to assess the effect of Tuina in rabbits, and the results showed improved imaging features and significantly lowered pathology scores of lumbar disc degeneration in the Tuina group compared to the model group (P < 0.01). Targeted Tuina in the lumbar region may be beneficial in the alleviation of lumbar disc degeneration, but further verification is needed. By regularly performing Tuina and recording the mechanical information involved enables reproducible manipulation prescriptions and helps to observe the basic features of the underlying mechanism of Tuina for IDD.

Mitochondria in cancer stem cells: Achilles heel or hard armor.

Previous studies have shown that mitochondria play core roles in not only cancer stem cell (CSC) metabolism but also the regulation of CSC stemness maintenance and differentiation, which are key regulators of cancer progression and therapeutic resistance. Therefore, an in-depth study of the regulatory mechanism of mitochondria in CSCs is expected to provide a new target for cancer therapy. This article mainly introduces the roles played by mitochondria and related mechanisms in CSC stemness maintenance, metabolic transformation, and chemoresistance. The discussion mainly focuses on the following aspects: mitochondrial morphological structure, subcellular localization, mitochondrial DNA, mitochondrial metabolism, and mitophagy. The manuscript also describes the recent clinical research progress on mitochondria-targeted drugs and discusses the basic principles of their targeted strategies. Indeed, an understanding of the application of mitochondria in the regulation of CSCs will promote the development of novel CSC-targeted strategies, thereby significantly improving the long-term survival rate of patients with cancer.

The prelimbic cortex regulates itch processing by controlling attentional bias.

Itch is a complex and unpleasant sensory experience. Recent studies have begun to investigate the neural mechanisms underlying the modulation of sensory and emotional components of itch in the brain. However, the key brain regions and neural mechanism involved in modulating the attentional processing of itch remain elusive. Here, we showed that the prelimbic cortex (PrL) is associated with itch processing and that the manipulation of itch-responsive neurons in the PrL significantly disrupted itch-induced scratching. Interestingly, we found that increasing attentional bias toward a distracting stimulus could disturb itch processing. We also demonstrated the existence of a population of attention-related neurons in the PrL that drive attentional bias to regulate itch processing. Importantly, itch-responsive neurons and attention-related neurons significantly overlapped in the PrL and were mutually interchangeable in the regulation of itch processing at the cellular activity level. Our results revealed that the PrL regulates itch processing by controlling attentional bias.

Water-Tree Characteristics and Its Mechanical Mechanism of Crosslinked Polyethylene Grafted with Polar-Group Molecules.

In order to restrain electric-stress impacts of water micro-droplets in insulation defects under alternating current (AC) electric fields in crosslinked polyethylene (XLPE) material, the present study represents chemical graft modifications of introducing chloroacetic acid allyl ester (CAAE) and maleic anhydride (MAH) individually as two specific polar-group molecules into XLPE material with peroxide melting approach. The accelerated water-tree aging experiments are implemented by means of a water-blade electrode to measure the improved water resistance and the affording mechanism of the graft-modified XLPE material in reference to benchmark XLPE. Melting−crystallization process, dynamic viscoelasticity and stress-strain characteristics are tested utilizing differential scanning calorimeter (DSC), dynamic thermomechanical analyzer (DMA) and electronic tension machine, respectively. Water-tree morphology is observed for various aging times to evaluate dimension characteristics in water-tree developing processes. Monte Carlo molecular simulations are performed to calculate free-energy, thermodynamic phase diagram, interaction parameter and mixing energy of binary mixing systems consisting of CAAE or MAH and water molecules to evaluate their thermodynamic miscibility. Water-tree experiments indicate that water-tree resistance to XLPE can be significantly improved by grafting CAAE or MAH, as indicated by reducing the characteristic length of water-trees from 120 to 80 µm. Heterogeneous nucleation centers of polyethylene crystallization are rendered by the grafted polar-group molecules to ameliorate crystalline microstructures, as manifested by crystallinity increment from 33.5 to 36.2, which favors improving water-tree resistance and mechanical performances. The highly hydrophilic nature of CAAE can evidently inhibit water molecules from aggregating into water micro-droplets in amorphous regions between crystal lamellae, thus acquiring a significant promotion in water-tree resistance of CAAE-modified XLPE. In contrast, the grafted MAH molecules can enhance van der Waals forces between polyethylene molecular chains in amorphous regions much greater than the grafted CAAE and simultaneously act as more efficient crystallization nucleation centers to ameliorate crystalline microstructures of XLPE, resulting in a greater improvement (relaxation peak magnitude increases by >10%) of mechanical toughness in amorphous phase, which primarily accounts for water-tree resistance promotion.

Itch-specific neurons in the ventrolateral orbital cortex selectively modulate the itch processing.

Itch is a cutaneous sensation that is critical in driving scratching behavior. The long-standing question of whether there are specific neurons for itch modulation inside the brain remains unanswered. Here, we report a subpopulation of itch-specific neurons in the ventrolateral orbital cortex (VLO) that is distinct from the pain-related neurons. Using a Tet-Off cellular labeling system, we showed that local inhibition or activation of these itch-specific neurons in the VLO significantly suppressed or enhanced itch-induced scratching, respectively, whereas the intervention did not significantly affect pain. Conversely, suppression or activation of pain-specific neurons in the VLO significantly affected pain but not itch. Moreover, fiber photometry and immunofluorescence verified that these itch- and pain-specific neurons are distinct in their functional activity and histological location. In addition, the downstream targets of itch- and pain-specific neurons were different. Together, the present study uncovers an important subpopulation of neurons in the VLO that specifically modulates itch processing.

Magnetic Force Probe Characterizations of Nanoscaled Ferromagnetic Domains: Finite-Element Magnetostatic Simulations.

Microscopic characterization of magnetic nanomaterials by magnetic probe interacting with ferromagnetic nano-domains is proposed according to finite-element magnetostatic field simulations. Magnetic forces detected by microscopic probe are systematically investigated on magnetic moment orientation, magnetization intensity and geometry of ferromagnetic nano-domains, and especially on permanent magnetic coating thickness and tilting angle of probe, to provide a theoretical basis for developing magnetic force microscopy. Magnetic force direction is primarily determined by magnetic moment orientation of nanosample, and the tip curvature dominates magnetic force intensity that is meanwhile positively correlated with nanosample magnetization and probe magnetic coating thickness. Nanosample should reach a critical thickness determined by its transverse diameter to be capable of accurately detecting the magnetic properties of ferromagnetic nanomaterials. Magnetic force signal relies on probe inclination when the sample magnetic moment is along probe tilting direction, which, however, is not disturbed by probe inclination when sample magnetic moment is perpendicular to probe tilting plane. Within the geometry of satisfying a critical size requirement, the magnetic force can successfully image the ferromagnetic nano-domains by characterizing their sizes and magnetic moment orientations. The present study is expected to provide effective analyzing schemes and theoretical evidences for magnetic force microscopy of characterizing magnetic structures in ferromagnetic nanomaterials.

An aldehyde dehydrogenase 1A3 inhibitor attenuates the metastasis of human colorectal cancer.

Metastasis is the leading cause of death for patients with colorectal cancer (CRC). The development of therapeutic regimens that selectively inhibit the biological processes involved in CRC cell dissemination is important. We used multiple Affymetrix DNA microarray hybridization datasets to identify genes related to metastasis and have significant prognostic value for patients with CRC. Quantitative real-time PCR, immunofluorescent and immunohistochemical staining were used to evaluate mRNA and protein expression. The function of aldehyde dehydrogenase 1A3 (ALDH1A3) in invasion was assessed by performing transwell assays and animal experiments. Real-time PCR, luciferase reporter assays, and western blotting were used to identify the genes regulated by ALDH1A3. Molecular docking, MTS assays, cellular thermal shift assays, isothermal titration calorimetry, microscale thermophoresis, and enzymatic activity assays were used to screen and verify the efficacy of the ALDH1A3-specific inhibitor YD1701 (dibenzo-30-crown10-ether). Finally, subcutaneous or orthotopic xenograft models were established to investigate the therapeutic potential of YD1701. Human ALDH1A3 was identified to correlate with a metastatic phenotype in CRC cells and a poor patient prognosis. Moreover, ALDH1A3 upregulated the expression of ZEB1 and SNAI2 by inhibiting miR-200 family members. The ALDH1A3-specific inhibitor YD1701 was screened, attenuated the invasion of CRC cells in vitro, and prolonged the survival of mice bearing subcutaneous or orthotopic xenografts. Our results show that ALDH1A3 promotes invasion and metastasis via the miR-200-ZEB1/SANI2 axis and is thus a plausible marker for predicting CRC progression. Inhibiting ALDH1A3 with the identified compound YD1701 might represent an effective therapeutic approach to prevent the metastasis of CRC.

Effects of acupuncture on cartilage p38MAPK and mitochondrial pathways in animal model of knee osteoarthritis: A systematic evaluation and meta-analysis.

Background: Most previous studies on acupuncture in the treatment of knee osteoarthritis (KOA) have focused on improving functional efficacy and safety, while related mechanisms have not been systematically reviewed. Acupuncture modulates cytokines to attenuate cartilage extracellular matrix degradation and apoptosis, key to the pathogenesis of KOA, but the mechanisms are complex. Objectives: The purpose of this study is to assess the efficacy of acupuncture quantitatively and summarily in animal studies of KOA. Methods: Nine databases including PubMed, Embase, Web of Science (including Medline), Cochrane library, Scopus, CNKI, Wan Fang, and VIP were searched to retrieve animal studies on acupuncture interventions in KOA published since the inception of the journal. Relevant literature was screened, and information extracted. Meta-analysis was performed using Revman 5.4 and Stata 17.0 software. Results: The 35 included studies involved 247 animals, half of which were in acupuncture groups and half in model groups. The mean quality level was 6.7, indicating moderate quality. Meta-analysis showed that acupuncture had the following significant effects on cytokine levels in p38MAPK and mitochondrial pathways: (1) p38MAPK pathway: It significantly inhibits p38MAPK, interleukin-1beta (IL-1ß), tumor necrosis factor alpha (TNF-α), phosphorylated (p)-p38MAPK, matrix metalloproteinase-13 (MMP-13), MMP-1, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMST-5) expression, and significantly increased the expression of collagen II and aggrecan. (2) mitochondrial pathway: It significantly inhibited the expression of Bcl-2-associated X protein (Bax), cysteine protease-3 (caspase-3), caspase-9, and Cytochrome-c (Cyt-c). And significantly increased the expression of B cell lymphocytoma-2 (Bcl-2). In addition, acupuncture significantly reduced chondrocyte apoptosis, Mankin's score (a measure of cartilage damage), and improved cartilage morphometric characteristics. Conclusion: Acupuncture may inhibit cytokine expression in the p38MAPK pathway to attenuate cartilage extracellular matrix degradation, regulate cytokines in the mitochondrial pathway to inhibit chondrocyte apoptosis, and improve cartilage tissue-related phenotypes to delay cartilage degeneration. These findings provide possible explanations for the therapeutic mechanisms and clinical benefits of acupuncture for KOA. Systematic review registration: https://inplasy.com, identifier INPLASY20 2290125.

[Distribution Characteristics and Source Analysis of Dustfall Trace Elements During Winter in Beijing].

The dustfall content is one of the evaluation indexes of atmospheric pollution. Trace elements especially heavy metals in dustfall can lead to risks to ecological environment and human health. In order to study the distribution characteristics of trace elements, heavy metals pollution and their sources in winter atmospheric dust, 49 dustfall samples were collected in Beijing City and nearby during November 2013 to March 2014. Then the contents (mass percentages) of 40 trace elements were measured by Elan DRC It type inductively coupled plasma mass (ICP-MS). Test results showed that more than half of the trace elements in the dust were less than 10 mg x kg(-1); about a quarter were between 10-100 mg x kg-1); while 7 elements (Pb, Zr, Cr, Cu, Zn, Sr and Ba) were more than 100 mg x kg(-1). The contents of Pb, Cu, Zn, Bi, Cd and Mo of winter dustfall in Beijing city.were respectively 4.18, 4.66, 5.35, 6.31, 6.62, and 8.62 times as high as those of corresponding elements in the surface soil in the same period, which went beyond the soil background values by more than 300% . The contribution of human activities to dustfall trace heavy metals content in Beijing city was larger than that in the surrounding region. Then sources analysis of dustfall and its 20 main trace elements (Cd, Mo, Nb, Ga, Co, Y, Nd, Li, La, Ni, Rb, V, Ce, Pb, Zr, Cr, Cu, Zn, Sr, Ba) was conducted through a multi-method analysis, including Pearson correlation analysis, Kendall correlation coefficient analysis and principal component analysis. Research results indicated that sources of winter dustfall in Beijing city were mainly composed of the earth's crust sources (including road dust, construction dust and remote transmission of dust) and the burning of fossil fuels (vehicle emissions, coal combustion, biomass combustion and industrial processes).

Dustfall Heavy Metal Pollution During Winter in North China.

In order to study heavy metal pollution in dustfall during Winter in North China, forty-four dustfall samples were collected in North China Region from November 2013 to March 2014. Then forty trace elements content were measured for each sample by inductively coupled plasma-mass spectrometry. Finally, the contamination characteristics of the main heavy metals were studied through a multi-method analysis, including variability analysis, Pearson correlation analysis and principal component analysis. Results showed that the relative contents of cadmium (Cd), zinc (Zn), copper (Cu), bismuth (Bi), lead (Pb) exceeded the standards stipulated in Chinese soil elements background values by amazing 4.9 times. In this study, conclusions were drawn that dustfall heavy metal pollution in the region was mainly caused by transport pollution, metallurgy industrial pollution, coal pollution and steel industrial pollution.