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Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy of the skin, and its incidence is increasing annually. Once cSCC becomes metastatic, its associated mortality rate is much higher than that of cSCC in situ. However, the current treatments for progressive cSCC have several limitations. The aim of this study was to suggest a potential compound for future research that may benefit patients with cSCC. Methods: In this study, we screened the following differentially expressed genes from the Gene Expression Omnibus database: GSE42677, GSE45164, GSE66359, and GSE98767. Using strategies such as protein-protein interaction network analysis and the CYTOSCAPE plugin MCODE, key modules were identified and then verified by Western blotting. Subsequently, related signalling pathways were constituted in the SIGNOR database. Finally, molecular docking analyses and cell viability assay were used to identify a potential candidate drug and verify its growth inhibition ability to A431 cell line. Results: Fifty-one common differentially expressed genes were screened and two key modules were identified. Among them, three core genes were extracted, constituting two signalling pathways, both of which belong to the module associated with mitotic spindles and cell division. A pathway involving CDK1, the TPX2-KIF11 complex, and spindle organization was validated in a series of analyses, including analyses for overall survival, genetic alteration, and molecular structure. Molecular docking analyses identified the pyridine 2-carbaldehyde thiosemicarbazone (NSC689534), which interacts with TPX2 and KIF11, as a potential candidate for the treatment of cSCC. Conclusions: NSC689534 might be a candidate drug for cSCC targeting TPX2 and KIF11, which are hub genes in cSCC.

Endoplasmic reticulum (ER) and mitochondria are two important organelles that are highly dynamic in mammalian cells. The physical connection between them is mitochondria associated ER membranes (MAM). In recent years, studies on endoplasmic reticulum and mitochondria have shifted from independent division to association and comparison, especially MAM has gradually become a research hotspot. MAM connects the two organelles, not only to maintain their independent structure and function, but also to promote metabolism and signal transduction between them. This paper reviews the morphological structure and protein localization of MAM, and briefly analyzes the functions of MAM in regulating Ca2+ transport, lipid synthesis, mitochondrial fusion and fission, endoplasmic reticulum stress and oxidative stress, autophagy and inflammation. Since ER stress and mitochondrial dysfunction are important pathological events in neurological diseases including ischemic stroke, MAM is likely to play an important role in cerebral ischemia by regulating the signaling of the two organelles and the crosstalk of the two pathological events.

Background: Ischemic stroke seriously threatens human health because of high rates of morbidity, mortality and disability. This study compared the effects of nicotinamide adenine dinucleotide (NAD+) and butylphthalide (NBP) on in vitro and in vivo ischemic stroke models.Methods: Transient middle cerebral artery occlusion/reperfusion (t-MCAO/R) model was established in mice, and the cultured primary cortical neurons were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cerebral infarct volume, neurobehavioral indices, antioxidant activity, ATP level and lactic acid content were determined. The neuroprotective effects of NAD+ or NBP were compared using sirtuin inhibitor niacinamide (NAM).Results: Intraperitoneal injection of NBP within 4 h or intravenous injection of NAD+ within 1 h after t-MCAO/R significantly reduced the volume of infarcts, cerebral edema, and neurological deficits. Administration of NAD+ and NBP immediately after t-MCAO/R in mice showed similar neuroprotection against acute and long-term ischemic injury. Both NAD+ and NBP significantly inhibited the accumulation of MDA and H2O2 and reduced oxidative stress. NAD+ was superior to NBP in inhibiting lipid oxidation and DNA damage. Furthermore, although both NAD+ and NBP improved the morphology of mitochondrial damage induced by ischemia/reperfusion, NAD+ more effectively reversed the decrease of ATP and increase of lactic acid after ischemia/reperfusion compared with NBP. NAD+ but not NBP treatment significantly upregulated SIRT3 in the brain, but the sirtuin inhibitor NAM could abolish the protective effect of NAD+ and NBP by inhibiting SIRT1 or SIRT3.Conclusions: These results confirmed the protective effects of NAD+ and NBP on cerebral ischemic injury. NBP and NAD+ showed similar antioxidant effects, while NAD+ had better ability in restoring energy metabolism, possibly through upregulating the activity of SIRT1 and SIRT3. The protection provided by NBP against cerebral ischemia/reperfusion may be achieved through SIRT1.

Introduction Ankyloglossia is a situation where the tongue tip cannot go beyond the mandibular incisor because the frenulum linguae is short. It could affect children’s health by interfering with their ability to talk, breast feeding and dental development. The most effective measure to control ankyloglossia is the surgical method. However, which surgical procedure is the best one is still controversial. Thus, this protocol aims to assess the effectiveness of different surgical interventions in children with ankyloglossia.Methods and analysis PubMed, EMBASE, Cochrane Library, Web of Science and OVID will be searched for relevant information from inception to 31 May 2022. Observational studies in English that investigate the association between surgical methods and ankyloglossia will be included in this protocol. This protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. The Critical Appraisal Checklist for Analytical Cross-Sectional Studies and the Newcastle–Ottawa Quality Assessment Scale for longitudinal studies will be used to assess the included studies. The improvement of breast feeding and nipple pain will be the primary outcome. STATA V.15.1 will do the statistical analysis in the meta-analysis. Subgroup and meta-regression will be carried out based on the characteristics of included studies.Ethics and dissemination This systematic review and meta-analysis will summarise relevant information on the effects of different surgical treatments on patients with ankyloglossia. The results will be disseminated through peer-reviewed publications. The data included in this study will be extracted from the published original studies. Thus, ethical approval and informed consent will not be required.PROSPERO registration number CRD42022323350.

Very early onset inflammatory bowel disease (VEO-IBD) is characterized by multifactorial chronic recurrent intestinal inflammation. Compared with elderly patients, those with VEO-IBD have a more serious condition, not responsive to conventional treatments, with a poor prognosis. Recent studies found that genetic and immunologic abnormalities are closely related to VEO-IBD. Intestinal immune homeostasis monogenic defects (IIHMDs) are changed through various mechanisms. Recent studies have also revealed that abnormalities in genes and immune molecular mechanisms are closely related to VEO-IBD. IIHMDs change through various mechanisms. Epigenetic factors can mediate the interaction between the environment and genome, and genetic factors and immune molecules may be involved in the pathogenesis of the environment and gut microbiota. These discoveries will provide new directions and ideas for the treatment of VEO-IBD.

Background: Ischemic stroke seriously threatens human health because of high rates of morbidity, mortality and disability. This study compared the effects of nicotinamide adenine dinucleotide (NAD+) and butylphthalide (NBP) on in vitro and in vivo ischemic stroke models. Methods: Transient middle cerebral artery occlusion/reperfusion (t-MCAO/R) model was established in mice, and the cultured primary cortical neurons were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cerebral infarct volume, neurobehavioral indices, antioxidant activity, ATP level and lactic acid content were determined. The neuroprotective effects of NAD+ or NBP were compared using sirtuin inhibitor niacinamide (NAM). Results: Intraperitoneal injection of NBP within 4 h or intravenous injection of NAD+ within 1 h after t-MCAO/R significantly reduced the volume of infarcts, cerebral edema, and neurological deficits. Administration of NAD+ and NBP immediately after t-MCAO/R in mice showed similar neuroprotection against acute and long-term ischemic injury. Both NAD+ and NBP significantly inhibited the accumulation of MDA and H2O2 and reduced oxidative stress. NAD+ was superior to NBP in inhibiting lipid oxidation and DNA damage. Furthermore, although both NAD+ and NBP improved the morphology of mitochondrial damage induced by ischemia/reperfusion, NAD+ more effectively reversed the decrease of ATP and increase of lactic acid after ischemia/reperfusion compared with NBP. NAD+ but not NBP treatment significantly upregulated SIRT3 in the brain, but the sirtuin inhibitor NAM could abolish the protective effect of NAD+ and NBP by inhibiting SIRT1 or SIRT3. Conclusions: These results confirmed the protective effects of NAD+ and NBP on cerebral ischemic injury. NBP and NAD+ showed similar antioxidant effects, while NAD+ had better ability in restoring energy metabolism, possibly through upregulating the activity of SIRT1 and SIRT3. The protection provided by NBP against cerebral ischemia/reperfusion may be achieved through SIRT1. [ABSTRACT FROM AUTHOR]

In this paper, the structural, electronic, and elastic properties of Fe3SnC were calculated based on local density approximation (LDA) and generalized gradient approximation (GGA) in density functional theory (DFT). Compared with GGA, LDA underestimates lattice constants and overestimates binding energy and elastic constants. The calculated lattice constants are 3.76 Å (LDA) and 3.83 Å (GGA), respectively, and the latter is closer to the experimental values. With U correction in GGA and LDA, the magnetic properties of the system are shown in the band structure. The GGA calculation results are more accurate, and the calculated magnetic moment of Fe3SnC is 5.74μB. The band structure indicates that Fe3SnC is a metallic compound. The elastic constants show that Fe3SnC has a large elastic constant and bulk modulus, in which the C11 calculated by GGA is as high as 463.81GPa, and the Young's modulus is as high as 350.72GPa. This indicates that Fe3SnC is a potential cermet due to a strong deformation resistance. At the same time, with the minimum thermal conductivity of 1.65 W/mK calculated by the Cahill model.

In this paper, the elastic properties, chemical bonds, electronic properties, magnetic properties, and phonon spectra of CuNFe3 and CuNCo3 synthesized in the experiment are calculated by first principles. The results show they are ferromagnetic metal compounds with covalent and ionic bonds. CuNFe3 and CuNCo3 have large bulk modulus B, Young's modulus Y, and shear modulus G, which are 191.01 GPa, 202.33 GPa, 159.65 GPa, 247.01 GPa, 58.67 GPa and 95.26 GPa, respectively, which indicates that they have compressive solid resistance. The total magnetic moment of CuNFe3 is 6.96 μB, and that of CuNCo3 is 4.17 μB, which suggests that they have broad application prospects in magnetic storage, computer core, magnetic recording materials and other fields.

The stability, electronic, optical and thermodynamic properties of X3OI (X = Na, K, Rb) have been calculated by first principles. The Birch-Murnaghan method was used to fit the optimal lattice constants of the three materials. The results show that the three compounds are stable and the calculated thermodynamic properties show that they conform to Dulong-Petit's law. They absorb light more strongly in the ultraviolet region and are direct bandgap semiconductors, which can be potential photodetector materials. Rb3OI has a band gap value of 1.69eV, which has the potential to be used as the absorption layer material for perovskite solar cells. The results provide a theoretical basis for further experimental study of these three materials.

AIM: To investigate the effect of modulated autophagy activity on subepithelial haze after photorefractive keratectomy(PRK)in rabbits.METHODS: Totally 64 New Zealand white rabbits were randomly divided into 4 groups according to different postoperative medication after PRK operation, including simple PRK group, 14μmol/L DMSO group, 50μmol/L rapamycin group and 100μmol/L rapamycin group. According to the group situation, two hours after the operation, eye drops were given, 3 times a day for 7d. Another 16 rabbits were selected as normal control group. The postoperative inflammatory response and corneal epithelial healing were observed with slit-lamp microscope every day. Haze formation of each group at 1 and 4wk after PRK was collected by slit-lamp microscopy system. Eight rabbits in each group were killed by air embolization 1 and 4wk after PRK, and corneal tissue was extracted and frozen for later use. Immunohistochemistry was used to detect the expression levels of transforming growth factor-β1(TGF-β1), α-smooth muscle actin(α-SMA), and matrix metalloproteinase-2(MMP-2). Real-time PCR was used to detect the relative expression levels of autophage-5(ATG5), autophage-12(ATG12), B lymphocytoma gene-2(Bcl-2)and cysteine aspartic proteinase-3(Caspase3)genes.RESULTS: Corneal epithelium of all operative rabbits healed completely at 3-4d and no significant difference in healing time between the groups after operation(F=0.745, P=0.530). During the observation period, haze was the most obvious at 4wk after operation in all groups. The haze symptoms were more serious in the simple operation group and the 14μmol/L DMSO group, followed by the 50μmol/L rapamycin group. The haze symptoms in the 100μmol/L rapamycin group were significantly relieved than those in other groups. There was no significant difference in the haze grading with different time points after operation among all groups(all P

In this study, we examined the effect of the GP130-targeting molecule, LMT-28, on lipopolysaccharide- (LPS-) induced bone resorption around implants in diabetic models using in vitro and rat animal experiments. First, LMT-28 was added to osteoblasts stimulated by LPS and advanced glycation end products (AGEs), and nuclear factor-κB receptor-activating factor ligand (RANKL) and associated pathways were evaluated. Then, LMT-28 was administered by gavage at 0.23 mg/kg once every 5 days for 2 weeks to type 2 diabetic rats with peri-implantitis induced by LPS injection and silk ligature. The expression of IL-6 and RANKL was evaluated by immunohistochemistry, and the bone resorption around implants was evaluated by microcomputed tomography. The results showed that LMT-28 downregulated the expression of RANKL through the JAK2/STAT3 signaling pathway in osteoblasts stimulated by LPS and AGEs, reduced bone resorption around implants with peri-implantitis, decreased the expression of IL-6 and RANKL, and decreased osteoclast activity in type 2 diabetic rats. This study confirmed the ability of LMT-28 to reduce LPS-induced bone resorption around implants in diabetic rats.

Objectives: To explore the association between left atrial (LA) strain and the GRACE score in patients with acute coronary syndrome (ACS) and to investigate the utility of LA function in predicting short-term adverse cardiovascular events post ACS. Methods: This retrospective study included ACS patients who underwent coronary angiography (CAG) in two independent cohorts from October 2020 to July 2022. The patients were classified into low-intermediate risk group and high-risk group based on the GRACE score. All participants underwent a transthoracic echocardiogram, with LA strain analysis before CAG. Correlation analysis was used to determine the relationship between LA strain and the GRACE score. The predictive value of LA strain was examined utilizing the area under the curve (AUC). Participants were followed for 10.5 ± 2.9 months for the primary endpoint of major adverse cardiovascular events (MACE). Results: A total of 229 patients were included in this study, including 196 in the primary group and 33 in the validation group. Spearman’s correlation analysis showed there was a moderate negative correlation between the GRACE and left atrial reservoir strain (LASr) in both the primary (r = −0.63, P < 0.001) and validation (r = −0.73, P < 0.001) cohorts. Receiver operator characteristic (ROC) curve analysis showed that the AUC of LASr for prediction of the high-risk group was 0.86. Taking LASr 19.6% as the cut-off value, the sensitivity and specificity were 0.71 and 0.92, respectively. The cut-off value of 19.6% remains good at identifying high-risk group in the validation group (AUC = 0.87, sensitivity: 77.8%, specificity: 95.8%). Furthermore, 49 patients reached the endpoint in the primary cohort during the follow-up. On multivariable regression analysis, LASr (P = 0.03) was the independent echocardiographic predictor for the primary endpoint, rather than left atrial volume index (LAVI). Conclusions: LASr can identify high-risk patients with ACS as defined by the GRACE score and may be superior to Max LAVI in predicting incidents of MACE in the short-term following ACS.

Circulating tumor cells (CTCs) play a crucial role in solid tumor metastasis, but obtaining high purity and viability CTCs is a challenging task due to their rarity. Although various works using spiral microchannels to isolate CTCs have been reported, the sorting purity of CTCs has not been significantly improved. Herein, we developed a novel double spiral microchannel for efficient separation and enrichment of intact and high-purity CTCs based on the combined effects of two-stage inertial focusing and particle deflection. Particle deflection relies on the second sheath to produce a deflection of the focused sample flow segment at the end of the first-stage microchannel, allowing larger particles to remain focused and entered the second-stage microchannel while smaller particles moved into the first waste channel. The deflection of the focused sample flow segment was visualized. Testing by a binary mixture of 10.4 and 16.5 μm fluorescent microspheres, it showed 16.5 μm with separation efficiency of 98% and purity of 90% under the second sheath flow rate of 700 μl min−1. In biological experiments, the average purity of spiked CTCs was 74% at a high throughput of 1.5 × 108 cells min−1, and the recovery was more than 91%. Compared to the control group, the viability of separated cells was 99%. Finally, we validated the performance of the double spiral microchannel using clinical cancer blood samples. CTCs with a concentration of 2–28 counts ml−1 were separated from all 12 patients’ peripheral blood. Thus, our device could be a robust and label-free liquid biopsy platform in inertial microfluidics for successful application in clinical trials.

Abstract Background To evaluate the significance and benefit of radiotherapy (RT) in young early‐stage breast cancer patients according to different molecular subtypes. Methods We conducted a retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results database with known hormone receptor (HoR) and human epidermal growth factor receptor 2 (HER2) status. Female patients aged 18‐45, received RT treatment, and diagnosed with stage T1‐3, N0‐3, M0 primary breast cancer between 2010 and 2013 were identified. Results Of all the 23 148 included patients, 14 708 (63.54%), 3385 (14.62%), 1225 (5.29%), and 3830 (16.55%) were diagnosed with luminal‐A (HoR + HER2‐), luminal‐B (HoR + HER2+), HER2‐enriched (HoR‐HER2+), and triple‐negative (HoR‐HER2‐) breast cancer, respectively. RT was significantly correlated with improved overall survival (OS, HR: 0.295; 95% CI:0.138‐0.63, P = 0.002) and breast cancer‐specific survival (BCSS, HR: 0.328; 95% CI: 0.153‐0.702, P = 0.004) in HER2‐enriched patients. In addition, a significantly prolonged OS was also observed when RT was given to luminal‐A (HR: 0.696; 95% CI: 0.538‐0.902, P = 0.006) and luminal‐B (HR: 0.385; 95% CI:0.199‐0.744, P = 0.005) breast cancer patients compared to those without RT. Multivariable‐adjusted analyses showed that HER2 was a significant favorable factor for RT benefit in breast cancer patients. Conclusions RT could offer significant survival benefit in luminal‐A, luminal‐B, and especially HER2‐enriched young early‐stage breast cancer female patients. The results enabled clinicians to predict the benefits of RT and improve evidence‐based treatment for breast cancer patients.

Aim to the complexity and zonality of Paleozoic marine hydrocarbon accumulation caused by foreland basin tectonic in northwestern Sichuan Basin, the influence and differential characteristics of foreland basin tectonic evolution on Paleozoic marine hydrocarbon accumulation are analyzed from the perspective of reservoir forming conditions. It is supposed that the foreland basin structure in western Sichuan Basin longitudinally promoted the thermal evolution of the Paleozoic source rocks into the high-mature and over-mature stage. Laterally, there was a delay effect on the source rocks in the thrust belt and depression zone. The reservoir with characteristics of low porosity and permeability was caused by foreland basin squeezing action, and the porosity of the reservoir conforms to the compaction law. And the uplift destroyed the capping ability of the cover in the foreland thrust belt, reduced the effectiveness of traps, and fault block traps and tectonic-lithologic traps are developed in an area covering the front of thrust belt, and the preserve condition are well. The Paleozoic oil and gas accumulation in the study area has obvious zonation, in which the foreland thrust nappe belt affected by lateral migration system has the characteristics of late adjustment of early oil to gas, and reservoir controlled by preservation. The area in front of thrust belt is affected by stage migration system of permeable bed-fault, with characteristics of multi-source injection, multi-period migration and accumulation, and reservoir controlled by source faults. The depression zone is characterized by near source injection, continuous hydrocarbon supply, and reservoir controlled by vertical migration system of intraformational faults. The comprehensive analysis shows that the area in front of thrust belt is a favorable hydrocarbon accumulation area of Paleozoic marine formation. [ABSTRACT FROM AUTHOR]