The effect of inflammatory cytokines on the risk of hypertrophic scar: a mendelian randomization study.

Hypertrophic scar (HS) results from burns or trauma, causing aesthetic and functional issues. However, observational studies have linked inflammatory cytokines to HS, but the causal pathways involved are unclear. We aimed to determine how circulating inflammatory cytokines contribute to HS formation. Two-sample Mendelian randomization (MR) was used to identify genetic variants associated with hypertrophic scar in a comprehensive, publicly available genome-wide association study (GWAS) involving 766 patients and 207,482 controls of European descent. Additionally, data on 91 plasma proteins were drawn from a GWAS summary involving 14,824 healthy participants. Causal relationships between exposures and outcomes were investigated primarily using the inverse variance weighted (IVW) method. Furthermore, a suite of sensitivity analyses, including MR‒Egger and weighted median approaches, were concurrently employed to fortify the robustness of the conclusive findings. Finally, reverse MR analysis was conducted to evaluate the plausibility of reverse causation between hypertrophic scar and the cytokines identified in our study. In inflammatory cytokines, there was evidence of inverse associations of osteoprotegerin(OPG) levels(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01), and leukemia inhibitory factor(LIF) levels(OR = 0.51, 95% CI = 0.32 ∼ 0.82, p = 0.01) are a nominally negative association with hypertrophic scar risk, while CUB domain-domain-containing protein 1(CDCP1) level(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01) glial cell line-derived neurotrophic factor(GDNF) levels(OR = 1.42, 95% CI = 1.03 ∼ 1.96, p = 0.01) and programmed cell death 1 ligand 1(PD-L1) levels(OR = 1.47, 95% CI = 1.92 ∼ 2.11, p = 0.04) showed a positive association with hypertrophic scar risk. These associations were similar in the sensitivity analyses. According to our MR findings, OPG and LIF have a protective effect on hypertrophic scar, while CDCP1, GDNF, and PD-L1 have a risk-increasing effect on Hypertrophic scar. Our study adds to the current knowledge on the role of specific inflammatory biomarker pathways in hypertrophic scar. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for hypertrophic scar prevention and treatment.

A study on the impact of gargling with compound Scutellaria baicalensis Georgi on oral health and microflora changes in fixed orthodontic patients: An experimental study.

PURPOSE: To investigate the effect of Scutellaria baicalensis Georgi gargle on oral health and changes in oral bacteria among orthodontic patients. METHODS: About 110 cases of oral fixed orthodontic patients were screened from January 2020 to June 2022 at Taizhou Hospital in Zhejiang Province. They were randomly divided into the experimental group (receiving compound S. baicalensis Georgi gargle once a day) and the control group (receiving 0.9% NS gargle once a day), with 55 cases in each group. Gingival samples were collected from both groups before and 3 months after the orthodontic surgery for bacterial culture, and the differences between the 2 groups of patients in Plaque Index (PLI), gingival bleeding index (sBl), and periodontal depth (PD) before and after the operation were compared. Results: The detection levels of PLI, PD, and sBI in the experimental group were lower than those in the control group (P < .05) 3 months after orthodontic surgery (P < .05); after orthodontic correction for 3 months, there was a significant difference in coccus, bacillus, Campylobacter, Clostridium, Helicobacter, and filamentous bacteria between the experimental group and the control group (P < .05); and Porphyromonas gingivalis, Fusobacterium nucleatum, Bacteroides forsythus (B.f), and Agglomerata actinomycetes in the 2 groups were statistically significant after 3 months of orthodontic treatment (P < .05). CONCLUSION SUBSECTIONS: In fixed orthodontic treatment, S. baicalensis Georgi gargle can effectively inhibit oral pathogens and maintain periodontal health.

Photoredox-catalyzed C(sp2)-H trifluoromethylation of 3-methylene-isoindolin-1-ones under metal-free conditions.

A facile synthetic method for direct C(sp2)-H bond trifluoromethylation of 3-methylene-isoindolin-1-ones under visible-light-induced metal-free conditions is presented. This protocol features mild reaction conditions, broad substrate scope and excellent functional group tolerance, resulting in a range of structurally diverse trifluoromethylated products in good to excellent yields.

Nucleation and growth process of a softened-spark layer during microarc oxidation on a selective laser melted Ti alloy.

A two-step method for preparing composite coatings with different composition on Ti alloys using softened spark microarc oxidation technology was proposed. The nucleation and growth processes of a softened spark layer, as well as the influence of softened sparks on the deposition of anions in electrolytes, were studied. The results show that the process voltage of the softened spark discharge on the selective laser-melted Ti6Al4V alloy was lower than the breakdown voltage of its anodic oxide film. The softened sparks prioritized nucleation at the coating/substrate interface in the initial spark discharge area rather than in the microarc discharge area. On one hand, the softened spark layer grew towards the Ti6Al4V substrate, and on the other hand, the molten oxide generated by the softened sparking was transferred into the external porous layer. The softened sparks generated inside the coating promoted the rutile phase formation and linear growth in the thickness of the softened spark layer. Ca and P are mainly distributed in the external porous layer or at the interface between the softened-spark and external porous layers. Nevertheless, softened sparking had little effect on the initial micro/nanoporous structures of the coatings.

Gefitinib (an EGFR tyrosine kinase inhibitor) plus anlotinib (an multikinase inhibitor) for untreated, EGFR-mutated, advanced non-small cell lung cancer (FL-ALTER): a multicenter phase III trial.

Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1-14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48-0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Dietary bile acids supplementation decreases hepatic fat deposition with the involvement of altered gut microbiota and liver bile acids profile in broiler chickens.

BACKGROUND: High-fat diets (HFD) are known to enhance feed conversion ratio in broiler chickens, yet they can also result in hepatic fat accumulation. Bile acids (BAs) and gut microbiota also play key roles in the formation of fatty liver. In this study, our objective was to elucidate the mechanisms through which BA supplementation reduces hepatic fat deposition in broiler chickens, with a focus on the involvement of gut microbiota and liver BA composition. RESULTS: Newly hatched broiler chickens were allocated to either a low-fat diet (LFD) or HFD, supplemented with or without BAs, and subsequently assessed their impacts on gut microbiota, hepatic lipid metabolism, and hepatic BA composition. Our findings showed that BA supplementation significantly reduced plasma and liver tissue triglyceride (TG) levels in 42-day-old broiler chickens (P < 0.05), concurrently with a significant decrease in the expression levels of fatty acid synthase (FAS) in liver tissue (P < 0.05). These results suggest that BA supplementation effectively diminishes hepatic fat deposition. Under the LFD, BAs supplementation increased the BA content and ratio of Non 12-OH BAs/12-OH BAs in the liver and increased the Akkermansia abundance in cecum. Under the HFD, BA supplementation decreased the BAs and increased the relative abundances of chenodeoxycholic acid (CDCA) and cholic acid (CA) in hepatic tissue, while the relative abundances of Bacteroides were dramatically reduced and the Bifidobacterium, Escherichia, and Lactobacillus were increased in cecum. Correlation analyses showed a significant positive correlation between the Akkermansia abundance and Non 12-OH BA content under the LFD, and presented a significant negative correlation between the Bacteroides abundance and CA or CDCA content under the HFD. CONCLUSIONS: The results indicate that supplementation of BAs in both LFD and HFD may ameliorate hepatic fat deposition in broiler chickens with the involvement of differentiated microbiota-bile acid profile pathways.

Comparison of oXiris and Conventional Continuous Renal Replacement Therapy in Managing Severe Abdominal Infections: Impact on Septic Shock Mortality.

OBJECTIVE: The objective of this study is to assess and compare the efficacy of oXiris with conventional continuous renal replacement therapy (CRRT) in managing severe abdominal infections. METHODS: A retrospective analysis encompassing cases from 2017 to 2023 was conducted at the Department of Critical Care Medicine within the First Affiliated Hospital of Fujian Medical University. Parameters including heart rate (HR), mean arterial pressure (MAP), oxygenation index (OI), lactate (Lac), platelet count (PLT), neutrophil ratio (N%), procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6), norepinephrine (NE) dosage, acute physiology and chronic health evaluation II (APACHE II), and sequential organ failure assessment (SOFA) were recorded prior to treatment initiation, at 24 hours, and 72 hours post-treatment for both the oXiris and conventional CRRT groups. Additionally, the duration of respiratory support, CRRT treatment, length of stay in the intensive care unit (ICU), total hospitalization period, as well as mortality rates at 14 and 28 days for both groups were recorded. RESULTS: 1) Within the conventional CRRT group, notable enhancement was observed solely in Lac levels at 24 hours post-treatment compared to pre-treatment levels. Also, at 72 hours post-treatment, improvements were evident in HR, Lac, CRP, and IL-6 levels. 2) Conversely, the oXiris group exhibited improvements in HR, MAP, Lac, OI, N%, and IL-6 at 24 hours post-treatment when compared to baseline values. Additionally, reductions were observed in APACHE II and SOFA scores. At 72 hours post-treatment, all parameters demonstrated enhancement except for PLT. 3) Analysis of the changes in the indexes (Δ) between the two groups at 24 hours post-treatment revealed variances in HR, MAP, Lac, NE dosage, CRP levels, IL-6 levels, APACHE II scores, and SOFA scores. 4) The Δ indexes at 72 hours post-treatment indicated more significant improvements following oXiris treatment for both groups, except for PCT. 5) The 14-day mortality rate (24.4%) exhibited a significant reduction in the oXiris group when compared to the conventional group (43.6%). However, no significant difference was observed in the 28-day mortality rate between the two groups. 6) Subsequent to multifactorial logistic regression analysis, the results indicated that oXiris treatment correlated with a noteworthy decrease in the 14-day and 28-day mortality rates associated with severe abdominal infections, by 71.3% and 67.6%, respectively. CONCLUSION: oXiris demonstrates clear advantages over conventional CRRT in the management of severe abdominal infections. Notably, it reduces the fatality rates, thereby establishing itself as a promising and potent therapeutic option.

Recurrent spinal subdural hematoma following percutaneous kyphoplasty: A unique case report.

Spinal intradural (subdural and subarachnoid) hematoma following percutaneous kyphoplasty is an extremely rare complication. In this report, we described a case of 2 episodes of subarachnoid hemorrhage with delayed paralysis after kyphoplasty. A 73-year-old man underwent percutaneous kyphoplasty in our hospital an osteoporotic vertebral fracture at the T12 level. On the 55 h after kyphoplasty for T12 osteoporotic vertebral fracture, he developed paralysis of the lower limbs. An emergency posterior decompression from T8 to L2 was performed. And the subarachnoid hematomas were removed. Postoperatively, the neurological symptoms improved rapidly. However, 2 weeks after the operation, the patient experienced a setback with severe neurological decline (paraplegia with sensory and autonomic dysfunction). An emergency posterior decompression from T5 to L2 was performed. The subarachnoid hematomas were removed. This case reflects the cause and progression of spinal subdural hematoma. Previous literature has debated the best treatment approach for spinal subarachnoid hemorrhage, but the prognosis of patients is heavily dependent on precise symptom evaluation and localization.

Genome assembly and resequencing shed light on evolution, population selection, and sex identification in Vernicia montana.

Vernicia montana is a dioecious plant widely cultivated for high-quality tung oil production and ornamental purposes in the Euphorbiaceae family. The lack of genomic information has severely hindered molecular breeding for genetic improvement and early sex identification in V. montana. Here, we present a chromosome-level reference genome of a male V. montana with a total size of 1.29 Gb and a contig N50 of 3.69 Mb. Genome analysis revealed that different repeat lineages drove the expansion of genome size. The model of chromosome evolution in the Euphorbiaceae family suggests that polyploidization-induced genomic structural variation reshaped the chromosome structure, giving rise to the diverse modern chromosomes. Based on whole-genome resequencing data and analyses of selective sweep and genetic diversity, several genes associated with stress resistance and flavonoid synthesis such as CYP450 genes and members of the LRR-RLK family, were identified and presumed to have been selected during the evolutionary process. Genome-wide association studies were conducted and a putative sex-linked insertion and deletion (InDel) (Chr 2: 102 799 917-102 799 933 bp) was identified and developed as a polymorphic molecular marker capable of effectively detecting the gender of V. montana. This InDel is located in the second intron of VmBASS4, suggesting a possible role of VmBASS4 in sex determination in V. montana. This study sheds light on the genome evolution and sex identification of V. montana, which will facilitate research on the development of agronomically important traits and genomics-assisted breeding.

A predictive model for therapy failure in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor therapy.

Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20-30% of people still experienced therapy failure. Data from 1,955 consecutive subjects with chronic-phase CML diagnosed by the European LeukemiaNet (ELN) recommendations from 1 center receiving initial TKI imatinib or a second-generation (2G-) TKI therapy were interrogated to develop a clinical prediction model for TKI therapy failure. This model was subsequently validated in 3,454 subjects from 76 other centers. Using the predictive clinical co-variates associated with TKI therapy failure, we developed a model that stratified subjects into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (p < 0.001). There was good discrimination and calibration in the external validation dataset, and the performance was consistent with that of the training dataset. Our model had the better prediction discrimination than the Sokal and ELTS scores did, with the greater time-dependent area under the receiver-operator characteristic curve (AUROC) values and a better ability to re-defined the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G-TKI therapy failure in people with chronic-phase CML.

Universal Entanglement Spectrum in One-Dimensional Gapless Symmetry Protected Topological States.

Quantum entanglement marks a definitive feature of topological states. However, the entanglement spectrum remains insufficiently explored for topological states without a bulk energy gap. Using a combination of field theory and numerical techniques, we accurately calculate and analyze the entanglement spectrum of gapless symmetry protected topological states in one dimension. We highlight that the universal entanglement spectrum not only encodes the nontrivial edge degeneracy, generalizing the Li-Haldane conjecture to gapless topological states, but also contains the operator content of the underlying boundary conformal field theory. This implies that the bulk wave function can act as a fingerprint of both quantum criticality and topology in gapless symmetry protected topological states. We also identify a symmetry enriched conformal boundary condition that goes beyond the conventional conformal boundary condition.

Effects of low dietary calcium and lipopolysaccharide challenges on production performance, eggshell quality, and bone metabolism of laying hens.

Dietary calcium supply is essential for bone development and egg production in laying hens. This study investigated the effects of low dietary calcium and lipopolysaccharide (LPS) induced immune challenge in aged laying hens. A total of thirty-two Hy-Line Brown laying hens at 80 weeks old with an average laying rate of 62% were randomly divided into two groups and fed a normal calcium diet (3.57% Ca, NCA) or low calcium diet (2.08% Ca, LCA). At 88 weeks, the experiment was designed using a 2 × 2 factorial arrangement, and hens were intraperitoneally injected with saline (SAL) or LPS (0.5 mg/kg, 0.5 mg/kg, or 1.5 mg/kg body weight) once every 48 h intervals over 5 days. Production performance, egg quality, and bone physiology were evaluated. Results showed that LPS challenge decreased the hen-day egg production, egg mass, and eggshell traits (p < 0.05), but increased (p < 0.05) the calcium content of the tibia compared to SAL-injected hens. LCA diet decreased (p < 0.05) the hen-day egg production, and eggshell traits such as weight, percentage, strength, and thickness compared to the NCA diet. LCA diet increased the serum alkaline phosphatase (ALP) activity (p < 0.01) and tibial expression of ALP (p < 0.05) compared to NCA diet. LPS injection suppressed both the serum ALP activity (p < 0.05) and tibial expression of ALP (p < 0.001) compared to SAL injection. Furthermore, LPS injection increased (p < 0.05) the expression of both pro and anti-inflammatory cytokines in the spleen and tibia. The expression of cathepsin K ( Cts K ) and matrix metalloproteinase 9 ( MMP-9 ) were downregulated by LPS injection (p < 0.001). Broken and shell-less egg production and calcium content of eggshell, as well as tibial mRNA expression of osteocalcin ( Ocn ), tumor necrosis factor-alpha ( TNF-α ) and tartrate-resistant acid phosphatase ( TRAP ) were affected by the interaction (p < 0.05) of diet and injection. Therefore, this study demonstrated that to certain extents, low dietary calcium and LPS challenge dysregulated bone homeostasis and metabolism, with detrimental effects on the performance and eggshell quality of aged laying hens.

Efficacy and safety of upadacitinib in the treatment of moderate-to-severe atopic dermatitis: A systematic review.

OBJECTIVE: To evaluate the efficacy and safety of upadacitinib in the treatment of moderate-to-severe atopic dermatitis (AD), and provide reference for rational clinical medication. METHODS: PubMed, Medline, Embase, Web of Science, Clinical Trials Website, and Cochrane Library databases were searched from the time of establishment until January 6, 2024, to compile a list of all randomized controlled trials (RCTs) including upadacitinib in the treatment of moderate-to-severe AD. The quality of the included studies was evaluated using the Cochrane Systematic Review. Review Manager 5.3 software was utilized for statistical analysis of outcome measures. RESULTS: A total of five studies were included in the meta-analysis. The results revealed that the 15 mg and 30 mg upadacitinib significantly improved Eczema Area and Severity Index (EASI) 75% {[Odds Ratio (OR) = 8.58, 95% confidence interval (CI) (5.84-12.60), P < 0.00001] [OR = 15.62, 95% CI (10.89-22.42), P < 0.00001]}, Numerical Rating Scale (NRS) ≥ 4 {[OR = 7.13, 95% CI (5.63-9.01), P < 0.00001] [OR = 11.30, 95% CI (8.93-14.31), P < 0.00001]}, and Investigator's Global Assessment (IGA) 0/1 {[OR = 8.63, 95% CI (6.60-11.27), P < 0.00001] [OR = 16.04, 95% CI (12.26-20.99), P < 0.00001]} compared to placebo. In terms of safety, although 15 mg and 30 mg upadacitinib significantly increased the overall adverse events rate compared to placebo {[OR = 1.31, 95% CI (1.09-1.58), P = 0.004] [OR = 1.85, 95% CI (1.54-2.21), P < 0.00001]}, there was no significant difference in the serious adverse events rate {[OR = 0.73, 95% CI (0.41-1.29), P = 0.28] [OR = 0.69, 95% CI (0.39-1.23), P = 0.21]} and withdrawal rate due to adverse events {[OR = 0.66, 95% CI (0.39-1.11), P = 0.12] [OR = 0.85, 95% CI (0.52-1.38), P = 0.50]} compared to placebo. CONCLUSION: This meta-analysis preliminarily suggests that upadacitinib is effective and safe for usage in the treatment of moderate-to-severe AD. Additionally, upadacitinib can instantly relieve itchiness and effectively reduce symptoms and signs, with its 30-mg dose being more effective than the 15-mg dose.

Malignant glaucoma treated by low-dose laser cycloplasty: a 1-year multicenter prospective non-comparative study.

AIM: To report a one-year clinical outcomes of low-dose laser cycloplasty (LCP) among malignant glaucoma patients. METHODS: In this prospective, multicenter, non-comparative clinical study, participants with malignant glaucoma were recruited and underwent LCP at eight ophthalmic centers in China. Patients were followed up at 1wk, 1, 3, 6, and 12mo. Intraocular pressure (IOP), number of glaucoma medications, anterior chamber depth (ACD), and complications were recorded. Anatomical success was defined as the reformation of the anterior chamber based on slit-lamp biomicroscopy. Recurrence was defined by the presence of a shallow or flat anterior chamber after initial recovery from treatment. RESULTS: A total of 34 eyes received LCP. Mean IOP and medications decreased from 36.1±11.5 mm Hg with 3.3±1.5 glaucoma medications pre-treatment to 20.9±9.8 mm Hg (P<0.001) with 2.9±1.6 medications (P=0.046) at 1d, and 17.4±6.7 mm Hg (P<0.001) with 1.3±1.7 medications (P<0.001) at 12mo. The ACD increased from 1.1±0.8 mm at baseline to 1.7±1.0 mm and to 2.0±0.5 mm at 1d and 12mo, respectively. A total of 32 (94.1%) eyes achieved initial anatomical success. During follow-up, 2 (5.9%) eyes failed and 8 (23.5%) eyes relapsed, yielding a 12-month anatomical success rate of 64.3%. Complications including anterior synechia (8.82%), choroidal/ciliary detachment (5.88%) and hypopyon (2.94%) were observed within 1wk. CONCLUSION: LCP is simple, safe, and effective in reforming the anterior chamber in malignant glaucoma.

Modular access to diarylmethyl sulfonamides via visible light-promoted cross-coupling reactions.

We report a novel and efficient method for the preparation of diarylmethyl sulfonamide derivatives through visible-light-induced sulfamoylation of para-quinone methides with sulfamoyl chlorides under mild, metal-free conditions. This protocol demonstrates excellent tolerance toward a wide range of functional groups, affording the corresponding products in moderate to high yields. Preliminary mechanism studies revealed that the excited photocatalyst rhodamine 6G* was mainly quenched by para-quinone methides and the generated diarylmethyl radical intermediates then underwent radical-radical cross-coupling with sulfamoyl radicals to yield the diarylmethyl sulfonamides.

Dynamic responses of systemic immunity and splenic inflammation to long-term cyclic high-temperature exposure in growing pullets and laying hens.

Two trials were conducted to draw the phase-response curve of productive and immunological variables in heat-exposed layer chickens at different ages (71 to 130 d, and 211 to 270 d). Birds were acclimated to the following conditions for 60 d: constant optimal ambient temperature at 24°C and high ambient temperature at 34°C for 8 h/d (10:00-18:00). Data collection and biochemical measurements were performed every 10 d. In both age ranges, high temperature favored the innate immunity (P < 0.01) at the cost of performance (P < 0.05) during a given period, including the relative abundance of B and T-helper lymphocytes, lymphocyte proliferation ratio (B and T lymphocytes), and serum immunoglobulin contents (IgG and IgM) in the peripheral blood, as well as splenic expression of inflammation-related genes (iNOS, TLR-4, TNF-α, IL-6, and INF-γ). Compared with laying hens, growing pullets showed a time-delayed activation of immune response following heat challenge, and had no immunosuppression up to the end of exposure. Overall, the immune system of layer birds has a trade-off with production tissues in a hot environment, and exhibits distinct age-range-specific responses of acclimatization.

A Lu3Sc2Ga3O12: Eu3+ red-emitting phosphor with excellent optical properties and thermal stability was obtained by partially replacing Lu3+ with Gd3+ / Y3.

A novel red phosphor Lu3(1-x)Sc2Ga3O12: xEu3+(0 ≤ x ≤ 0.3) was successfully prepared by high temperature solid state method. The Lu2.4Sc2Ga3O12: 0.2Eu3+ phosphor shows strong high internal quantum efficiency and thermal stability with values of 64.79 % and 87.0 %, respectively. Based on Lu2.4Sc2Ga3O12: 0.2Eu3+ phosphor, the partial replacement of Lu3+ ions in the host by Gd3+ / Y3+ ions changes the local crystal field environment of Eu3+ ions, resulting in wonderful changes in the luminous center, and the luminous intensity at 593 nm is increased by 3.66 and 3.54 times, respectively. The decay time of Eu3+ ions is analyzed from the perspective of dynamics, and the reasons for the enhancement of luminescence after partial replacement of Lu3+ ions are discussed in detail from two aspects of phosphor structure and crystal field effect around Eu3+ ions. In addition, with the substitution of Gd3+ / Y3+ ions, the thermal stability of the sample is 90.3 %/89.4 % with excellent low thermal quenching. The thermal quenching mechanism is described by combining Debye temperature and activation energy. The sample also has a high internal quantum efficiency IQE=79.03 % / 78.24 %. Finally, under the excitation of 365 nm chip, the phosphors of Lu2.34Sc2Ga3O12: 0.2Eu3+, 0.02Gd3+ and Lu2.34Sc2Ga3O12: 0.2Eu3+, 0.02Y3+ synthesized R-LED device has extremely high color rendering index, Ra is 78.23/77.15 and color temperature is 1640.38 K/1642.97 K. The experimental results show that the Lu2.34Sc2Ga3O12: 0.2Eu3+, 0.02Gd3+ / Y3+ phosphors prepared has a wide application prospect in w-LED devices.

GDNF-induced phosphorylation of MUC21 promotes pancreatic cancer perineural invasion and metastasis by activating RAC2 GTPase.

Perineural invasion (PNI) is an adverse prognostic feature of pancreatic ductal adenocarcinoma (PDAC). However, the understanding of the interactions between tumors and neural signaling within the tumor microenvironment is limited. In the present study, we found that MUC21 servers as an independent risk factor for poor prognosis in PDAC. Furthermore, we demonstrated that MUC21 promoted the metastasis and PNI of PDAC cells by activating JNK and inducing epithelial-mesenchymal transition (EMT). Mechanistically, glial cell-derived neurotrophic factor, secreted by Schwann cells, phosphorylates the intracellular domain S543 of MUC21 via CDK1 in PDAC cells, facilitating the interaction between MUC21 and RAC2. This interaction leads to membrane anchoring and activation of RAC2, which in turn activates the JNK/ZEB1/EMT axis, ultimately enhancing the metastasis and PNI of PDAC cells. Our results present a novel mechanism of PNI, suggesting that MUC21 is a potential prognostic marker and therapeutic target for PDAC.

Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia.

To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CP-CML previously treated with tyrosine kinase inhibitors (TKIs). Patients with CML-CP were evaluated for the probabilities of responses including complete hematologic response (CHR), cytogenetic response, and molecular response (MR) and adverse events (AEs) after the later-line flumatinib therapy. Of 336 enrolled patients with median age 50 years, median duration of treatment with flumatinib was 11.04 (2-25.23) months. Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR)/2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR responses were achieved in 86.4%, 52.7%, 49.6%, and 23.5% patients respectively, which showed the lack of respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as 2L TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR. The AEs observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who are resistant or intolerant to other TKIs. In particular, 2L flumatinib treatment induced high response rates and was more beneficial to patients without previous 2G TKI resistance, thus serving as a probable treatment option for these patients.

Subtle Structural Differences Affect the Inhibitory Potency of RGD-Containing Cyclic Peptide Inhibitors Targeting SPSB Proteins.

The SPRY domain-containing SOCS box proteins SPSB1, SPSB2, and SPSB4 utilize their SPRY/B30.2 domain to interact with a short region in the N-terminus of inducible nitric oxide synthase (iNOS), and recruit an E3 ubiquitin ligase complex to polyubiquitinate iNOS, resulting in the proteasomal degradation of iNOS. Inhibitors that can disrupt the endogenous SPSB-iNOS interactions could be used to augment cellular NO production, and may have antimicrobial and anticancer activities. We previously reported the rational design of a cyclic peptide inhibitor, cR8, cyclo(RGDINNNV), which bound to SPSB2 with moderate affinity. We, therefore, sought to develop SPSB inhibitors with higher affinity. Here, we show that cyclic peptides cR7, cyclo(RGDINNN), and cR9, cyclo(RGDINNNVE), have ~6.5-fold and ~2-fold, respectively, higher SPSB2-bindng affinities than cR8. We determined high-resolution crystal structures of the SPSB2-cR7 and SPSB2-cR9 complexes, which enabled a good understanding of the structure-activity relationships for these cyclic peptide inhibitors. Moreover, we show that these cyclic peptides displace full-length iNOS from SPSB2, SPSB1, and SPSB4, and that their inhibitory potencies correlate well with their SPSB2-binding affinities. The strongest inhibition was observed for cR7 against all three iNOS-binding SPSB proteins.