[Application of metal cushion block combined with Jumbo cup in reconstruction of acetabular bone defect in revision of artificial hip joint].

OBJECTIVE: To investigate the application effect and imaging changes of metal cushion block combined with Jumbo cup in the reconstruction of acetabular bone defect after revision of artificial hip joint. METHODS: Retrospective analysis was made on the clinical data of 83 patients who underwent revision acetabular bone defect reconstruction of the artificial hip joint in our hospital from September 2019 to October 2021. They were divided into group A and group B according to different surgical methods. There were 42 patients in group A, including 26 males and 16 females, aged from 44 to 72 years old with an average of (60.57±4.62) years, who underwent revision with metal cushion block and Jumbo cup. There were 41 patients in group B, including 22 males and 19 females, aged from 42 to 71 years old with an average of (58.74±4.25) years, who underwent revision with metal cushion block and bone cement mortar cup. The operation related indexes, Harris hip function score and visual analogue scale (VAS) of pain before operation, 1 month and 12 month after operation were compared between two groups. The results of X-ray imaging examination (hip rotation center height, acetabular abduction angle, femoral eccentricity and imaging standard qualification rate) before and 12 month after operation were evaluated, and the incidence of complications was compared between two groups. RESULTS: There was no significant difference in operation time, intraoperative bleeding volume and postoperative drainage volume between two groups (P>0.05). Both groups were followed up for 12 to 36 months with an average of (25.36±3.59) months. The scores of pain, function, deformity and Harris' total score in the two groups at 1 month after operation were higher than those before operation (P<0.05), and the scores of pain, function, deformity, joint activity and Harris' total score in two groups at 1 year after operation were higher than those before operation and 1 month after operation (P<0.05), and the above scores in group A were higher than those in group B at 1 year after operation (P<0.05). The VAS of two groups decreased successively at 1 month and 1 year after operation (P<0.05), but there was no significant difference in both groups at each time point (P>0.05). The femoral eccentricity increased in both groups at 1 year after operation (P<0.05), and group A was higher than group B (P<0.05). The height of rotation center and acetabular abduction angle decreased in both groups at 1 year after operation (P<0.05), and the height of rotation center in group A was lower than that in group B (P<0.05), but there was no significant difference in acetabular abduction angle between two groups (P>0.05). The imaging qualification rate of group A was higher than that of group B (P<0.05). There was no significant difference in the incidence of adverse reactions between two groups (P>0.05). CONCLUSION: Metal cushion block combined with Jumbo cup in the treatment of acetabular bone defects can provide the hip joint function, and restore the hip joint rotation center, femoral eccentricity and acetabular abduction angle, with obvious clinical effect.

A case report of phacolytic glaucoma in lens cortex behind posterior capsule: A CARE-compliant article.

RATIONALE: Phacolytic glaucoma (PLG), a secondary open-angle glaucoma caused by high molecular weight proteins leaking through the capsule of a hypermature cataract. Leakage of liquefied lens cortex behind the posterior capsule is rare. In this paper, we review a case of phacolytic glaucoma in the lens cortex behind posterior capsule. PATIENT CONCERNS: This case report describes a 79-year-old male patient with a 7-year history of progressive blurred vision and a 1-day history of distended in his left eye. He underwent phacoemulsification combined with intraocular lens implantation at our facility 7 years ago. DIAGNOSES: The patient had lower vision (light perception vision) and increased intraocular pressure (IOP) (60 mmHg) in the left eye. Auxiliary inspection found that the left eye had deep anterior chamber depth (around 1 corneal thickness of the peripheral AC angle) as well as vitreous and aqueous humor opacity in the left eye. Combining the clinical symptoms and examinations, we made the diagnosis of PLG in the left eye. INTERVENTIONS: The patient underwent trabeculectomy and extracapsular cataract extraction of the left after a stable ocular condition, during the operation to see that white chyous cortex was visible under the posterior capsule and posterior capsule membrane of the lens was avulsed circularly. OUTCOMES: The postoperative condition was stable. During the follow up of 3 months, the IOP of the left eye was stable without ocular discomfort. LESSONS: This case reported a patient with phacolytic glaucoma in the lens cortex behind posterior capsule who underwent successful surgery, indicating spontaneous capsule rupture can occur in the posterior capsules in PLG and when this situation is detected during the operation, the posterior capsule tearing method can be applied to absorb the lens cortex sticking at the posterior surface of the posterior capsule.

Green Vertical-Cavity Surface-Emitting Lasers Based on InGaN Quantum Dots and Short Cavity.

Room temperature low threshold lasing of green GaN-based vertical cavity surface emitting laser (VCSEL) was demonstrated under continuous wave (CW) operation. By using self-formed InGaN quantum dots (QDs) as the active region, the VCSEL emitting at 524.0 nm has a threshold current density of 51.97 A cm-2, the lowest ever reported. The QD epitaxial wafer featured with a high IQE of 69.94% and the δ-function-like density of states plays an important role in achieving low threshold current. Besides, a short cavity of the device (~ 4.0 λ) is vital to enhance the spontaneous emission coupling factor to 0.094, increase the gain coefficient factor, and decrease the optical loss. To improve heat dissipation, AlN layer was used as the current confinement layer and electroplated copper plate was used to replace metal bonding. The results provide important guidance to achieving high performance GaN-based VCSELs.

Rhein attenuates cerebral ischemia-reperfusion injury via inhibition of ferroptosis through NRF2/SLC7A11/GPX4 pathway.

BACKGROUND: Ischemic stroke, a major cause of death and disability worldwide, results from reduced blood flow to the brain, leading to irreversible neuronal damage. Recent evidence suggests that ferroptosis, a form of regulated cell death, plays a critical role in the pathogenesis of ischemic stroke. Rhein, a natural anthraquinone compound, has demonstrated neuroprotective effects; However, its role in ferroptosis and the underlying mechanisms remain unclear. Here, we investigated the protective effects of Rhein against ischemia/reperfusion (I/R) injury in a rat model of middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cells. Rhein treatment dose-dependently ameliorated neurological deficits, reduced infarct volume, and attenuated blood-brain barrier (BBB) disruption in the MCAO model. Furthermore, Rhein suppressed oxidative stress, intracellular ROS generation, and ferroptosis-related protein expression in both in vivo and in vitro models. Mechanistically, Rhein protected against OGD/R-induced HT22 cell injury by regulating the NRF2/SLC7A11/GPX4 signaling pathway. This effect was abolished upon NRF2 inhibition, suggesting that Rhein's neuroprotective action is NRF2-dependent. Molecular docking and microscale thermophoresis analyses further supported the direct interaction between Rhein and the ferroptosis-related protein NRF2. Collectively, our findings reveal that Rhein confers neuroprotection against cerebral I/R injury by inhibiting ferroptosis via the NRF2/SLC7A11/GPX4 axis, providing a potential therapeutic avenue for ischemic stroke. AIMS: To investigate the neuroprotective effects of Rhein, a natural anthraquinone compound, against ischemia/reperfusion (I/R) injury and elucidate the underlying mechanisms involving ferroptosis and the NRF2/SLC7A11/GPX4 pathway. METHODS: A rat model of middle cerebral artery occlusion (MCAO) was employed for in vivo assessments, while oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cells were used as an in vitro model. Comprehensive analyses, including neurological score assessment, triphenyl tetrazolium chloride staining, Evans Blue leakage assay, intracellular ROS detection, MTT assay, dual-luciferase reporter assay, oxidative stress and Fe2+ content assessment, immunofluorescence, Western blot, flow cytometry, molecular docking, and microscale thermophoresis, were performed to evaluate the effects of Rhein on I/R injury and ferroptosis. RESULTS: Rhein conferred dose-dependent neuroprotection against cerebral I/R injury, reducing infarct volume and blood-brain barrier (BBB) disruption in the MCAO model. In both in vivo and in vitro models, Rhein suppressed oxidative stress, intracellular ROS generation, and ferroptosis-related protein expression. Furthermore, Rhein protected HT22 cells from OGD/R-induced injury by regulating the NRF2/SLC7A11/GPX4 signaling pathway, with NRF2 inhibition abolishing these therapeutic effects. Molecular docking and microscale thermophoresis analyses supported a direct interaction between Rhein and NRF2, a ferroptosis-related protein. CONCLUSION: Rhein attenuates cerebral I/R injury by inhibiting ferroptosis via the NRF2/SLC7A11/GPX4 axis, highlighting its potential as a therapeutic agent for ischemic stroke.

BCL2 Inhibition Reveals a Dendritic Cell-Specific Immune Checkpoint That Controls Tumor Immunosurveillance.

We developed a phenotypic screening platform for the functional exploration of dendritic cells (DC). Here, we report a genome-wide CRISPR screen that revealed BCL2 as an endogenous inhibitor of DC function. Knockout of BCL2 enhanced DC antigen presentation and activation as well as the capacity of DCs to control tumors and to synergize with PD-1 blockade. The pharmacologic BCL2 inhibitors venetoclax and navitoclax phenocopied these effects and caused a cDC1-dependent regression of orthotopic lung cancers and fibrosarcomas. Thus, solid tumors failed to respond to BCL2 inhibition in mice constitutively devoid of cDC1, and this was reversed by the infusion of DCs. Moreover, cDC1 depletion reduced the therapeutic efficacy of BCL2 inhibitors alone or in combination with PD-1 blockade and treatment with venetoclax caused cDC1 activation, both in mice and in patients. In conclusion, genetic and pharmacologic BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance. SIGNIFICANCE: BCL2 inhibition improves the capacity of DCs to stimulate anticancer immunity and restrain cancer growth in an immunocompetent context but not in mice lacking cDC1 or mature T cells. This study indicates that BCL2 blockade can be used to sensitize solid cancers to PD-1/PD-L1-targeting immunotherapy. This article is featured in Selected Articles from This Issue, p. 2293.

Anticancer effects of ikarugamycin and astemizole identified in a screen for stimulators of cellular immune responses.

BACKGROUND: Most immunotherapies approved for clinical use rely on the use of recombinant proteins and cell-based approaches, rendering their manufacturing expensive and logistics onerous. The identification of novel small molecule immunotherapeutic agents might overcome such limitations. METHOD: For immunopharmacological screening campaigns, we built an artificial miniature immune system in which dendritic cells (DCs) derived from immature precursors present MHC (major histocompatibility complex) class I-restricted antigen to a T-cell hybridoma that then secretes interleukin-2 (IL-2). RESULTS: The screening of three drug libraries relevant to known signaling pathways, FDA (Food and Drug Administration)-approved drugs and neuroendocrine factors yielded two major hits, astemizole and ikarugamycin. Mechanistically, ikarugamycin turned out to act on DCs to inhibit hexokinase 2, hence stimulating their antigen presenting potential. In contrast, astemizole acts as a histamine H1 receptor (H1R1) antagonist to activate T cells in a non-specific, DC-independent fashion. Astemizole induced the production of IL-2 and interferon-γ (IFN-γ) by CD4+ and CD8+ T cells both in vitro and in vivo. Both ikarugamycin and astemizole improved the anticancer activity of the immunogenic chemotherapeutic agent oxaliplatin in a T cell-dependent fashion. Of note, astemizole enhanced the CD8+/Foxp3+ ratio in the tumor immune infiltrate as well as IFN-γ production by local CD8+ T lymphocytes. In patients with cancer, high H1R1 expression correlated with low infiltration by TH1 cells, as well as with signs of T-cell exhaustion. The combination of astemizole and oxaliplatin was able to cure the majority of mice bearing orthotopic non-small cell lung cancers (NSCLC), then inducing a state of protective long-term immune memory. The NSCLC-eradicating effect of astemizole plus oxaliplatin was lost on depletion of either CD4+ or CD8+ T cells, as well as on neutralization of IFN-γ. CONCLUSIONS: These findings underscore the potential utility of this screening system for the identification of immunostimulatory drugs with anticancer effects.

Bile acids regulate MAdCAM-1 expression to link the gut microbiota to cancer immunosurveillance.

In a recent paper in Science, Fidelle et al. unravel a gut immune checkpoint that is subverted by antibiotic treatment. Post-antibiotic dysbiosis of the ileum causes an increase in bile acids that downregulate MAdCAM-1, thereby triggering the exodus of immunosuppressive T cells from gut-associated lymphoid tissues toward tumors.

A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.

Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4ß7+CD4+ regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4ß7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4ß7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.

The immunomodulatory effect of IL-4 accelerates bone substitute material-mediated osteogenesis in aged rats via NLRP3 inflammasome inhibition.

Background: Bone defect repair by implanting bone substitute materials has been a common clinical treatment. With the understanding of substance-immune system interactions and increasing evidence indicating that the post-implantation immune response determines the fate of bone substitute materials, active modulation of host macrophage polarization is considered a promising strategy. However, whether the same regulatory effects exist when an individual immune system is altered with aging is unclear. Methods: In this study, we mechanistically investigated the effect of immunosenescence on the active regulation of macrophage polarization by establishing a cranial bone defect model in young and aged rats implanted with Bio-Oss®. Forty-eight young and 48 aged specific pathogen-free (SPF) male SD rats were randomly divided into two groups. In the experimental group, 20 µL of IL-4 (0.5 µg/mL) was injected locally on the third to seventh postoperative days, while an equal volume of PBS was injected in the control group. Specimens were collected at 1, 2, 6, and 12 weeks postoperatively, and bone regeneration at the defect site was evaluated by micro-CT, histomorphometry, immunohistochemistry, double-labeling immunofluorescence, and RT-qPCR. Results: The application of exogenous IL-4 reduced activation of NLRP3 inflammasomes by promoting the polarization of M1 macrophages to M2 macrophages, thus promoting bone regeneration at the site of bone defects in aged rats. However, this effect was gradually weakened after the IL-4 intervention was discontinued. Conclusion: Our data confirmed that a strategy to regulate macrophage polarization is also feasible under conditions of immunosenescence, i.e., the local inflammatory microenvironment can be regulated by reducing M1-type macrophages. However, further experiments are needed to determine an exogenous IL-4 intervention that can maintain a more sustained effect.

Alterations in the microenvironment and the effects produced of TRPV5 in osteoporosis.

The pathogenesis of osteoporosis involves multiple factors, among which alterations in the bone microenvironment play a crucial role in disrupting normal bone metabolic balance. Transient receptor potential vanilloid 5 (TRPV5), a member of the TRPV family, is an essential determinant of the bone microenvironment, acting at multiple levels to influence its properties. TRPV5 exerts a pivotal influence on bone through the regulation of calcium reabsorption and transportation while also responding to steroid hormones and agonists. Although the metabolic consequences of osteoporosis, such as loss of bone calcium, reduced mineralization capacity, and active osteoclasts, have received significant attention, this review focuses on the changes in the osteoporotic microenvironment and the specific effects of TRPV5 at various levels.

Macrolide antibiotics activate the integrated stress response and promote tumor proliferation.

Macrolide antibiotics are widely used antibacterial agents that are associated with autophagy inhibition. This study aimed to investigate the association between macrolide antibiotics and malignant tumors, as well as the effect on autophagy, reactive oxygen species (ROS) accumulation and integrated stress response (ISR). The meta-analysis indicated a modestly higher risk of cancer in macrolide antibiotic ever-users compared to non-users. Further experiments showed that macrolides block autophagic flux by inhibiting lysosomal acidification. Additionally, azithromycin, a representative macrolide antibiotic, induced the accumulation of ROS, and stimulated the ISR and the activation of transcription factor EB (TFEB) and TFE3 in a ROS-dependent manner. Finally, animal experiments confirmed that azithromycin promoted tumor progression in vivo, which could be receded by N-acetylcysteine, an inhibitor of ROS and ISR. Overall, this study reveals the potential role of macrolide antibiotics in malignant progression and highlights the need for further investigation into their effects.

Dual-wavelength switching in InGaN quantum dot micro-cavity light-emitting diodes.

Dual-wavelength switchable emission has been demonstrated in InGaN quantum dot (QD) micro-cavity light-emitting diodes (MCLEDs). By simply modulating the injected current levels, the output of the device can be dynamically tuned between the two distinct cavity modes at 498.5 and 541.7 nm, exhibiting deterministic mode switching in the green spectral range. Owing to the microcavity effect, high spectral purity with a narrow linewidth of 0.21 nm was obtained. According to the experimental and theoretical results, it can be concluded that the dual-wavelength switching for the investigated MCLEDs is ascribed to the broad and tunable gain of a thin InGaN QD active region, together with the mode selection and enhancement effect of the cavity. To provide additional guidelines for controllable dual-wavelength switchable operation in nitride-based light-emitting devices, detailed design and fabrication strategies are discussed. This work presents an effective method to achieve mode switching for practical applications such as multi-wavelength optical recording, frequency mixing, flip-flop and optical switches.

Improved Binary Grasshopper Optimization Algorithm for Feature Selection Problem.

The migration and predation of grasshoppers inspire the grasshopper optimization algorithm (GOA). It can be applied to practical problems. The binary grasshopper optimization algorithm (BGOA) is used for binary problems. To improve the algorithm's exploration capability and the solution's quality, this paper modifies the step size in BGOA. The step size is expanded and three new transfer functions are proposed based on the improvement. To demonstrate the availability of the algorithm, a comparative experiment with BGOA, particle swarm optimization (PSO), and binary gray wolf optimizer (BGWO) is conducted. The improved algorithm is tested on 23 benchmark test functions. Wilcoxon rank-sum and Friedman tests are used to verify the algorithm's validity. The results indicate that the optimized algorithm is significantly more excellent than others in most functions. In the aspect of the application, this paper selects 23 datasets of UCI for feature selection implementation. The improved algorithm yields higher accuracy and fewer features.

Fenofibrate improves GLOBE and UK-PBC scores and histological features in primary biliary cholangitis.

BACKGROUND: Fenofibrate (FF) has been suggested as a second-line therapy for primary biliary cholangitis (PBC) with suboptimal response to ursodeoxycholic acid (UDCA). But its long-term effect is unclear. METHODS: From a retrospective cohort (N.=838), we enrolled 106 UDCA-refractory PBC patients, among them 62 received UDCA monotherapy (UDCA group) and 44 received FF combined with UDCA (UDCA+FF group). Changes of liver biochemistries and prognosis after treatment were determined. In addition, sequential liver biopsies were used to assess the effect of FF on histological parameters. RESULTS: We found adding FF could significantly reduce serum levels of alkaline phosphatase (ALP), but for patients with pretreatment ALP≥1.67 upper limit of normal (ULN), the significant decline of serum ALP was only observed in the UDCA+FF group after 1 year of therapy. The mean GLOBE Score and the liver transplant-free survival predicted by GLOBE Score were both improved significantly in patients receiving UDCA+FF after 1 year of therapy. The liver-related death or liver transplant calculated using UK-PBC risk score was significantly reduced in patients receiving UDCA+FF after 1 year of therapy. Although there was no marked difference in the final histological analysis after 3 years of therapy, patients receiving UDCA+FF had improvements or stabilization in fibrosis (85.7%), and bile duct loss (78.6%) were more than that of patients receiving UDCA (70.6% and 76.5%, respectively). CONCLUSIONS: Adding FF improves GLOBE and UK-PBC scores and is also associated with the improvements or stabilization of disease features, including fibrosis and ductular injury.

A Series of Polyoxometalate-Viologen Photochromic Materials for UV Probing, Amine Detecting and Inkless and Erasable Printing.

In this work, by using two kinds of viologen ligands three POM-based Compounds were obtained under hydrothermal conditions, namely [AgI (bmypd)0.5 (ß-Mo8 O26 )0.5 ] (1) (bmypd ⋅ 2Cl=1,1'-[Biphenyl-4,4'-bis(methylene)]bis(4,4'-bipyridyinium)dichloride), [AgI 2 (bypy)4 (HSiW12 O40 )2 ] ⋅ 14H2 O (2) and [AgI (bypy)(γ-Mo8 O26 )0.5 ] (3) (bypy⋅Cl=1-Benzyl-4,4'-bipyridyinium chloride). The structures were characterized by Fourier transform infrared spectroscopy (FT-IR), Powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS) and single crystal X-ray diffraction. Compounds 1-3 show excellent photochromic ability with fast photoresponse under the irradiation of ultraviolet light with different degrees of color changes. So compounds 1-3 can be used as visible ultraviolet detectors. Compounds 1-3 also possess photoluminescence properties with fast and excellent fluorescence quenching effect. Compounds 1-3 also can be used as inkless and erasable printing materials with suspensions of 1-3 applied to filter paper. Compounds 1-3 can also produce color changes in amine vapor environment, especially in an NH3 atmosphere. Compounds 1-3 can be used as organic amine detectors.

Successful outcomes of unilateral vs bilateral pedicle screw fixation for lumbar interbody fusion: A meta-analysis with evidence grading.

BACKGROUND: Whether it's better to adopt unilateral pedicle screw (UPS) fixation or to use bilateral pedicle screw (BPS) one for lumbar degenerative diseases is still controversially undetermined. AIM: To make a comparison between UPS and BPS fixation as to how they work efficaciously and safely in patients suffering from lumbar degenerative diseases. METHODS: We have searched a lot in the databases through 2020 with index terms such as "unilateral pedicle screw fixation" and "bilateral pedicle screw fixation." Only randomized controlled trials and some prospective cohort studies could be found, yielding 15 studies. The intervention was unilateral pedicle screw fixation; Primarily We've got outcomes of complications and fusion rates. Secondarily, we've achieved outcomes regarding total blood loss, operative time, as well as length of stay. Softwares were installed and utilized for subgroup analysis, analyzing forest plots, sensitivity, heterogeneity, forest plots, publication bias, and risk of bias. RESULTS: Fifteen previous cases of study including 992 participants have been involved in our meta-analysis. UPS had slightly lower effects on fusion rate [relative risk (RR) = 0.949, 95%CI: 0.910 to 0.990, P = 0.015], which contributed mostly to this meta-analysis, and similar complication rates (RR = 1.140, 95%CI: 0.792 to 1.640, P = 0.481), Δ visual analog scale [standard mean difference (SMD) = 0.178, 95%CI: -0.021 to 0.378, P = 0.080], and Δ Oswestry disability index (SMD = -0.254, 95%CI: -0.820 to 0.329, P = 0.402). In contrast, an obvious difference has been observed in Δ Japanese Orthopedic Association (JOA) score (SMD = 0.305, 95%CI: 0.046 to 0.563, P = 0.021), total blood loss (SMD = -1.586, 95%CI: -2.182 to -0.990, P = 0.000), operation time (SMD = -2.831, 95%CI: -3.753 to -1.909, P = 0.000), and length of hospital stay (SMD = -0.614, 95%CI: -1.050 to -0.179, P = 0.006). CONCLUSION: Bilateral fixation is more effective than unilateral fixation regarding fusion rate after lumbar interbody fusion. However, JOA, operation time, total blood loss, as well as length of stay were improved for unilateral fixation.

Everolimus and plicamycin specifically target chemoresistant colorectal cancer cells of the CMS4 subtype.

Colorectal cancers (CRC) can be classified into four consensus molecular subtypes (CMS), among which CMS1 has the best prognosis, contrasting with CMS4 that has the worst outcome. CMS4 CRC is notoriously resistant against therapeutic interventions, as demonstrated by preclinical studies and retrospective clinical observations. Here, we report the finding that two clinically employed agents, everolimus (EVE) and plicamycin (PLI), efficiently target the prototypic CMS4 cell line MDST8. As compared to the prototypic CMS1 cell line LoVo, MDST8 cells treated with EVE or PLI demonstrated stronger cytostatic and cytotoxic effects, increased signs of apoptosis and autophagy, as well as a more pronounced inhibition of DNA-to-RNA transcription and RNA-to-protein translation. Moreover, nontoxic doses of EVE and PLI induced the shrinkage of MDST8 tumors in mice, yet had only minor tumor growth-reducing effects on LoVo tumors. Altogether, these results suggest that EVE and PLI should be evaluated for their clinical activity against CMS4 CRC.

Glucosylceramide synthase regulates hepatocyte repair after concanavalin A-induced immune-mediated liver injury.

BACKGROUND: Sphingolipids produce pleiotropic signaling pathways, and participate in the pathological mechanism of hepatocyte apoptosis and necrosis during liver injury. However, the role of glucosylceramide synthase (GCS)-key enzyme that catalyzes the first glycosylation step, in liver injury is still vague. METHODS: All experiments were conducted using 7-9-week-old pathogen-free male C57BL/6 mice. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected in murine models of liver disease, in addition to histological characterization of liver injuries. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative expression of the GCS, matrix metallopeptidase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) genes. The GCS was observed through a fluorescence microscope, and the flow cytometry was used to detect hepatocyte apoptosis. The concentrations of serum IL-4, IL-6, and IL-10 were measured using enzyme-linked immune-sorbent assay (ELISA) kit. MMP-1 and TIMP-1 protein expression was measured via western blot (WB) analysis. RESULTS: Con A is often used as a mitogen to activate T lymphocytes and promote mitosis. A single dose of Con A injected intravenously will cause a rapid increase of ALT and AST, which is accompanied by the release of cytokines that cause injury and necrosis of hepatocytes. In this study, we successfully induced acute immune hepatitis in mice by Con A. Con A administration resulted in GCS upregulation in liver tissues. Moreover, the mice in the Con A group had significantly higher levels of ALT, AST, IL-4, IL-6, IL-10 and increased hepatocyte apoptosis than the control group. In contrast, all of the aforementioned genes were significantly downregulated after the administration of a GCS siRNA or Genz-123346 (i.e., a glucosylceramide synthase inhibitor) to inhibit the GCS gene. Additionally, the histopathological changes observed herein were consistent with our ALT, AST, IL-4, IL-6, and IL-10 expression results. However, unlike this, hepatocyte apoptosis has been further increased on the basis of the Con A group. Moreover, our qRT-PCR and WB results indicated that the expression of MMP-1 in the Con A group was significantly lower than that in the control group, whereas TIMP-1 exhibited the opposite trend. Conversely, MMP-1 expression in the GCS siRNA and Genz-123346 groups was higher than that in the Con A group, whereas TIMP-1 expression was lower. CONCLUSIONS: GCS inhibition reduces Con A-induced immune-mediated liver injury in mice, which may be due to the involvement of GCS in the hepatocyte repair process after injury.

Biomechanical Role of Trabecular Microstructure on Peri-implant Strain Based on Micro-CT Finite Element Modeling of Aging Mice.

PURPOSE: To evaluate the influence of age and trabecular microstructure on peri-implant strain in aging and young mice models under compressive load. MATERIALS AND METHODS: Eighteen 4-week-old female C57BL/6 mice (n = 6) were subjected to a 1.2% calcium content diet (young normal calcium group), and 7-month-old mice (n = 12) were randomly subjected to 0.01% and 1.2% calcium content diets (aging low and normal calcium groups, respectively) for 3 weeks. Histomorphometric and microcomputed tomography (micro-CT) analyses were used to investigate local alveolar bone microstructure. One maxilla segment from each group was reconstructed using micro-CT images to highlight the trabecular microstructure. A finite element analysis based on a computational model of the maxilla segment was performed to investigate peri-implant strain. Implants with three different diameters (0.3, 0.4, and 0.5 mm) were analyzed in these models. RESULTS: The aging low calcium group showed worse cancellous microstructure in hematoxylin and eosin (HE) staining, significantly increased osteoclast numbers (P < .05), and reduced bone volume fraction and trabecular thickness compared with the aging normal calcium group (P < .05). However, the young normal calcium group presented no difference in trabecular microstructure and osteoclast numbers compared with the aging normal calcium group. The aging low calcium group demonstrated increased strain intensity compared with the aging normal calcium group, whereas the young normal calcium and aging normal calcium groups showed comparable strain magnitude. The strain intensity of peri-implant bone increased with worse cancellous microstructure. When the diameter increased from 0.3 mm to 0.4 mm, the percentages of pathologic overload decreased regardless of bone microstructure. CONCLUSION: Deteriorated bone microstructure induced by a low calcium diet determined higher strain intensity, whereas, whenever age had no significant effect on trabecular microstructure, consequently, there was no substantial influence on strain. An increase of implant diameters can improve the strain distribution. Clinical decision-making should take into consideration the patient-specific and site-specific trabecular microstructure in preoperative assessment.