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Calcium phosphate, particularly hydroxyapatite (HA), bears a close resemblance to human bones, rendering it a prevalent material in biomedical applications. This study focuses on the successful preparation of HA using a precipitation method with eggshell as a raw material. Subsequently, the HA powder was press-formed and sintered at various temperatures to investigate the impact of sintering temperature on the mechanical properties, including hardness, compressive strength, and fracture toughness, of the sintered HA samples (E-HA). Statistical analyses, including one-way ANOVA and Tukey's post-hoc test, were conducted to determine significant differences in these properties at different sintering temperatures. Experimental findings revealed that as the sintering temperature increased, HA partially transformed into β-TCP between 800 and 1300 °C, with α-TCP observed at 1400 °C. The elimination of pores led to an increase in relative density, with a maximum relative density of 94.5% achieved at 1200 and 1300 °C. E-HA sintered at 1200 °C exhibited the highest hardness (5.08 GPa), compressive strength (255.79 MPa), and fracture toughness (1.21 MPa·m0.5). However, at 1400 °C, a slight decrease in apparent density (2.90 g/cm 3 ) was noted due to the presence of α-TCP, along with significant grain growth. This study's objective is clearly aligned with the study design, incorporating detailed statistical analyses to validate the findings. Furthermore, bacterial culture experiments were conducted using sintered E-HA, Chem-HA (HA synthesized from reagent-grade calcium carbonate), and Comm-HA (commercial HA). Streptococcus mutans was cultured on the surfaces of sintered E-HA, Chem-HA, and Comm-HA samples for 20 h. After culturing, the OD values for all samples were below 0.2, indicating significant antibacterial efficacy. The comparable OD values and bacterial counts ( p > 0.05) suggest that the source of HA does not impact its antibacterial properties. This underscores the potential of eggshell-derived HA as an effective material for biomedical applications.

Metal implants require an elastic modulus close to cortical bone (<30 GPa) to avoid stress shielding and ensure adequate load-bearing strength. The metastable β-type Ti-25Nb-8Sn alloy has a low elastic modulus (52 GPa), but its yield strength (<500 MPa) needs enhancement. This study enhances Ti-25Nb-8Sn's elastic admissible strain through cold rolling and aging heat treatments, investigating the microstructure's impact on mechanical and corrosion properties. The results show that lower-temperature aging (<450 °C) leads to ω-phase precipitation, yielding a 300% increase in yield strength (>1900 MPa). However, this also increases the elastic modulus (~80 GPa), limiting the deformation ability. Higher-temperature aging (>500 °C) eliminates the ω phase, transforming it into α precipitates, resulting in a lower elastic modulus (~65 GPa) and improved deformation ability, with substantial yield strength (>1000 MPa). In summary, the optimal process conditions are determined as 90% cold rolling followed by aging treatment at 550 °C. Under these conditions, Ti-25Nb-8Sn achieves the most suitable yield strength (1207 MPa) and high corrosion resistance, retaining a relatively low elastic modulus (64.7 GPa) and high elastic admissible strain (1.93%). This positions it as an ideal material for biomedical implants.

In this study, a series of Ti-5Cr-xNb alloys with varying Nb content (ranging from 1 to 40 wt.%) were investigated to assess their suitability as implant materials. Comprehensive analyses were conducted, including phase analysis, microscopy examination, mechanical testing, and corrosion resistance evaluation. The results revealed significant structural alterations attributed to Nb addition, notably suppressing the formation of the ω phase and transitioning from α' + β + ω to single β phase structures. Moreover, the incorporation of Nb markedly improved the alloys' plastic deformation ability and reduced their elastic modulus. In particular, the Ti-5Cr-25Nb alloy demonstrated high values in corrosion potential and polarization resistance, signifying exceptional corrosion resistance. This alloy also displayed high bending strength (approximately 1500 MPa), a low elastic modulus (approximately 80 GPa), and outstanding elastic recovery and plastic deformation capabilities. These aggregate outcomes indicate the promising potential of the β-phase Ti-5Cr-25Nb alloy for applications in orthopedic and dental implants.

Background: a low PNI in patients with NPC is linked to poor survival, but prior studies have focused on single-timepoint measurements. Our study aims to employ joint modeling to analyze longitudinal PNI data from each routine visit, exploring its relationship with overall survival., Methods: In this retrospective study using data from the Chang Gung Research Database (2007-2019), we enrolled patients with NPC undergoing curative treatment. We analyzed the correlation between patient characteristics, including the PNI, and overall survival. A joint model combining a longitudinal sub-model with a time-to-event sub-model was used to further evaluate the prognostic value of longitudinal PNI., Results: A total of 2332 patient were enrolled for the analysis. Separate survival analyses showed that longitudinal PNI was an independent indicator of a reduced mortality risk (adjusted HR 0.813; 95% CI, 0.805 to 0.821). Joint modeling confirmed longitudinal PNI as a consistent predictor of survival (HR 0.864; 95% CI, 0.850 to 0.879). An ROC analysis revealed that a PNI below 38.1 significantly increased the risk of 90-day mortality, with 90.0% sensitivity and 89.6% specificity., Conclusions: Longitudinal PNI data independently predicted the overall survival in patients with NPC, significantly forecasting 90-day survival outcomes. We recommend routine PNI assessments during each clinic visit for these patients.

The aim of this study was to investigate the low-temperature degradation (LTD) kinetics of tetragonal zirconia with 3 mol% yttria (3Y-TZP) dental ceramic using two degradation methods: hydrothermal degradation and immersed degradation. To study transformation kinetics, we prepared 3Y-TZP powders. We pressed these powders uniaxially into a stainless mold at 100 MPa. We then sintered the compacted bodies at intervals of 50 °C between 1300 °C and 1550 °C and immersed the specimens at various temperatures from 60 °C to 80 °C in 4% acetic acid or from 110 °C to 140 °C for the hydrothermal method. We used a scanning electron microscope (SEM) to confirm crystalline grain size and used X-ray diffraction to analyze the zirconia phase. As the sintering temperature increased, the calculated crystalline grain size also increased. We confirmed this change with the SEM image. The higher sintering temperatures were associated with more phase transformation. According to the Mehl-Avrami-Johnson equation, the activation energies achieved using the hydrothermal method were 101 kJ/mol, 95 kJ/mol, and 86 kJ/mol at sintering temperatures of 1450 °C, 1500 °C, and 1550 °C, respectively. In addition, the activation energies of the specimens immersed in 4% acetic acid were 60 kJ/mol, 55 kJ/mol, 48 kJ/mol, and 35 kJ/mol, with sintered temperatures of 1400 °C, 1450 °C, 1500 °C, and 1550 °C, respectively. The results showed that a lower sintering temperature would restrain the phase transformation of zirconia because of the smaller crystalline grain size. As a result, the rate of LTD decreased.

Titanium-rich metastable medium-entropy alloys, designed for low elastic moduli, sacrifice strength. However, enhancing their mechanical strength is crucial for bio-implant applications. This study aims to enhance the mechanical properties and corrosion resistance of a metastable Ti 80 -Nb 10 -Mo 5 -Sn 5 medium-entropy alloy using various treatments, including cold rolling (at 50% and 75% reduction) and precipitation hardening (at room temperature, 150 °C, 350 °C, 550 °C, and 750 °C). The results showed that the alloy underwent a stress-induced martensitic transformation during the rolling process. Notably, the α phase was precipitated in the β grain boundaries after 30 days of precipitation hardening at room temperature. The yield strengths of the alloy increased by 51% and 281.9% after room-temperature precipitation and 75% cold rolling, respectively. In potentiodynamic corrosion tests conducted in phosphate-buffered saline solution, the pitting potentials of the alloy treated using various conditions were higher than 1.8 V, and no pitting holes were observed on the surface of the alloys. The surface oxide layer of the alloy was primarily composed of TiO 2 , Nb 2 O 5 , MoO 3 , and SnO 2 , contributing to the alloy's exceptional corrosion and pitting resistance. The 75% rolled Ti 80 -Nb 10 -Mo 5 -Sn 5 demonstrates exceptional mechanical properties and high corrosion resistance, positioning it as a promising bio-implant candidate.

β-Ti alloys have long been investigated and applied in the biomedical field due to their exceptional mechanical properties, ductility, and corrosion resistance. Metastable β-Ti alloys have garnered interest in the realm of biomaterials owing to their notably low elastic modulus. Nevertheless, the inherent correlation between a low elastic modulus and relatively reduced strength persists, even in the case of metastable β-Ti alloys. Enhancing the strength of alloys contributes to improving their fatigue resistance, thereby preventing an implant material from failure in clinical usage. Recently, a series of biomedical high-entropy and medium-entropy alloys, composed of biocompatible elements such as Ti, Zr, Nb, Ta, and Mo, have been developed. Leveraging the contributions of the four core effects of high-entropy alloys, both biomedical high-entropy and medium-entropy alloys exhibit excellent mechanical strength, corrosion resistance, and biocompatibility, albeit accompanied by an elevated elastic modulus. To satisfy the demands of biomedical implants, researchers have sought to synthesize the strengths of high-entropy alloys and metastable β-Ti alloys, culminating in the development of metastable high-entropy/medium-entropy alloys that manifest both high strength and a low elastic modulus. Consequently, the design principles for new-generation biomedical medium-entropy alloys and conventional metastable β-Ti alloys can be converged. This review focuses on the design from β-Ti alloys to the novel metastable medium-entropy alloys for biomedical applications.

Urothelial cancer, a common urinary system malignancy, often presents treatment challenges due to metastasis and chemotherapy side effects. Angiogenesis, crucial for tumor growth, has become a target for drug development. This study explores the expression, prognostic value, and clinical correlation of RHOJ in the TCGA BLCA, GSE31684, and GSE32894 datasets. We identify common differentially expressed genes across these databases and utilize g:Profiler and Cytoscape ClueGO for functional assessment. Further, we perform a gene set enrichment analysis (GSEA) using Hallmark gene sets and use the imsig package for immune cell infiltration analysis. Our analysis indicates that RHOJ expression levels significantly impact survival rates, tumor progression, and immune response in urothelial tumors. High RHOJ expression correlated with poor prognosis, advanced disease stages, and an increase in monocyte population within the tumor microenvironment. This aligns with current literature indicating a key role of immune infiltration in bladder cancer progression and treatment response. Moreover, the GSEA and imsig results further suggest a potential mechanistic link between RHOJ expression and immune-related pathways. Considering the increasing emphasis on immunotherapeutic strategies in bladder cancer management, our findings on RHOJ 's potential as a diagnostic biomarker and its association with immune response open new avenues for therapeutic interventions.

Osteoarthritis (OA) is the most common age-related degenerative joint disease. Inflammaging, linking inflammation and aging, is found in senescent cells with the secretions of matrix-degrading proteins and proinflammatory cytokines. The senescence-associated secretory phenotype (SASP) plays a very important role in OA progression. However, there remains no effective way to suppress OA progression, especially by suppressing inflammaging and/or the chondrocyte SASP. Recent studies have shown that exosomes derived from hypoxia-cultured BMSCs can regenerate cartilage in OA animal models. Some reports have further indicated that exosomes secreted from MSCs contribute to the efficacy of MSC therapy in OA. However, whether hypoxia-cultured ADSC-secreted exosomes (hypoxia-ADSC-Exos) can alleviate the chondrocyte SASP or OA progression remains unclear. Accordingly, we hypothesized that hypoxia-ADSC-Exos have a beneficial effect on the normal functions of human articular chondrocytes (HACs), can attenuate the SASP of OA-like HACs in vitro, and further suppress OA progression in rats. Hypoxia-ADSC-Exos were derived from ADSCs cultured in 1% O 2 and 10% de-Exo-FBS for 48 h. The molecular and cell biological effects of hypoxia-ADSC-Exos were tested on IL1-β-induced HACs as OA-like HACs in vitro, and the efficacy of OA treatment was tested in ACLT-induced OA rats. The results showed that hypoxia-ADSC-Exos had the best effect on GAG formation in normal HACs rather than those cultured in normoxia or hypoxia plus 2% de-Exo-FBS. We further found that hypoxia-ADSC-Exos alleviated the harmful effect in OA-like HACs by decreasing markers of normal cartilage (GAG and type II collagen) and increasing markers of fibrous or degenerative cartilage (type I or X collagen), matrix degradation enzymes (MMP13 and ADAMT5), and inflammatory cytokines (TNFα and IL-6). More importantly, intra-articular treatment with hypoxia-ADSC-Exos suppressed OA progression, as evidenced by the weight-bearing function test and cartilage GAG quantification in ACLT rats. Moreover, through NGS and bioinformatic analysis, seven potential miRNAs were found in hypoxia-ADSC-Exos, which may contribute to regulating cellular oxidative stress and attenuating cell senescence. In summary, we demonstrated that hypoxia-ADSC-Exos, carrying potent miRNAs, not only improve normal HAC function but also alleviate HAC inflammaging and OA progression. The results suggest that hypoxia-ADSC-Exo treatment may offer another strategy for future OA therapy.

Hydroxyapatite (HA) is a major component of the inorganic minerals in the hard tissues of humans and has been widely used as a biomedical ceramic material in orthopedic and dentistry applications. Because human bone contains several impurities, including carbonates, chlorides, fluorides, magnesium, and strontium, human bone minerals differ from stoichiometric HA. Additionally, natural bone is composed of nano-sized HA, and the nanoscale particles exhibit a high level of biological activity. In this paper, HA is prepared via the hydrothermal process because its reaction conditions are easy to control and it has been shown to be quite feasible for large-scale production. Therefore, the hydrothermal process is an effective and convenient method for the preparation of HA. Furthermore, eggshell is adopted as a source of calcium, and mulberry leaf extract is selectively added to synthesize HA. The eggshell accounts for 11% of the total weight of a whole egg, and it consists of calcium carbonate, calcium phosphate, magnesium carbonate, and organic matter. Eggshell contains a variety of trace elements, such as magnesium and strontium, making the composition of the synthesized HA similar to that of the human skeleton. These trace elements exert considerable benefits for bone growth. Moreover, the use of eggshell as a raw material can permit the recycling of biowaste and a reduction in process costs. The purpose of this study is to prepare HA powder via the hydrothermal method and to explore the effects of hydrothermal conditions on the structure and properties of the synthesized HA. The room-temperature precipitation method is used for the control group. Furthermore, the results of an immersion test in simulated body fluid confirm that the as-prepared HA exhibits good apatite-forming bioactivity, which is an essential requirement for artificial materials to bond to living bones in the living body and promote bone regeneration. In particular, it is confirmed that the HA synthesized with the addition of the mulberry leaf extract exhibits good in vitro biocompatibility. The morphology, crystallite size, and composition of the carbonated nano-HA obtained herein are similar to those of natural bones. The carbonated nano-HA appears to be an excellent material for bioresorbable bone substitutes or drug delivery. Therefore, the nano-HA powder prepared in this study has great potential in biomedical applications.

Patients with advanced esophageal squamous cell carcinoma (SCC) have a poor prognosis when treated with standard chemotherapy. Programmed death ligand 1 (PD-L1) expression in esophageal cancer has been associated with poor survival and more advanced stage. Immune checkpoint inhibitors, such as PD-1 inhibitors, showed benefits in advanced esophageal cancer in clinical trials. We analyzed the prognosis of patients with unresectable esophageal SCC who received nivolumab with chemotherapy, dual immunotherapy (nivolumab and ipilimumab), or chemotherapy with or without radiotherapy. Patients who received nivolumab with chemotherapy had a better overall response rate (ORR) (72% vs. 66.67%, p = 0.038) and longer overall survival (OS) (median OS: 609 days vs. 392 days, p = 0.04) than those who received chemotherapy with or without radiotherapy. In patients receiving nivolumab with chemotherapy, the duration of the treatment response was similar regardless of the treatment line they received. According to clinical parameters, liver and distant lymph nodes metastasis showed a trend of negative and positive impacts, respectively, on treatment response in the whole cohort and in the immunotherapy-containing regimen cohort. Nivolumab add-on treatment showed less gastrointestinal and hematological adverse effects, compare with chemotherapy. Here, we showed that nivolumab combined with chemotherapy is a better choice for patients with unresectable esophageal SCC.

In the case of small-cell lung carcinoma, the highly metastatic nature of the disease and the propensity for several chromatin modifiers to harbor mutations suggest that epigenetic manipulation may also be a promising route for oncotherapy, but histone deacetylase inhibitors on their own do not appear to be particularly effective, suggesting that there may be other regulatory parameters that dictate the effectiveness of vorinostat's reversal of histone deacetylation. Recent discoveries that serotonylation of histone H3 alters the permissibility of gene expression have led to renewed attention to this rare modification, as facilitated by transglutaminase 2, and at the same time introduce new questions about whether this modification belongs to a part of the concerted cohort of regulator events for modulating the epigenetic landscape. This review explores the mechanistic details behind protein serotonylation and its possible connections to the epigenome via histone modifications and glycan interactions and attempts to elucidate the role of transglutaminase 2, such that optimizations to existing histone deacetylase inhibitor designs or combination therapies may be devised for lung and other types of cancer.

Titanium and titanium alloys are widely used in medical devices and implants; thus, the biocompatibility of these metals is of great importance. In this study, glioblastoma astrocytoma cellular responses to Ti 65 -Zr 18 -Nb 16 -Mo 1 (Ti65M, metastable medium-entropy alloy), Ti-13Nb-7Sn-4Mo (TNSM, titanium alloy), and commercially pure titanium (CP-Ti) were studied. Several physical parameters (crystal phase structure, surface roughness and hardness) of the titanium alloys were measured, and the correlation with the cellular viability was investigated. Finally, the relative protein expression in cellular proliferation pathways was measured and compared with mRNA expression assessed with quantitative real-time reverse transcription polymerase chain reaction assay (qRT-PCR).

Five Ti-rich β+α″+α′ Ti−Zr−Nb−Ta biomedical medium-entropy alloys with excellent mechanical properties and corrosion resistance were developed by considering thermodynamic parameters and using the valence electron concentration formula. The results of this study demonstrated that the traditional valence electron concentration formula for predicting phases is not entirely applicable to medium-entropy alloys. All solution-treated samples with homogeneous compositions were obtained at a low temperature (900 °C) and within a short period (20 min). All solution-treated samples exhibited low elastic moduli ranging from 49 to 57 GPa, which were significantly lower than those of high-entropy alloys with β phase. Solution-treated Ti65−Zr29−Nb3−Ta3 exhibited an ultra-high bending strength (1102 MPa), an elastic recovery angle (>30°), and an ultra-low elastic modulus (49 GPa), which are attributed to its α″ volume fraction as high as more than 60%. The pitting potentials of all samples were higher than 1.8 V, and their corrosion current densities were lower than 10−5 A/cm3 in artificially simulated body fluid at 37 °C. The surface oxide layers on Ti65−Zr29−Nb3−Ta3 comprised TiO2, ZrO2, Nb2O5, and Ta2O5 (as discovered through X-ray photoelectron spectroscopy) and provided the alloy with excellent corrosion and pitting resistance.

Osteoarthritis (OA) is one of the most common diseases leading to physical disability, with age being the main risk factor, and degeneration of articular cartilage is the main focus for the pathogenesis of OA. Autophagy is a crucial intracellular homeostasis system recycling flawed macromolecules and cellular organelles to sustain the metabolism of cells. Growing evidences have revealed that autophagy is chondroprotective by regulating apoptosis and repairing the function of damaged chondrocytes. Then, OA is related to autophagy depending on different stages and models. In this review, we discuss the character of autophagy in OA and the process of the autophagy pathway, which can be modulated by some drugs, key molecules and non-coding RNAs (microRNAs, long non-coding RNAs and circular RNAs). More in-depth investigations of autophagy are needed to find therapeutic targets or diagnostic biomarkers through in vitro and in vivo situations, making autophagy a more effective way for OA treatment in the future. The aim of this review is to introduce the concept of autophagy and make readers realize its impact on OA. The database we searched in is PubMed and we used the keywords listed below to find appropriate article resources.

State-of-charge (SOC) is a relative quantity that describes the ratio of the remaining capacity to the present maximum available capacity. Accurate SOC estimation is essential for a battery-management system. In addition to informing the user of the expected usage until the next recharge, it is crucial for improving the utilization efficiency and service life of the battery. This study focuses on applying deep-learning techniques, and specifically convolutional residual networks, to estimate the SOC of lithium-ion batteries. By stacking the values of multiple measurable variables taken at many time instants as the model inputs, the process information for the voltage or current generation, and their interrelations, can be effectively extracted using the proposed convolutional residual blocks, and can simultaneously be exploited to regress for accurate SOCs. The performance of the proposed network model was evaluated using the data obtained from a lithium-ion battery (Panasonic NCR18650PF) under nine different driving schedules at five ambient temperatures. The experimental results demonstrated an average mean absolute error of 1.260%, and an average root-mean-square error of 0.998%. The number of floating-point operations required to complete one SOC estimation was 2.24 × 10 6 . These results indicate the efficacy and performance of the proposed approach.

Purpose: To investigate the clinical characteristics, risk factors, and clinical outcomes of long-latent recurrence (>five years) of nasopharyngeal carcinoma (NPC). Methods: This retrospective study enrolled newly diagnosed NPC patients from the Chang Gung Research Database between January 2007 and December 2019. We analyzed the patients’ characteristics and survival outcomes after recurrence. Results: A total of 2599 NPC patients were enrolled. The overall recurrence rate was 20.5%, while 8.1% of patients had long-latent recurrence (>five years). These patients had a higher percentage of initial AJCC (The American Joint Committee on Cancer) stage I/II (60.5%, p = 0.001) and local recurrence (46.5%, p < 0.001). Unresectable rT3 and rT4 were found in 60% of patients when recurrence and 30% of local recurrence occurred in the skull base, which could not be detected by the regular endoscopy. The five-year overall survival rate of long-latent recurrence was 19.7%. Alive patients tended to be asymptomatic but have regular follow-ups with the interval less than six months. Multivariate analysis showed age and initial advanced AJCC stages were independent risk factors of death after recurrence. In contrast, patients with recurrence between two and five years, salvage surgeries, and regional recurrence had favorable survival outcomes. Conclusion: Long-latent NPC recurrence is not rare, and the survival outcome is poor. Regular follow-up for early detection of NPC recurrence is necessary even after five years of disease-free period.

The use of rocuronium/sugammadex in otorhinolaryngologic surgery improves intubation conditions and surgical rating scales. This study primarily aimed to evaluate the effect of the combination of rocuronium and sugammadex on intraoperative anesthetic consumption. The secondary outcomes were the intraoperative and postoperative morphine milligram equivalent (MME) consumption, duration of intraoperative hypertension, extubation time, incidence of delayed extubation and postoperative nausea and vomiting, pain score, and length of stay. A total of 2848 patients underwent otorhinolaryngologic surgery at a tertiary medical center in southern Taiwan. After applying the exclusion criteria, 2648 of these cases were included, with 167 and 2481 in the rocuronium/sugammadex and cisatracurium/neostigmine groups, respectively. To reduce potential bias, 119 patients in each group were matched by propensity scores for sex, age, body weight, and type of surgery. We found that the rocuronium/sugammadex group was associated with significant preservation of the intraoperative sevoflurane and MME consumption, with reductions of 14.2% ( p = 0.009) and 11.8% ( p = 0.035), respectively. The use of the combination of rocuronium and sugammadex also significantly increased the dose of intraoperative labetalol ( p = 0.002), although there was no significant difference in intraoperative hypertensive events between both groups. In conclusion, our results may encourage the use of the combination of rocuronium and sugammadex as part of volatile-sparing and opioid-sparing anesthesia in otorhinolaryngologic surgery.

Background: Neurological deficits following subarachnoid hemorrhage (SAH) are caused by early or delayed brain injuries. Our previous studies have demonstrated that hyperglycemia induces profound neuronal apoptosis of the cerebral cortex. Morphologically, we found that hyperglycemia exacerbated late vasospasm following SAH. Thus, our previous studies strongly suggest that post-SAH hyperglycemia is not only a response to primary insult, but also an aggravating factor for brain injuries. In addition, mitochondrial fusion and fission are vital to maintaining cellular functions. Current evidence also shows that the suppression of mitochondrial fission alleviates brain injuries after experimental SAH. Hence, this study aimed to determine the effects of mitochondrial dynamic modulation in hyperglycemia-related worse SAH neurological prognosis. Materials and methods: In vitro, we employed an enzyme-linked immunosorbent assay (ELISA) to detect the effect of mitochondrial division inhibitor-1 (Mdivi-1) on lipopolysaccharide (LPS)-induced BV-2 cells releasing inflammatory factors. In vivo, we produced hyperglycemic rats via intraperitoneal streptozotocin (STZ) injections. Hyperglycemia was confirmed using blood-glucose measurements (>300 mg/dL) 7 days after the STZ injection. The rodent model of SAH, in which fresh blood was instilled into the craniocervical junction, was used 7 days after STZ administration. We investigated the mechanism and effect of Mdivi-1, a selective inhibitor of dynamin-related protein (Drp1) to downregulate mitochondrial fission, on SAH-induced apoptosis in a hyperglycemic state, and evaluated the results in a dose−response manner. The rats were divided into the following five groups: (1) control, (2) SAH only, (3) Diabetes mellitus (DM) + SAH, (4) Mdivi-1 (0.24 mg/kg) + DM + SAH, and (5) Mdivi-1 (1.2 mg/kg) + DM + SAH. Results: In vitro, ELISA revealed that Mdivi-1 inhibited microglia from releasing inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. In vivo, neurological outcomes in the high-dose (1.2 mg/kg) Mdivi-1 treatment group were significantly reduced compared with the SAH and DM + SAH groups. Furthermore, immunofluorescence staining and ELISA revealed that a high dose of Mdivi-1 had attenuated inflammation and neuron cell apoptosis by inhibiting Hyperglycemia-aggravated activation, as well as microglia and astrocyte proliferation, following SAH. Conclusion: Mdivi-1, a Drp-1 inhibitor, attenuates cerebral vasospasm, poor neurological outcomes, inflammation, and neuron cell apoptosis following SAH + hyperglycemia.

Hemagglutinin (HA) and neuraminidase (NA) are the two major envelope proteins of influenza viruses. The spatial organization of HA and NA on the virus surface needs to be optimized to promote viral fitness, host specificity, transmissibility, infectivity, and virulence. We previously demonstrated that the recombinant NA protein of the 2009 pandemic H1N1 (pH1N1) with the I365T/S366N mutation in the NA 370-loop elicited higher NA-inhibition antibody titers against the homologous pH1N1 virus and three heterologous H5N1, H3N2, and H7N9 viruses in mice. In this study, we used PR8-based reverse genetics (RG) by replacing the HA and NA genes of A/Texas/05/2009 pH1N1 virus to obtain the wild-type pH1N1 and three NA 370-loop mutant viruses of pH1N1 (I365T/S366N), RG pH1N1 (I365E/S366D), and RG pH1N1 (I365T/S366A). Our results revealed that the viral NA enzyme activity increased for the RG pH1N1(I365T/S366N) and RG pH1N1 (I365E/S366D) viruses but reduced for the RG pH1N1 (I365T/S366A) virus. The increased or decreased NA enzyme activity was found to correlate with the increase or decrease in HA titers of these NA 370-loop mutant viruses. All of these three NA 370-loop mutant RG pH1N1 viruses were less virulent than the wild-type RG pH1N1 virus in mice. Immunizations with the inactivated viruses carrying the three NA 370-loop mutations and the wild-type RG pH1N1 virus were found to elicit approximately the same titers of NA-inhibition antibodies against H1N1 and H5N1 viruses. These results may provide information for developing NA-based influenza virus vaccines.

Developing a biomaterial suitable for adipose-derived stem cell (ADSCs)-laden scaffolds that can directly bond to cartilage tissue surfaces in tissue engineering has still been a significant challenge. The bioinspired hybrid hydrogel approaches based on hyaluronic acid methacryloyl (HAMA) and gelatin methacryloyl (GelMA) appear to have more promise. Herein, we report the cartilage tissue engineering application of a novel photocured hybrid hydrogel system comprising HAMA, GelMA, and 0~1.0% ( w / v ) acrylate-functionalized nano-silica (AFnSi) crosslinker, in addition to describing the preparation of related HAMA, GelMA, and AFnSi materials and confirming their related chemical evidence. The study also examines the physicochemical characteristics of these hybrid hydrogels, including swelling behavior, morphological conformation, mechanical properties, and biodegradation. To further investigate cell viability and chondrogenic differentiation, the hADSCs were loaded with a two-to-one ratio of the HAMA-GelMA (HG) hybrid hydrogel with 0~1.0% ( w / v ) AFnSi crosslinker to examine the process of optimal chondrogenic development. Results showed that the morphological microstructure, mechanical properties, and longer degradation time of the HG+0.5% ( w / v ) AFnSi hydrogel demonstrated the acellular novel matrix was optimal to support hADSCs differentiation. In other words, the in vitro experimental results showed that hADSCs laden in the photocured hybrid hydrogel of HG+0.5% ( w / v ) AFnSi not only significantly increased chondrogenic marker gene expressions such as SOX-9, aggrecan, and type II collagen expression compared to the HA and HG groups, but also enhanced the expression of sulfated glycosaminoglycan (sGAG) and type II collagen formation. We have concluded that the photocured hybrid hydrogel of HG+0.5% ( w / v ) AFnSi will provide a suitable environment for articular cartilage tissue engineering applications.

Zika virus (ZIKV) infections in humans are mainly transmitted by the mosquito vectors, but human-to-human sexual transmission is also another important route. Developing a ZIKV mucosal vaccine that can elicit both systemic and mucosal immune responses is of particular interest. In this study, we constructed a recombinant ZIKV envelope DIII (ZDIII) protein genetically fused with Salmonella typhimurium flagellin (FliC-ZDIII) as a novel mucosal antigen for intranasal immunization. The results indicated that the FliC-ZDIII fusion proteins formulated with E. coli heat-labile enterotoxin B subunit (LTIIb-B5) adjuvant greatly increased the ZDIII-specific IgG, IgA, and neutralizing titers in sera, and the ZDIII-specific IgA titers in bronchoalveolar lavage and vaginal fluids. Protective immunity was further assessed by subcutaneous and intravaginal ZIKV challenges. The second-generation FliCΔD3-2ZDIII was shown to result in a reduced titer of anti-FliC IgG antibodies in sera and still retained the same levels of serum IgG, IgA, and neutralizing antibodies and mucosal IgA antibodies without compromising the vaccine antigenicity. Therefore, intranasal immunization with FliCΔD3-2ZDIII fusion proteins formulated with LTIIb-B5 adjuvant elicited the greatest protective immunity against subcutaneous and intravaginal ZIKV challenges. Our findings indicated that the combination of FliCΔD3-2ZDIII fusion proteins and LTIIb-B5 adjuvant for intranasal immunization can be used for developing ZIKV mucosal vaccines.

During the sustained COVID-19 pandemic, global mass vaccination to achieve herd immunity can prevent further viral spread and mutation. A protein subunit vaccine that is safe, effective, stable, has few storage restrictions, and involves a liable manufacturing process would be advantageous to distribute around the world. Here, we designed and produced a recombinant spike (S)-Trimer that is maintained in a prefusion state and exhibits a high ACE2 binding affinity. Rodents received different doses of S-Trimer (0.5, 5, or 20 μg) antigen formulated with aluminum hydroxide (Alum) or an emulsion-type adjuvant (SWE), or no adjuvant. After two vaccinations, the antibody response, T-cell responses, and number of follicular helper T-cells (Tfh) or germinal center (GC) B cells were assessed in mice; the protective efficacy was evaluated on a Syrian hamster infection model. The mouse studies demonstrated that adjuvating the S-Trimer with SWE induced a potent humoral immune response and Th1-biased cellular immune responses (in low dose) that were superior to those induced by Alum. In the Syrian hamster studies, when S-Trimer was adjuvanted with SWE, higher levels of neutralizing antibodies were induced against live SARS-CoV-2 from the original lineage and against the emergence of variants (Beta or Delta) with a slightly decreased potency. In addition, the SWE adjuvant demonstrated a dose-sparing effect; thus, a lower dose of S-Trimer as an antigen (0.5 μg) can induce comparable antisera and provide complete protection from viral infection. These data support the utility of SWE as an adjuvant to enhance the immunogenicity of the S-Trimer vaccine, which is feasible for further clinical testing.

Increasing clinical evidence supports the use of direct oral anticoagulants (DOACs) as a potential new therapeutic option for patients suffering from cancer-associated thromboembolism. However, the clinical impact of DOACs compared with traditional anticoagulants on the survival of patients with head and neck cancer has not been well studied. A total of 1025 patients diagnosed as having head and neck cancer, including 92 DOAC users, 113 warfarin users, and 820 nonusers of anticoagulants, were selected from the Chang Gung Research Database between January 2001 and December 2019. The patients were matched using the propensity-score method. The survival rates were estimated among the three groups using the Kaplan-Meier method. The protective effects and side effects of the two anticoagulants were compared using the chi-square test. The death rate (18 patients, 19.57%) in patients using DOACs was significantly lower than that in patients using warfarin (68 patients, 60.18%) and those not using any anticoagulant (403 patients, 49.15%). DOAC users had significantly better disease-specific survival (DSS) than warfarin users ( p = 0.019) and those who did not use any anticoagulant ( p = 0.03). Further, DOAC users had significantly higher overall survival (OS) rates than warfarin users and those who did not use any anticoagulant ( p = 0.003). Patients with oropharyngeal and laryngeal cancer and DOAC users had a significantly lower hazard ratio for survival, whereas patients with American Joint Committee on Cancer stage IV disease and those receiving multidisciplinary treatment (e.g., surgery with radiotherapy or concurrent radiochemotherapy) had a significantly higher hazard ratio for survival. Among them, patients with laryngeal cancer (HR = 0.47, 95% CI = 0.26-0.86, p = 0.0134) and DOAC users (HR = 0.53, 95% CI = 0.29-0.98, p = 0.042) had the lowest hazard ratio from DSS analysis. Similarly, patients with laryngeal cancer (HR = 0.48, 95% CI = 0.30-0.76, p = 0.0018) and DOAC users (HR = 0.58, 95% CI = 0.36-0.93, p = 0.0251) had the lowest hazard ratio from OS analysis. As for the protective effects or side effects of anticoagulants, there were no significant differences in the occurrence rate of bleeding or ischemic events between DOAC and warfarin users. In our study, DOACs were found to be better than warfarin in terms of survival in patients with head and neck cancer. As regards thromboembolism prevention and side effects, DOACs were comparable to warfarin in our patients. DOACs can be a treatment choice or prophylaxis for tumor emboli in head and neck cancer patients and they might be a better choice than traditional anticoagulants according to the results of our study.

Cancer/testis (CT) antigens exhibit selective expression predominantly in immunoprivileged tissues in non-pathological contexts but are aberrantly expressed in diverse cancers. Due to their expression pattern, they have historically been attractive targets for immunotherapies. A growing number of studies implicate CT antigens in almost all hallmarks of cancer, suggesting that they may act as cancer drivers. CT antigens are expressed in head and neck squamous cell carcinomas. However, their role in the pathogenesis of these cancers remains poorly studied. Given that CT antigens hold intriguing potential as therapeutic targets and as biomarkers for prognosis and that they can provide novel insights into oncogenic mechanisms, their further study in the context of head and squamous cell carcinoma is warranted.

Paracrine factors of human mesenchymal stem cells (hMSCs) have the potential of preventing adverse cardiac remodeling after myocardial infarction (MI). S100A8 and S100A9 are calcium-binding proteins playing essential roles in the regulation of inflammation and fibrous tissue formation, and they might modulate the paracrine effect of hMSCs. We isolated human amniotic mesenchymal stem cells (hAMSCs) and examined the changes in the expression level of regulatory genes of inflammation and fibrosis after hAMSCs were treated with S100A8/A9. The anti-inflammatory and anti-fibrotic effects of hAMSCs pretreated with S100A8/A9 were shown to be superior to those of hAMSCs without S100A8/A9 pretreatment in the cardiomyocyte hypoxia/reoxygenation experiment. We established a murine myocardial ischemia/reperfusion model to compare the therapeutic effects of the conditioned medium of hAMSCs with or without S100A8/A9 pretreatment. We found the hearts administered with a conditioned medium of hAMSCs with S100A8/A9 pretreatment had better left ventricular systolic function on day 7, 14, and 28 after MI. These results suggest S100A8/A9 enhances the paracrine therapeutic effects of hAMSCs in aspects of anti-inflammation, anti-fibrosis, and cardiac function preservation after MI.

The delayed healing response of diabetic wounds is a major challenge for treatment. Negative pressure wound therapy (NPWT) has been widely used to treat chronic wounds. However, it usually requires a long treatment time and results in directional growth of wound healing skin tissue. We investigated whether nonthermal microplasma (MP) treatment can promote the healing of skin wounds in diabetic mice. Splint excision wounds were created on diabetic mice, and various wound healing parameters were compared among MP treatment, NPWT, and control groups. Quantitative analysis of the re-epithelialization percentage by detecting Ki67 and DSG1 expression in the extending epidermal tongue (EET) of the wound area and the epidermal proliferation index (EPI) was subsequently performed. Both treatments promoted wound healing by enhancing wound closure kinetics and wound bed blood flow; this was confirmed through histological analysis and optical coherence tomography. Both treatments also increased Ki67 and DSG1 expression in the EET of the wound area and the EPI to enhance re-epithelialization. Increased Smad2/3/4 mRNA expression was observed in the epidermis layer of wounds, particularly after MP treatment. The results suggest that the Smad-dependent transforming growth factor β signaling contributes to the enhancement of re-epithelialization after MP treatment with an appropriate exposure time. Overall, a short-term MP treatment (applied for 30 s twice a day) demonstrated comparable or better efficacy to conventional NPWT (applied for 4 h once a day) in promoting wound healing in diabetic mice. Thus, MP treatment exhibits promise for treating diabetic wounds clinically.

Macrophages emerge in the milieu around innervated neurons after nerve injuries. Following nerve injury, autophagy is induced in macrophages and affects the regulation of inflammatory responses. It is closely linked to neuroinflammation, while the immunosuppressive drug tacrolimus (FK506) enhances nerve regeneration following nerve crush injury and nerve allotransplantation with additional neuroprotective and neurotrophic functions. The combined use of FK506 and adipose-derived stem cells (ADSCs) was employed in cell therapy for organ transplantation and vascularized composite allotransplantation. This study aimed to investigate the topical application of exosomes secreted by ADSCs following FK506 treatment (ADSC-F-exo) to the injured nerve in a mouse model of sciatic nerve crush injury. Furthermore, isobaric tags for relative and absolute quantitation (iTRAQ) were used to profile the potential exosomal proteins involved in autophagy. Immunohistochemical analysis revealed that nerve crush injuries significantly induced autophagy in the dorsal root ganglia and dorsal horn of the spinal segments. Locally applied ADSC-F-exo significantly reduced autophagy of macrophages in the spinal segments after nerve crush injury. Proteomic analysis showed that of the 22 abundant exosomal proteins detected in ADSC-F-exo, heat shock protein family A member 8 (HSPA8) and eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) are involved in exosome-mediated autophagy reduction.

Oyster shells are rich in calcium, and thus, the potential use of waste shells is in the production of calcium phosphate (CaP) minerals for osteopathic biomedical applications, such as scaffolds for bone regeneration. Implanted scaffolds should stimulate the differentiation of induced pluripotent stem cells (iPSCs) into osteoblasts. In this study, oyster shells were used to produce nano-grade hydroxyapatite (HA) powder by the liquid-phase precipitation. Then, biphasic CaP (BCP) bioceramics with two different phase ratios were obtained by the foaming of HA nanopowders and sintering by two different two-stage heat treatment processes. The different sintering conditions yielded differences in structure and morphology of the BCPs, as determined by scanning electron microscopy (SEM), X-ray diffraction (XRD), and Brunauer-Emmett-Teller (BET) surface area analysis. We then set out to determine which of these materials were most biocompatible, by co-culturing with iPSCs and examining the gene expression in molecular pathways involved in self-renewal and differentiation of iPSCs. We found that sintering for a shorter time at higher temperatures gave higher expression levels of markers for proliferation and (early) differentiation of the osteoblast. The differences in biocompatibility may be related to a more hierarchical pore structure (micropores within macropores) obtained with briefer, high-temperature sintering.

Hepatocellular carcinoma (HCC) is the most common cause of primary liver cancer deaths worldwide. The major risk factors for liver cancer development are cirrhosis, hepatitis B virus (HBV), hepatitis C virus (HCV) infection, and chronic alcohol abuse. HCC displays heterogeneity in terms of biology, etiology, and epidemiology. In Southeast Asia and Africa, chronic HBV infection is a major risk factor for HCC, whereas chronic HCV infection is a risk factor for HCC in western countries and Japan. Environmental and genetic conditions also play a role in the regional and temporal variations in the incidence of HCC. In this study, we used the ESTIMATE (ESTIMATE, Estimation of stromal and immune cells in malignant tumor tissues using expression data) algorithm and the CIBERSOFT tool to analyze gene expression profiles and infiltrating immune cells in HCC between Asian and non-Asian patients. The results showed that stromal and immune scores were dependent on overall survival (OS) in non-Asian patients but not in Asian patients. Kaplan-Meier survival analysis revealed four differentially expressed genes (DEGs) that were significantly associated with OS in non-Asian patients only. CIBERSORT (CIBERSORT, Cell type identification by estimating relative subsets of known RNA transcripts) analysis indicated that the composition of infiltrating immune cells was significantly different between Asian and non-Asian patients. By parsing the subclasses of HCC, the ability to predict prognosis and guide therapeutic targets for potentially actionable HCC may be improved.

Exosomes secreted by adipose-derived stem cells (ADSCs) enhance angiogenesis and wound healing. However, in clinical settings, wounds may be infected by various bacteria or pathogens. We investigated whether human ADSCs stimulated with lipopolysaccharide (LPS) secrete exosomes (ADSC-LPS-exo) that augment the angiogenesis of human umbilical vein endothelial cells (HUVECs). ExoQuick-TC exosome precipitation solution was used to purify exosomes from human ADSC culture media in the presence or absence of 1 µg/mL LPS treatment for 24 h. The uptake of ADSC-LPS-exo significantly induced the activation of cAMP response element binding protein (CREB), activating protein 1 (AP-1), and nuclear factor-κB (NF-κB) signaling pathways and increased the migration of and tube formation in HUVECs. RNA interference with CREB, AP-1, or NF-κB1 significantly reduced the migration of and tube formation in HUVECs treated with ADSC-LPS-exo. An experiment with an antibody array for 25 angiogenesis-related proteins revealed that only interleukin-8 expression was significantly upregulated in HUVECs treated with ADSC-LPS-exo. In addition, proteomic analysis revealed that eukaryotic translation initiation factor 4E, amyloid beta A4 protein, integrin beta-1, and ras-related C3 botulinum toxin substrate 1 may be potential candidates involved in ADSC-LPS-exo-mediated enhanced angiogenesis.

Exosomes secreted by adipose-derived stem cells (ADSC-exo) reportedly improve nerve regeneration after peripheral nerve injury. Herein, we investigated whether pretreatment of ADSCs with FK506, an immunosuppressive drug that enhances nerve regeneration, could secret exosomes (ADSC-F-exo) that further augment nerve regeneration. Designed exosomes were topically applied to injured nerve in a mouse model of sciatic nerve crush injury to assess the nerve regeneration efficacy. Outcomes were determined by histomorphometric analysis of semi-thin nerve sections stained with toluidine blue, mouse neurogenesis PCR array, and neurotrophin expression in distal nerve segments. Isobaric tags for relative and absolute quantitation (iTRAQ) were used to profile potential exosomal proteins facilitating nerve regeneration. We observed that locally applied ADSC-exo and ADSC-F-exo significantly enhanced nerve regeneration after nerve crush injury. Pretreatment of ADSCs with FK506 failed to produce exosomes possessing more potent molecules for enhanced nerve regeneration. Proteomic analysis revealed that of 192 exosomal proteins detected in both ADSC-exo and ADSC-F-exo, histone deacetylases (HDACs), amyloid-beta A4 protein (APP), and integrin beta-1 (ITGB1) might be involved in enhancing nerve regeneration.

Osteoarthritis (OA) is still a recalcitrant musculoskeletal disease on account of its complex biochemistry and mechanical stimulations. Apart from stimulation by external mechanical forces, the regulation of intracellular mechanics in chondrocytes has also been linked to OA development. Recently, visfatin has received significant attention because of the clinical finding of the positive correlation between its serum/synovial level and OA progression. However, the precise mechanism involved is still unclear. This study determined the effect of visfatin on intracellular mechanics and catabolism in human primary chondrocytes isolated from patients. The intracellular stiffness of chondrocytes was analyzed by the particle-tracking microrheology method. It was shown that visfatin damages the microtubule and microfilament networks to influence intracellular mechanics to decrease the intracellular elasticity and viscosity via glycogen synthase kinase 3β (GSK3β) inactivation induced by p38 signaling. Further, microtubule network destruction in human primary chondrocytes is predominantly responsible for the catabolic effect of visfatin on the cyclooxygenase 2 upregulation. The present study shows a more comprehensive interpretation of OA development induced by visfatin through biochemical and biophysical perspectives. Finally, the role of GSK3β inactivation, and subsequent regulation of intracellular mechanics, might be considered as theranostic targets for future drug development for OA.

Mango peels are usually discarded as waste; however, they contain phytochemicals and could provide functional properties to food and promote human health. This study aimed to determine the optimal lactic acid bacteria for fermentation of mango peel and evaluate the effect of mango peel on neuronal protection in Neuron-2A cells against amyloid beta (Aβ) treatment (50 μM). Mango peel can be fermented by different lactic acid bacteria species. Lactobacillus acidophilus (BCRC14079)-fermented mango peel produced the highest concentration of lactic acid bacteria (exceeding 10 8 CFU/mL). Mango peel and fermented mango peel extracts upregulated brain-derived neurotrophic factor (BDNF) expression for 1.74-fold in Neuron-2A cells. Furthermore, mango peel fermented products attenuated oxidative stress in Aβ-treated neural cells by 27%. Extracts of L. acidophilus (BCRC14079)-fermented mango peel treatment decreased Aβ accumulation and attenuated the increase of subG1 caused by Aβ induction in Neuron-2A cells. In conclusion, L. acidophilus (BCRC14079)-fermented mango peel acts as a novel neuronal protective product by inhibiting oxidative stress and increasing BDNF expression in neural cells.

Potential risk factors for postoperative vomiting (POV) are important for daily anesthesia practice. To identify the risk factors associated with POV we retrospectively reviewed 553 adult patients who underwent scheduled simple laparoscopic cholecystectomy under sevoflurane-based general anesthesia between January and December 2018. Patients who experienced POV were predominantly women, had lower body weight, and higher ASA (American Society of Anesthesiologists) physical status. The POV group showed female sex predominance, lower body weight, and higher ASA physical status, with a significant difference when compared with the non-POV group. In univariate analysis, female sex and Apfel scores of 2, 3, and 4 were associated with a higher POV incidence. Age > 70 years, higher body weight, and ASA physical status III were associated with a lower POV incidence. In multivariate logistic regression, sex, age, Apfel score, and intraoperative crystalloid infusion rate were POV predictive factors. Receiver operating characteristic analysis showed a negative association between the intraoperative crystalloid infusion rate and POV occurrence with an area under the curve of 0.73 ( p = 0.001). The cutoff intraoperative crystalloid infusion rate was 2 mL/kg/h with 82% sensitivity and 49% specificity (≥2 mL/kg/h was associated with a lower POV incidence vs. <2 mL/kg/h (OR, 95% CI; 0.52 [0.33-0.83])). To decrease POV in these patients, identifying high-risk factors and an intraoperative crystalloid administration of ≥2 mL/kg/h should be considered in patients undergoing LC under sevoflurane-based general anesthesia.

The adductor canal block (ACB) is effective for treating postoperative pain during arthroscopic knee surgery, but its impact on anesthesia course and the optimal administration timing are unknown. This retrospective study addressed these questions. The aim of this study was to compare the effects of preoperative ACB and postoperative ACB on anesthesia course and postoperative recovery. We allocated 215 adult patients who underwent arthroscopic knee surgery under sevoflurane anesthesia between January 2019 and December 2019 to three groups. Group A received general anesthesia without ACB, Group B received ACB before general anesthesia induction, and Group C received ACB in the post-anesthesia recovery unit (PACU). Group B consumed significantly less sevoflurane (0.19 mL/kg/h) and milligram morphine equivalents (0.08 MME) intraoperatively than Groups A (0.22 mL/kg/h; 0.10 MME, respectively) and C (0.22 mL/kg/h; 0.09 MME, respectively). Groups B and C had lower visual analogue scale (VAS) scores upon PACU discharge than Group A . Dynamic, but not at-rest VAS scores, were significantly higher in Group A . Opioid consumption was similar in the ward, but Group A requested more intravenous parecoxib for pain relief. Length of hospital stay was similar. Thus, preoperative ACB reduced the amount of volatile anesthetic required and maintained stable hemodynamics intraoperatively. Preoperative or postoperative ACB improved postoperative pain control. Consequently, preoperative ACB is optimal for intraoperative stress suppression and postoperative pain control.

Thank you for Eduardo Mekitarian Filho's appreciation of our work on the study of stress-induced hyperglycemia (SIH) and diabetic hyperglycemia (DH) in patients with traumatic brain injuries [...].

Adult humans and mice possess significant classical brown adipose tissues (BAT) and, upon cold-induction, acquire brown-like adipocytes in certain depots of white adipose tissues (WAT), known as beige adipose tissues or WAT browning/beiging. Activating thermogenic classical BAT or WAT beiging to generate heat limits diet-induced obesity or type-2 diabetes in mice. Adiponectin is a beneficial adipokine resisting diabetes, and causing "healthy obese" by increasing WAT expansion to limit lipotoxicity in other metabolic tissues during high-fat feeding. However, the role of its receptors, especially adiponectin receptor 1 (AdipoR1), on cold-induced thermogenesis in vivo in BAT and in WAT beiging is still elusive. Here, we established a cold-induction procedure in transgenic mice over-expressing AdipoR1 and applied a live 3-D [ 18 F] fluorodeoxyglucose-PET/CT ( 18 F-FDG PET/CT) scanning to measure BAT activity by determining glucose uptake in cold-acclimated transgenic mice. Results showed that cold-acclimated mice over-expressing AdipoR1 had diminished cold-induced glucose uptake, enlarged adipocyte size in BAT and in browned WAT, and reduced surface BAT/body temperature in vivo. Furthermore, decreased gene expression, related to thermogenic Ucp1 , BAT-specific markers, BAT-enriched mitochondrial markers, lipolysis and fatty acid oxidation, and increased expression of whitening genes in BAT or in browned subcutaneous inguinal WAT of AdipoR1 mice are congruent with results of PET/CT scanning and surface body temperature in vivo. Moreover, differentiated brown-like beige adipocytes isolated from pre-adipocytes in subcutaneous WAT of transgenic AdipoR1 mice also had similar effects of lowered expression of thermogenic Ucp1 , BAT selective markers, and BAT mitochondrial markers. Therefore, this study combines in vitro and in vivo results with live 3-D scanning and reveals one of the many facets of the adiponectin receptors in regulating energy homeostasis, especially in the involvement of cold-induced thermogenesis.

The maternal-to-zygotic transition (MZT), which controls maternal signaling to synthesize zygotic gene products, promotes the preimplantation development of mouse zygotes to the two-cell stage. Our previous study reported that mouse granzyme g (Gzmg), a serine-type protease, is required for the MZT. In this study, we further identified the maternal factors that regulate the Gzmg promoter activity in the zygote to the two-cell stage of mouse embryos. A full-length Gzmg promoter from mouse genomic DNA, FL-p Gzmg (-1696~+28 nt), was cloned, and four deletion constructs of this Gzmg promoter, Δ1-p Gzmg (-1369~+28 nt), Δ2-p Gzmg (-939~+28 nt), Δ3-p Gzmg (-711~+28 nt) and Δ4-p Gzmg (-417~+28 nt), were subsequently generated. Different-sized Gzmg promoters were used to perform promoter assays of mouse zygotes and two-cell stage embryos. The results showed that Δ4-p Gzmg promoted the highest expression level of the enhanced green fluorescent protein (EGFP) reporter in the zygotes and two-cell embryos. The data suggested that time-specific transcription factors upregulated Gzmg by binding cis-elements in the -417~+28-nt Gzmg promoter region. According to the results of the promoter assay, the transcription factor binding sites were predicted and analyzed with the JASPAR database, and two transcription factors, signal transducer and activator of transcription 3 (STAT3) and GA-binding protein alpha (GABPα), were identified. Furthermore, STAT3 and GABPα are expressed and located in zygote pronuclei and two-cell nuclei were confirmed by immunofluorescence staining; however, only STAT3 was recruited to the mouse zygote pronuclei and two-cell nuclei injected with the Δ4-p Gzmg reporter construct. These data indicated that STAT3 is a maternal transcription factor and may upregulate Gzmg to promote the MZT. Furthermore, treatment with a STAT3 inhibitor, S3I-201, caused mouse embryonic arrest at the zygote and two-cell stages. These results suggest that STAT3, a maternal protein, is a critical transcription factor and regulates Gzmg transcription activity in preimplantation mouse embryos. It plays an important role in the maternal-to-zygotic transition during early embryonic development.

Background: Identification of malnutrition is especially important in severely injured patients, in whom hypermetabolism and protein catabolism following traumatic injury worsen their nutritional condition. The geriatric nutritional risk index (GNRI), based on serum albumin level and the current body weight/ideal body weight ratio, is useful for identifying patients with malnutrition in many clinical conditions. This study aimed to explore the association between admission GNRI and mortality outcomes of adult patients with polytrauma., Methods: From 1 January 2009 to 31 December 2019, a total of 348 adult patients with polytrauma, registered in the trauma database of a level I trauma center, were recognized and categorized into groups of death ( n = 71) or survival ( n = 277) and into four nutritional risk groups: a high-risk group (GNRI < 82, n = 87), a moderate-risk group (GNRI 82 to <92, n = 144), a low-risk group (GNRI 92-98, n = 59), and a no-risk group (GNRI > 98, n = 58). Univariate and multivariate logistic regression analyses were used to identify the independent risk factors for mortality. The mortality outcomes of patients at various nutritional risks were compared to those of patients in the no-risk group., Results: The comparison between the death group ( n = 71) and the survival group ( n = 277) revealed that there was no significant difference in gender predominance, age, pre-existing comorbidities, injury mechanism, systolic blood pressure, and respiratory rate upon arrival at the emergency room. A significantly lower GNRI and Glasgow Coma Scale score but higher injury severity score (ISS) was observed in the death group than in the survival group. Multivariate logistic regression analysis revealed that Glasgow Coma Scale (GCS), odds ratio (OR), 0.88; 95% confidence interval (CI), 0.83-0.95; p < 0.001), ISS (OR, 1.07; 95% CI, 1.04-1.11; p < 0.001), and GNRI (OR, 0.94; 95% CI, 0.91-0.97; p < 0.001) were significant independent risk factors for mortality in these patients. The mortality rates for the high-risk, moderate-risk, low-risk, and no-risk groups were 34.5%, 20.1%, 8.5%, and 12.1%, respectively. Unlike patients in the moderate-risk and low-risk groups, patients in the high-risk group had a significantly higher death rate than that of those in the no-risk group., Conclusions: This study revealed that the GNRI may serve as a simple, promising screening tool to identify the high risk of malnutrition for mortality in adult patients with polytrauma.

Background: Malnutrition is frequently underdiagnosed in geriatric patients and is considered to be a contributing factor for worse outcomes during hospitalization. In addition, elderly patients who undergo trauma are often malnourished at the time of incurring fractures. The geriatric nutritional risk index (GNRI), calculated based on the serum albumin level and the ratio of present body weight to ideal body weight, was proposed for the assessment of the nutritional status of elderly patients with various illnesses. This study aimed to investigate whether the GNRI has a prognostic value that links the nutritional status and mortality outcomes of elderly patients who have previously undergone trauma with femoral fractures., Methods: From January 1, 2009 to December 31, 2019, a total of 678 elderly patients with femoral fractures were categorized into four nutritional risk groups: a major-risk group (GNRI <82; group 1, n = 127), moderate-risk group (GNRI 82- <92; group 2, n = 179), low-risk group (GNRI 92-98; group 3, n = 123), and no-risk group (GNRI >98; group 4, n = 249). To minimize the confounding effects of sex, age, preexisting comorbidities, and injury severity of patients on outcome measurements, propensity score-matched patient cohorts were created to assess the impact of patients being in different nutritional risk groups on the in-hospital mortality outcomes against the no-risk group., Results: The patients in groups 1-3 were significantly older and presented a significantly lower body mass index and lower serum albumin levels than those in group 4. Compared with patients in group 4 (3.6%), a significantly higher mortality rate was found in the patients in group 1 (17.3%, p < 0.001), but not in those in group 2 (6.7%) or group 3 (2.4%). The study of propensity score-matched patient cohorts provided similar results; group 1 patients had significantly higher odds of mortality than group 4 patients (odds ratio, 6.3; 95% confidence interval, 1.34-29.37; p = 0.009), but there were no significant differences in mortality risks among patients in groups 2 and 3 compared with those in group 4., Conclusions: This preliminary study suggested that the GNRI may be used as a screening tool to identify patients with malnutrition at a high risk of mortality among elderly patients with femoral fractures. A prospective study is needed to validate the suggestion., Competing Interests: The authors declare no conflict of interest.

This study tested whether circulatory endothelial progenitor cells (EPCs) derived from peripheral arterial occlusive disease (PAOD) patients after receiving combined autologous CD34+ cell and hyperbaric oxygen (HBO) therapy (defined as rejuvenated EPCs) would salvage nude mouse limbs against critical limb ischemia (CLI). Adult-male nude mice ( n = 40) were equally categorized into group 1 (sham-operated control), group 2 (CLI), group 3 (CLI-EPCs (6 × 10 5 ) derived from PAOD patient's circulatory blood prior to CD34 + cell and HBO treatment (EPC Pr-T ) by intramuscular injection at 3 h after CLI induction) and group 4 (CLI-EPCs (6 × 10 5 ) derived from PAOD patient's circulatory blood after CD34 + cell and HBO treatment (EPC Af-T ) by the identical injection method). By 2, 7 and 14 days after the CLI procedure, the ischemic to normal blood flow (INBF) ratio was highest in group 1, lowest in group 2 and significantly lower in group 4 than in group 3 ( p < 0.0001). The protein levels of endothelial functional integrity (CD31/von Willebrand factor (vWF)/endothelial nitric-oxide synthase (eNOS)) expressed a similar pattern to that of INBF. In contrast, apoptotic/mitochondrial-damaged (mitochondrial-Bax/caspase-3/PARP/cytosolic-cytochrome-C) biomarkers and fibrosis (Smad3/TGF-ß) exhibited an opposite pattern, whereas the protein expressions of anti-fibrosis (Smad1/5 and BMP-2) and mitochondrial integrity (mitochondrial-cytochrome-C) showed an identical pattern of INBF (all p < 0.0001). The protein expressions of angiogenesis biomarkers (VEGF/SDF-1α/HIF-1α) were progressively increased from groups 1 to 3 (all p < 0.0010). The number of small vessels and endothelial cell surface markers (CD31 + /vWF + ) in the CLI area displayed an identical pattern of INBF (all p < 0.0001). CLI automatic amputation was higher in group 2 than in other groups (all p < 0.001). In conclusion, EPCs from HBO-C34+ cell therapy significantly restored the blood flow and salvaged the CLI in nude mice.

Background: Prediction of mortality outcomes in trauma patients in the intensive care unit (ICU) is important for patient care and quality improvement. We aimed to measure the performance of 11 prognostic scoring systems for predicting mortality outcomes in trauma patients in the ICU., Methods: Prospectively registered data in the Trauma Registry System from 1 January 2016 to 31 December 2018 were used to extract scores from prognostic scoring systems for 1554 trauma patients in the ICU. The following systems were used: the Trauma and Injury Severity Score (TRISS); the Acute Physiology and Chronic Health Evaluation (APACHE II); the Simplified Acute Physiology Score (SAPS II); mortality prediction models (MPM II) at admission, 24, 48, and 72 h; the Multiple Organ Dysfunction Score (MODS); the Sequential Organ Failure Assessment (SOFA); the Logistic Organ Dysfunction Score (LODS); and the Three Days Recalibrated ICU Outcome Score (TRIOS). Predictive performance was determined according to the area under the receiver operator characteristic curve (AUC)., Results: MPM II at 24 h had the highest AUC (0.9213), followed by MPM II at 48 h (AUC: 0.9105). MPM II at 24, 48, and 72 h (0.8956) had a significantly higher AUC than the TRISS (AUC: 0.8814), APACHE II (AUC: 0.8923), SAPS II (AUC: 0.9044), MPM II at admission (AUC: 0.9063), MODS (AUC: 0.8179), SOFA (AUC: 0.7073), LODS (AUC: 0.9013), and TRIOS (AUC: 0.8701). There was no significant difference in the predictive performance of MPM II at 24 and 48 h ( p = 0.37) or at 72 h ( p = 0.10)., Conclusions: We compared 11 prognostic scoring systems and demonstrated that MPM II at 24 h had the best predictive performance for 1554 trauma patients in the ICU.

Dengue virus (DENV), the pathogen that causes dengue fever, is mainly transmitted by Aedes aegypti . Surveillance of infected mosquitoes is a major component of integrated mosquito control methods for reducing the risk of vector-born disease outbreaks. However, a specialized rapid test for DENV detection in mosquitoes is not currently available. Utilizing immunoblotting, we found that the secretion of NS1 from both a DENV-infected mosquito cell line and mosquito bodies was below the detection threshold. However, when Triton X-100 was used to lyse infected mosquitoes, intracellular NS1 was released, and could then be effectively detected by the NS1 rapid test. The distribution of DENV NS1 in intrathoracically infected mosquitoes was different from that of orally infected mosquitoes. Next, we performed sensitivity tests by bisecting mosquitoes longitudinally; one half of each mosquito was subjected to the NS1 rapid test while the other half was used for qPCR confirmation. This modified test had a sensitivity of nearly 90% from five days post-infection onwards, while DENV had escaped from the midgut barrier. This adapted test offers a valuable, easy-to-use tool for mosquito surveillance, which is a crucial component of DENV disease control.

Limestone is a relatively abundant and low-cost material used for producing calcium oxide as a CO 2 adsorbent. However, the CO 2 capture capacity of limestone decreases rapidly after multiple carbonation/calcination cycles. To improve the CO 2 capture performance, we developed a process using limestone to transform the material into a rod Ca-based metal-organic framework (Ca-MOF) via a hydrothermal process with the assistance of acetic acid and terephthalic acid (H 2 BDC). The structural formation of rod Ca-MOF may result from the (200) face-oriented attachment growth of Ca-MOF sheets. Upon heat treatment, a highly stable porous rod network with a calcined Ca-MOF-O structure was generated with a pore distribution of 50-100 nm, which allowed the rapid diffusion of CO 2 into the interior of the sorbent and enhanced the CO 2 capture capacity with high multiple carbonation-calcination cycle stability compared to limestone alone at the intermediate temperature of 450 °C. The CO 2 capture capacity of the calcined porous Ca-MOF-O network reached 52 wt% with a CO 2 capture stability of 80% after 10 cycles. The above results demonstrated that rod Ca-MOF can be synthesized from a limestone precursor to form a porous network structure as a CO 2 capture sorbent to improve CO 2 capture performance at an intermediate temperature, thus suggesting its potential in environmental applications.

Background: Hyperglycemia at the time of hospital admission is associated with higher morbidity and mortality rates in patients with traumatic brain injury (TBI). Using data from the Chang Gung Research Database (CGRD), this study aimed to compare mortality outcomes between patients with stress-induced hyperglycemia (SIH), diabetic hyperglycemia (DH), and nondiabetic normoglycemia (NDN). The study occurred at Keelung, Linkou, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals (CGMHs). Methods: A total of 1166, 6318, 3622, and 5599 health records from Keelung, Linkou, Chiayi, and Kaohsiung CGMHs, respectively, were retrieved from the CGRD for hospitalized patients with TBI between January 2001 and December 2015. After propensity score matching for sex, age, and Glasgow Coma Scale (GCS) score, the matched cohorts were compared to evaluate differences in the primary outcome between patients with SIH, DH, and NDN. In-hospital mortality was the primary outcome. Results: The analysis of matched patient populations revealed that at the Kaohsiung CGMH, patients with SIH had 1.63-fold (95% CI: 1.09-2.44; p = 0.017) and 1.91-fold (95% CI: 1.12-3.23; p = 0.017) higher odds of mortality than patients with NDN and DH, respectively. Similar patterns were found at the Linkou CGMH; patients with SIH had higher odds of mortality than patients with NDN and DH. In contrast, at the Keelung CGMH, patients with SIH had significantly higher odds of mortality than those with NDN (OR: 3.25; 95% CI: 1.06-9.97; p = 0.039). At the Chiayi CGMH, there were no significant differences in mortality rates among all groups. Conclusions: This study's results suggest that SIH and DH differ in their effect on the outcomes of patients with TBI. The results were similar between medical centers but not nonmedical centers; in the medical centers, patients with SIH had significantly higher odds of mortality than patients with either NDN or DH.

Background : Aspirin use has been associated with improved survival rates in various cancers. However, it remains unclear if aspirin confers a survival benefit on patients with nasopharyngeal carcinoma (NPC). The aim of this study was to assess the associations between aspirin use and survival in different stages of NPC. Methods : This is a 10-year retrospective cohort study of NPC patients. A total of 565 NPC patients were recruited after we performed a 1:4 propensity score match between aspirin users and non-users. Cox regression models with adjusted covariates were employed to evaluate factors that influence the survival rate of NPC patients. Results : The Kaplan-Meier analysis revealed that the overall survival ( p < 0.0001) and disease-specific survival ( p < 0.0001) rates of 180-day aspirin users increased. Increased survival rates were also observed in 180-day aspirin users with Stages III and IV, T, N1 and 2, and N3 categories. Cox regression models indicated that factors, including aspirin use (univariate: HR = 0.28, 95% CI = 0.14-0.55, p < 0.001; multivariate: HR = 0.23, 95% CI = 0.12-0.46, p < 0.001), were independent prognostic factors for survival. Conclusions : Aspirin use for more than 180 days is associated with an increased survival rate and is a positive independent prognostic factor in NPC., Competing Interests: The authors declare no conflict of interest.

In this study, Ca-based multi-metals metal-organic framework (CaMgAl-MOF) has been designed as precursor material for carbon dioxide (CO 2 ) capture to enhance the CO 2 capture capacity and stability during multiple carbonation-calcination cycles. The CaMgAl-MOFs were constructed from self-assembly of metal ions and organic ligands through hydrothermal process to make metal ions uniformly distributed through the whole structure. Upon heat treatment at 600 °C, the Ca-based multi-metals CaMgAl-MOF would gradually transform to CaO and MgO nanoparticles along with the amorphous aluminum oxide distributed in the CaO matrix. XRD, Fourier transform infrared (FTIR), and SEM were used to identify the structure and characterize the morphology. The CO 2 capture capacity and multiple carbonation-calcination cyclic tests of calcined Ca-based metal-organic framework (MOF) (attached with O and indicated as Ca-MOF-O) were performed by thermal gravimetric analysis (TGA). The single metal component calcined Ca-MOF sorbent have the highest CO 2 capture capacity up to 72 wt.%, but a lower stability of 61% due to severe particle aggregation. In contrast, a higher Ca-rich MOF oxide sorbent with tailoring the Mg/Al ratios, Ca 0.97 Mg 0.025 Al 0.005 -MOF-O, showed the best performance, not only having the high stability of ~97%, but also maintaining the highest capacity of 71 wt.%. The concept of using Ca-based MOF materials combined with mixed-metal ions for CO 2 capture showed a potential route for achieving efficient multiple carbonation-calcination CO 2 cycles.

Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze BDH2 mRNA expression in the bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients with normal BM. Elevated BDH2 mRNA expression in BM is observed in MDS patients ( n = 187 vs. 43, normal BM; P = 0.009), and this is related to ferritin levels. Patients with higher BDH2 expression show a greater risk of leukemia progression (15.25% vs. 3.77%, lower expression; P = 0.017) and shorter leukemia-free-survival (medium LFS, 9 years vs. 7 years; P = 0.024), as do patients with a ferritin level ≥350 ng/mL. Additionally, we investigate the mechanisms related to the prognostic ability of BDH2 by using BDH2-KD THP1. The cell cycle analysis, surface markers, and special stain studies indicate that BDH2-KD induces differentiation and decreases the growth rate of THP1 cells, which is associated with the retardation of the cell cycle. Moreover, many genes, including genes related to mitochondrial catabolism, oncogenes, tumor suppressor genes, and genes related to cell differentiation and proliferation influence BDH2-KD THP1 cells. Herein, we demonstrate that BDH2 is involved in cell cycle arrest and the inhibition of differentiation in malignant cells. Furthermore, the high BDH2 expression in MDS patients could be suggestive of a poor prognostic factor. This study provides a foundation for further research on the roles of BDH2 and iron metabolism in the pathogenesis of MDS.

Background: In recent years, several versions of the Abbreviated Injury Scale (AIS) were updated and published. It was reported that the codeset in the dictionary of AIS-2005 had significant change from that of AIS-1998. This study was designed to evaluate the potential impact of adapting the AIS-2005 codeset from the AIS-1998 in an established trauma system of a single level I trauma center. The patients' outcome was measured in different Injury Severity Score (ISS) strata according to the double-coded injuries in a three-year period., Methods: The double-coded injuries sustained by 7520 trauma patients between 1 January, 2016, and 31 December, 2018, in a level I trauma center were used to compare the patient injury characteristics and outcomes between AIS-1998 and AIS-2005 and under different ISS strata, defined as <16 (mild to moderate injury), 16-24 (severe injury), and >24 (critical injury)., Results: The mean ISS was significantly lower using AIS-2005 than using AIS-1998 (7.5 ± 6.3 vs. 8.3 ± 7.1, respectively, p < 0.001). AIS-2005 scores in the body regions of the head/neck (2.94 ± 1.08 vs. 3.40 ± 1.15, respectively, p < 0.001) and extremity (2.19 ± 0.56 vs. 2.24 ± 0.58, respectively, p < 0.001), but not in other body regions, were significantly lower than AIS-1998 scores. The critically injured patients (ISS >24), but not severely injured patients or patients with mild-to-moderate injury, coded by AIS-2005 had a significantly higher mortality rate (34.2% vs. 26.2%, respectively, p = 0.031) than did patients coded by AIS-1998. The rate of intensive care unit admission was significantly higher for patients in all ISS strata after adapting AIS-2005 as the scoring system than after adapting AIS-1998. Regarding patients with major trauma, which was defined as ISS > 15, the number of patients with major trauma in this study was 17.0% (n = 1276) for AIS-1998 and 9.7% (n = 733) for AIS-2005. As a consequence, the mortality rate of patients with major trauma was significantly higher in AIS-2005 than in AIS-1998 (15.4% vs. 9.1%, respectively, p < 000.1)., Conclusions: In this study, we revealed that the adaptation of AIS-2005 from AIS-1998 had resulted in a significant decrease of severity scores in the measurement of the same injuries. The number of head/neck injuries classified as 16-24 was the key difference between AIS-1998 and AIS-2005. Furthermore, critically injured patients who had ISS > 24 coded by AIS-2005 had significantly higher mortality rates than did the patients coded by AIS-1998. This study also indicated that a direct comparison of the measurements that are generated from these two AIS versions can produce misleading results., Competing Interests: The authors declare that they have no competing interests.