Active strong coupling of exciton and nanocavity based on GSST-WSe2 hybrid nanostructures.

The strong coupling between optical resonance microcavity and matter excitations provides a practical path for controlling light-matter interactions. However, conventional microcavity, whose functions are fixed at the fabrication stage, dramatically limits the modulation of light-matter interactions. Here, we investigate the active strong coupling of resonance mode and exciton in GSST-WSe2 hybrid nanostructures. It is demonstrated that significant spectral splitting is observed in single nanostructures, tetramers, and metasurfaces. We further confirm the strong coupling by calculating the enhanced fluorescence spectra. The coupling effect between the excited resonance and exciton is dramatically modulated during the change of GSST from amorphous to crystalline, thus realizing the strong coupling switching. This switching property has been fully demonstrated in several systems mentioned earlier. Our work is significant in guiding the study of actively tunable strong light-matter interactions at the nanoscale.

The potent potential of MFAP2 in prognosis and immunotherapy of triple-negative breast cancer.

BACKGROUNDS: Microfibril-associated protein 2 (MFAP2) is a protein presenting in the extracellular matrix that governs the activity of microfibrils through its interaction with fibrillin. While the involvement of MFAP2 in metabolic disorders has been documented, its expression and prognostic significance in triple-negative breast cancer (TNBC) remain unexplored. METHODS: We acquired datasets pertaining to breast cancer (BC) from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Next, a Venn diagram was used to identify the differentially expressed genes (DEGs). The DEGs were used to perform Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI), immune and survival analysis. The expressions of MFAP2, PD-1 and PD-L1 were examined by immunohistochemistry and western blot and their relationship with clinical pathological parameters were analyzed by clinical specimen samples from patients with TNBC. Tumor Immune Estimation Resource (TIMER, https://cistrome.shinyapps.io/timer/ ) was adopted to calculate the immune infiltration level of TNBC. The link between gene expression and tumor mutational burden (TMB) was described using Spearman's correlation analysis. RESULTS: We identified 66 differentially expressed genes (DEGs) that were up-regulated. Among these DEGs, MFAP2 was found to be overexpressed in TNBC and was associated with a lower probability of survival. This finding was confirmed through the use of immunohistochemistry and western blot techniques. Additionally, MFAP2 was found to be related to various pathological parameters in TNBC patients. Mechanistically, gene set enrichment analysis (GSEA) revealed that MFAP2 primarily influenced cellular biological behavior in terms of epithelial mesenchymal transition, glycolysis, and apical junction. Notably, MFAP2 expression was positively correlated with the abundance of macrophages, while a negative correlation was observed with the abundance of B cells, CD4 + T cells, CD8 + T cells, neutrophils and dendritic cells through immune analysis. Furthermore, it was observed that MFAP2 displayed a negative correlation not only with tumor mutational burden (TMB), a recognized biomarker for PD-1/PD-L1 immunotherapy, but also with PD-L1 in samples of TNBC. CONCLUSION: MFAP2 may be an important prognostic biomarker for TNBC, as well as a viable target for immunotherapy in this disease.

Associations between smoking, sex steroid hormones, trouble sleeping, and depression among U.S. adults: a cross-sectional study from NHANES (2013-2016).

BACKGROUND: Dose-response and nonlinear relationships of cigarette exposure with sleep disturbances and depression are warranted, and the potential mechanism of sex hormones in such associations remains unclear. METHODS: Cigarette exposure, trouble sleeping, and depression were assessed by standard questionnaires, and the levels of cotinine and sex steroid hormones were determined among 9900 adults from the National Health and Nutrition Examination Survey (NHANES). Multiple linear regression, logistic regression, and mediation models were conducted to evaluate the associations between smoking, sex steroid hormones, trouble sleeping, and depression. RESULTS: With never smokers as a reference, current smokers had a higher prevalence of trouble sleeping (OR = 1.931, 95% CI: 1.680, 2.219) and depression (OR = 2.525, 95% CI: 1.936, 3.293) as well as testosterone level (ß = 0.083, 95% CI: 0.028, 0.140). Pack-years of smoking and cigarettes per day were positively associated with the prevalence of trouble sleeping and depression as well as testosterone level (Ptrend <0.05). The restricted cubic spline model showed linear relationships of cotinine with trouble sleeping, depression, and testosterone. The positive associations of cigarettes per day with trouble sleeping and depression were greater in females than that in males (Pmodification <0.05). However, the potential role of sex hormones was not observed in the association of cotinine with trouble sleeping or depression (Pmediation >0.05). CONCLUSION: Smoking may induce sex hormone disturbance and increase the risk of sleep problems and depression symptoms, and ceasing smoking may reduce the risk of such complications.

The temporal variation in the effects of extreme temperature on respiratory mortality: Evidence from 136 cities in China, 2006-2019.

BACKGROUND: In the context of climate change and urbanization, the temporal variation of the adverse health effect of extreme temperature has attracted increasing attention. METHODS: The meteorological data and the daily death records of mortality from respiratory diseases of 136 Chinese cities were from 2006 to 2019. Heat wave and cold spell were selected as the indicator events of extreme high temperature and extreme low temperature, respectively. The generalized linear model and time-varying distributed lag model were used to perform a two-stage time-series analysis to evaluate the temporal variation of the mortality risk associated with extreme temperature in the total population, sub-populations (sex- and age- specific) and different regions (climatic zone and relative humidity level). RESULTS: During the study period, relative risk (RR) of respiratory mortality associated with heat wave decreased from 1.22 (95 %CI: 1.07-1.39) to 1.13 (95 %CI: 1.01-1.26) in the total population, and RR of respiratory mortality associated with cold spell decreased from 1.30 (95 %CI: 1.14-1.49) to 1.17 (95 %CI: 1.08-1.26). The impact of heat wave reduced in the males (P = 0.044) and in the females as with cold spell (P < 0.001). The respiratory mortality risk of people over 65 associated with cold spell decreased (P = 0.040 for people aged 65-74 and P < 0.001 for people over 75). The effect of cold spell reduced in cities from tropical or arid zone (P = 0.035). The effects of both heat wave and cold spell decreased in cities with the relative humidity in the first quartile (P = 0.046 and 0.010, respectively). CONCLUSION: The impact of heat wave on mortality of respiratory diseases decreased mainly in males and cities with the lowest relative humidity, while the impact of cold spell reduced in females, people over 65 and tropical and arid zone, suggesting adaptation to extreme temperature of Chinese residents to some extent.

Anti-influenza activity of CPAVM1 protease secreted by Bacillus subtilis LjM2.

Bacillus spp. has been considered a promising source for identifying new antimicrobial substances, including anti-viral candidates. Here, we successfully isolated a number of bacteria strains from aged dry citrus peel (Chenpi). Of note, the culture supernatant of a new isolate named Bacillus subtilis LjM2 demonstrated strong inhibition of influenza A virus (IAV) infection in multiple experimental systems in vitro and in vivo. In addition, the anti-viral effect of LjM2 was attributed to its direct lysis of viral particles. Further analysis showed that a protease which we named CPAVM1 isolated from the culture supernatant of LjM2 was the key component responsible for its anti-viral function. Importantly, the therapeutic effect of CPAVM1 was still significant when applied 12 hours after IAV infection of experimental mice. Moreover, we found that the CPAVM1 protease cleaved multiple IAV proteins via targeting basic amino acid Arg or Lys. Furthermore, this study reveals the molecular structure and catalytic mechanism of CPAVM1 protease. During catalysis, Tyr75, Tyr77, and Tyr102 are important active sites. Therefore, the present work identified a special protease CPAVM1 secreted by a new strain of Bacillus subtilis LjM2 against influenza A virus infection via direct cleavage of critical viral proteins, thus facilitates future biotechnological applications of Bacillus subtilis LjM2 and the protease CPAVM1.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Building a novel TRUCK by harnessing the endogenous IFN-gamma promoter for cytokine expression.

Despite the remarkable success of CAR T therapy in hematological malignancies, its efficacy in solid tumors remains limited. Cytokine-engineered CAR T cells offer a promising avenue, yet their clinical translation is hindered by the risks associated with constitutive cytokine expression. In this proof-of-concept study, we leverage the endogenous IFN-γ promoter for transgenic IL-15 expression. We demonstrate that IFN-γ expression is tightly regulated by TCR signaling. By introducing IRES-IL15 into the 3'-UTR of the IFN-γ gene via HDR-mediated knock-in, we confirm that IL-15 expression can co-express with IFN-γ in an antigen-stimulation-dependent manner. Importantly, the insertion of transgenes does not compromise endogenous IFN-γ expression. In vitro and in vivo data demonstrate that IL-15 driven by the IFN-γ promoter dramatically improves CAR T cells' antitumor activity, suggesting the effectiveness of IL-15 expression. Lastly, as part of our efforts toward clinical translation, we have developed an innovative two-gene knock-in approach. This approach enables the simultaneous integration of CAR and IL-15 genes into TRAC and IFN-γ gene loci using a single AAV vector. CAR T cells engineered to express IL-15 using this approach demonstrate enhanced antitumor efficacy. Overall, our study underscores the feasibility of utilizing endogenous promoters for transgenic cytokines expression in CAR T cells.

Final analysis of camrelizumab plus chemotherapy for untreated advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st trial.

BACKGROUND: The interim analysis of the randomized phase 3 ESCORT-1st study demonstrated significantly longer overall survival (OS) and progression-free survival (PFS) for camrelizumab-chemotherapy than placebo-chemotherapy in untreated advanced/metastatic esophageal squamous cell carcinoma (ESCC). Here, we present the final analysis of this study and investigate potential indicators associated with OS. METHODS: Patients were randomized 1:1 to receive camrelizumab (200 mg) or placebo, both in combination with up to six cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All treatments were administered intravenously every 3 weeks. The co-primary endpoints were OS and PFS assessed by the independent review committee. FINDINGS: As of April 30, 2022, the median OS was significantly longer in the camrelizumab-chemotherapy group compared to the placebo-chemotherapy group (15.6 [95% confidence interval (CI): 14.0-18.4] vs. 12.6 months [95% CI 11.2-13.8]; hazard ratio [HR]: 0.70 [95% CI 0.58-0.84]; one-sided p < 0.0001), with 3-year OS rates of 25.6% and 12.8% in the two groups, respectively. The 2-year PFS rates were 20.4% in the camrelizumab-chemotherapy group and 3.4% in the placebo-chemotherapy group. Adverse events were consistent with those reported in the interim analysis. Higher PD-L1 expression correlated with extended OS, and multivariate analysis identified sex and prior history of radiotherapy as independent indicators of OS. CONCLUSIONS: The sustained and significant improvement in efficacy with camrelizumab-chemotherapy compared to placebo-chemotherapy, along with the absence of accumulating or delayed toxicities, supports the long-term use of camrelizumab-chemotherapy as a standard therapy in untreated advanced/metastatic ESCC. FUNDING: This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

A Novel Inhalable Nanobody Targeting IL-4Rα for the Treatment of Asthma.

BACKGROUND: Inhalable biologics represent a promising approach to improve the efficacy and safety of asthma treatment. Although several monoclonal antibodies (mAbs) targeting IL-4Rα have been approved or are undergoing clinical trials, the development of inhalable mAbs targeting IL-4Rα presents significant challenges. OBJECTIVE: Capitalizing on the distinctive advantages of nanobodies (Nbs) in maintaining efficacy during storage and administration, we sought to develop a novel inhalable IL-4Rα Nb for effectively treating asthma. METHODS: Three IL-4Rα immunized Nb libraries were utilized to generate specific and functional IL-4Rα Nbs. LQ036, a bivalent Nb comprising two HuNb103 units, was constructed with a high affinity and specificity for hIL-4Rα. The efficacy, pharmacokinetic and safety of inhaled LQ036 were evaluated in B-hIL4/hIL4Ra humanized mice. RESULTS: LQ036 inhibited secreted embryonic alkaline phosphatase (SEAP) reporter activity, TF-1 cell proliferation, and suppressed pSTAT6 in T cells from asthma patients. Crystal structure analysis revealed a binding region similar to Dupilumab but with higher affinity, leading to better efficacy in blocking the signaling pathway. HuNb103 competed with IL-4 and IL-13 for IL-4Rα binding. Additionally, LQ036 significantly inhibited OVA-specific IgE levels in serum, CCL17 levels in BALF, bronchial mucous cell hyperplasia, and airway goblet cell hyperplasia in B-hIL4/hIL4Ra humanized mice. Inhaled LQ036 exhibited favorable pharmacokinetics, safety and tissue distribution, with higher concentrations observed in the lungs and bronchi. CONCLUSION: These findings from preclinical studies establish the safety and efficacy of inhaled LQ036, underscoring its potential as a pioneering inhalable biologic therapy for asthma.

Impact of background music listening on anxiety in cancer patients undergoing initial radiation therapy: a randomized clinical trial.

BACKGROUND: Patients undergoing radiation therapy (RT) often experience anxiety, which may jeopardize the treatment success. The efficacy of music interventions in reducing anxiety remains contentious. This randomized trial aimed to evaluate the impact of music listening on anxiety symptoms in patients undergoing initial RT. METHODS: First-time RT patients were randomly allocated to experimental and control groups. The Brief Symptom Rating Scale (BSRS-5), Distress Thermometer (DT), and Beck Anxiety Inventory (BAI-C) were administered pre- and post-RT. Changes in physiological anxiety symptoms were monitored over 10 consecutive days starting from the first day of RT. The experimental group received music during RT; the control group did not. The generalized linear mixed model was used to estimate the pre-post difference in the BSRS-5, DT, and BAI-C scores between the music intervention and control group. RESULTS: This study included 50 patients each in the experimental and control groups. BSRS-5 and DT scores were significantly reduced in the experimental group post-RT (p = 0.0114 and p = 0.0023, respectively). When music listening was discontinued, these scores rebounded. While the posttest BAI-C score was significantly lower in the experimental group (p < 0.0001), the pre-post difference between the two groups was not significant (p = 0.0619). On cessation of music listening, the BAI-C score also rebounded. CONCLUSIONS: For cancer patients undergoing initial RT, music listening intervention significantly reduced anxiety symptoms measured using the BSRS-5, DT, and BAI-C scores after two weeks. Our results demonstrate the effectiveness of music listening intervention in reducing anxiety symptoms, thereby potentially improving the quality of life of cancer patients undergoing RT.

Modifiable risk factors of immediate and long-term outcomes in the operable and inoperable with left-sided infective endocarditis.

Objectives: To evaluate the outcomes of left-sided infective endocarditis that can be operated on and cannot be operated on, and to focus on modifiable risk factors for immediate and long-term mortality. Methods: This study retrospectively investigated patients with left-sided infective endocarditis who occurred in our medical center between January 2006 and November 2022. Results: 48 in-hospital deaths occurred (5.8 %, 48/832). We identified time from symptoms to admission and symptomatic neurological complications to be risk factors for multiple organ failure upon admission. Time from symptoms to admission and vegetation size in group of isolated medical treatment were significantly shorter than those in the group of heart operation. We also found that preoperative neurological complications, annulus destruction, levels of serum creatinine at 24 and 48 h post heart operation, and perivalvular leakage are risk factors for in-hospital mortality post heart operation. With 148 µmol/L as a cutoff level, the diagnostic sensitivity and specificity of serum creatinine level 48 h post surgery for in-hospital mortality post cardiac surgery are 100 % and 81.6 %, respectively. We found that vegetation size, ICU stay, postoperative serum creatinine at 48 h, left ventricular end diastolic size postoperative, and red blood cell transfusion were associated with all-time mortality. Conclusions: Early diagnosis and treatment, improvement of surgical techniques, good protection for heart, kidney and blood and close follow-up are advocated to conduce to better immediate and long-term outcomes of the operable and inoperable with left-sided infective endocarditis.

PD-1/PD-L1 Provides Protective Role in Hypoxia-Induced Pulmonary Vascular Remodeling.

BACKGROUND: Hypoxia-induced pulmonary hypertension (HPH) is a T helper 17 cell response-driven disease, and PD-1 (programmed cell death 1)/PD-L1 (programmed cell death-ligand 1) inhibitor-associated pulmonary hypertension has been reported recently. This study is designed to explore whether the PD-1/PD-L1 pathway participates in HPH via regulating endothelial dysfunction and T helper 17 cell response. METHODS: Lung tissue samples were obtained from eligible patients. Western blotting, immunohistochemistry, and immunofluorescence techniques were used to assess protein expression, while immunoprecipitation was utilized to detect ubiquitination. HPH models were established in C57BL/6 WT (wild-type) and PD-1-/- mice, followed by treatment with PD-L1 recombinant protein. Adeno-associated virus vector delivery was used to upregulate PD-L1 in the endothelial cells. Endothelial cell function was assessed through assays for cell angiogenesis and adhesion. RESULTS: Expression of the PD-1/PD-L1 pathway was downregulated in patients with HPH and mouse models, with a notable decrease in PD-L1 expression in endothelial cells compared with the normoxia group. In comparison to WT mice, PD-1-/- mice exhibited a more severe HPH phenotype following exposure to hypoxia, However, administration of PD-L1 recombinant protein and overexpression of PD-L1 in lung endothelial cells mitigated HPH. In vitro, blockade of PD-L1 with a neutralizing antibody promoted endothelial cell angiogenesis, adhesion, and pyroptosis. Mechanistically, hypoxia downregulated PD-L1 protein expression through ubiquitination. Additionally, both in vivo and in vitro, PD-L1 inhibited T helper 17 cell response through the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in HPH. CONCLUSIONS: PD-1/PD-L1 plays a role in ameliorating HPH development by inhibiting T helper 17 cell response through the PI3K/AKT/mTOR pathway and improving endothelial dysfunction, suggesting a novel therapeutic indication for PD-1/PD-L1-based immunomodulatory therapies in the treatment of HPH.

Corrigendum: A novel model based on necroptosis to assess progression for polycystic ovary syndrome and identification of potential therapeutic drugs.

[This corrects the article DOI: 10.3389/fendo.2023.1193992.].

Clinical value of serum tumor markers in assessing the efficacy of neoadjuvant chemotherapy in advanced ovarian cancer: single-center prospective clinical study.

Objective: This study aimed to assess the clinical importance of various biomarkers, including NLR, CEA, CA199, CA125, CA153, and HE4, through dynamic testing to evaluate the effectiveness of neoadjuvant chemotherapy (NACT) for individuals facing advanced ovarian cancer. This provides valuable information for tailoring treatment plans to individual patients, thereby leading to a more personalized and effective management of individuals facing ovarian cancer. Methods: The levels of NLR, CA125, CA199, CEA, CA153, and HE4 were detected before chemotherapy and after 3 courses of chemotherapy. Patients were categorized into ineffective and effective groups according to the effectiveness of NACT. To evaluate the factors influencing NACT's effectiveness in individuals facing advanced ovarian cancer, receiver operating characteristic (ROC) curves, predictive modeling, and multifactorial regression analysis were employed. Results: In the effective group, the patients' age, maximum tumor diameter, and CEA and HE4 levels of the patients were significantly higher compared to those in the ineffective group (P <.05). Additionally, the difference in HE4 levels before and after treatment between the effective and ineffective groups was statistically significant (P<.05). Multifactorial analysis showed that age and maximum tumor diameter were independent risk factors impacting the effectiveness of NACT in individuals facing advanced ovarian cancer (P<.05). The ROC curve for predicting the effectiveness of NACT in individuals facing advanced ovarian cancer showed a sensitivity of 93.3% for NLR and a specificity of 92.3% for CA199. HE4 emerged as the most reliable predictor, demonstrating a specificity of 84.6% and a sensitivity of 75.3%. The area under the curve of the combined CA125 and HE4 assays for predicting the ineffectiveness of NACT in individuals facing advanced ovarian cancer was 0.825, showcasing a specificity of 74.2% and a sensitivity of 84.6%. Conclusion: The predictive capacity for the effectiveness of NACT in individuals facing advanced ovarian cancer is notably high when considering the sensitivity of NLR and the specificity of CA199. Additionally, the combination of CA125 and HE4 assays can obtain a better predictive effect, which can accurately select patients suitable for NACT, determine the appropriate timing of the interval debulking surgery (IDS) surgery, and achieve a satisfactory tumor reduction effect.

Post-marketing Safety Concerns of Teprotumumab: A Real-World Pharmacovigilance Assessment.

PURPOSE: Teprotumumab is the only drug approval by The US Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED), which targets the insulin-like growth factor-1 receptor. This study aimed to identify potential safety signals of teprotumumab by analyzing post-marketing safety data from the FDA Adverse Event Reporting System (FAERS) database in 2023. METHODS: The case/non-case approach was used to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for adverse events (AEs) that numbered three or more. RESULTS: Total of 2158 cases were included in the analysis. Main safety signals identified were ear and labyrinth disorders, reproductive system and breast disorders, metabolism and nutrition disorders and gastrointestinal disorders. Specifically, autophony (ROR [95% CI] = 4188.34 [1403.29-12500.8]), eyelid retraction (ROR [95% CI] = 2094.17 [850.69-5155.29]), deafness permanent (ROR [95% CI] = 1552.35 [789.07-3053.98]), deafness bilateral (ROR [95% CI] = 73.12 [41.14-129.97]), inflammatory bowel disease (ROR [95% CI] = 23.26 [13.46-40.19]), hyperglycaemic hyperosmolar nonketotic syndrome (ROR [95% CI] = 17.75 [5.70-55.28]) and amenorrhoea (ROR [95% CI] = 47.98 [36.22-63.54]) showed significant safety signals of teprotumumab. CONCLUSIONS: This study identified ear and labyrinth disorders, reproductive system and breast disorders, as specific safety signals of teprotumumab. Clinicians and pharmacists should be vigilant regarding these AEs. However, available data are currently insufficient, and further pharmacovigilance and surveillance are needed to fully understand this issue.

Obg-like ATPase 1 exacerbated gemcitabine drug resistance of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a poor prognosis due to inefficient diagnosis and tenacious drug resistance. Obg-like ATPase 1 (OLA1) is overexpressed in many malignant tumors. The molecular mechanism of OLA1 underlying gemcitabine (GEM)-induced drug resistance was investigated in this study. An enhanced expression of OLA1 was observed in a GEM acquired resistant pancreatic cancer cell lines and in patients with pancreatic cancer. Overexpressed OLA1 showed poor overall survival rates in patients with pancreatic cancer. Dysregulation of the OLA1 reduced expression of CD44+/CD133+, and improved the sensitivity of pancreatic cancer cells to GEM. OLA1 highly expression facilitated the formation of the OLA1/Sonic Hedgehog (SHH)/Hedgehog-interacting protein (HHIP) complex in nuclei, resulting in the inhibition of negative feedback of Hedgehog signaling induced by HHIP. This study suggests that OLA1 may be developed as an innovative drug target for an effective therapy of pancreatic cancer.

Clinical features and lymphocyte immunophenotyping analysis in primary immunodeficiency patients with non-transplant lymphoproliferative disorders.

Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the "Disease of immune dysregulation" category. Of 96 Taiwanese patients during 2003-2022, 31 (median 66, range 0.03-675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3-252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (2 IL2RG; CD40L, ZAP70 and unknown each), syndromic features (2 STAT3-LOF, 1 WAS and 1 ATM) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.

Developmental toxicity assay of xanthatin in zebrafish embryos.

Xanthatin (XAN), a xanthanolide sesquiterpene lactone, isolated from Chinese herb, Xanthium strumarium L, has various pharmacological activities, such as antitumor activity and anti-inflammatory. However, little is known about its potential toxicity and the mechanism. Here, zebrafish model was used to study the developmental toxicity in vivo. Our results indicated that xanthatin increased the mortality and led to the morphological abnormalities including pericardial edema, yolk sac edema, curved body shape and hatching delay. Furthermore, xanthatin damaged the normal structure and/or function of heart, liver, immune and nervous system. ROS elevation and much more apoptosis cells were observed after xanthatin exposure. Gene expression results showed that oxidative stress-related genes nrf2 was inhibited, while oxidative stress-related genes (keap1 and nqo1) and apoptotic genes (caspase3, caspase9 and p53) were increased after xanthatin exposure. Mitophagy related genes pink1 and parkin, and wnt pathway (ß-catenin, wnt8a and wnt11) were significantly increased after xanthatin exposure. Taken together, our finding indicated that xanthatin induced developmental toxicity, and the ROS elevation, apoptosis activation, dysregulation of mitophagy and wnt pathways were involved in the toxicity caused by xanthatin.

Metabolomics reveals high fructose-1,6-bisphosphate from fluoride-resistant Streptococcus mutans.

BACKGROUND: Fluoride-resistant Streptococcus mutans (S. mutans) strains have developed due to the wide use of fluoride in dental caries prevention. However, the metabolomics of fluoride-resistant S. mutans remains unclear. OBJECTIVE: This study aimed to identify metabolites that discriminate fluoride-resistant from wild-type S. mutans. MATERIALS AND METHODS: Cell supernatants from fluoride-resistant and wild-type S. mutans were collected and analyzed by liquid chromatography-mass spectrometry. Principal components analysis and partial least-squares discriminant analysis were performed for the statistical analysis by variable influence on projection (VIP > 2.0) and p value (Mann-Whitney test, p < 0.05). Metabolites were assessed qualitatively using the Human Metabolome Database version 2.0 ( http://www.hmdb.ca ), or Kyoto Encyclopedia of Genes and Genomes ( http://www.kegg.jp ), and Metaboanalyst 6.0 ( https://www.metaboanalyst.ca ). RESULTS: Fourteen metabolites differed significantly between fluoride-resistant and wild-type strains in the early log phase. Among these metabolites, 5 were identified. There were 32 differential metabolites between the two strains in the stationary phase, 13 of which were identified. The pyrimidine metabolism for S. mutans FR was matched with the metabolic pathway. CONCLUSIONS: The fructose-1,6-bisphosphate concentration increased in fluoride-resistant strains under acidic conditions, suggesting enhanced acidogenicity and acid tolerance. This metabolite may be a promising target for elucidating the cariogenic and fluoride resistant mechanisms of S. mutans.

Green supply chain finance strategies with market competition and financial constraints.

In the context of sustainable development, market competition is intensifying, and financial constraints have emerged as a significant hindrance to green project investment. Green Supply Chain Finance (GSCF), characterized by long-term collaboration, has emerged as a crucial financial approach to mitigate corporate financial limitations and channel capital flows into environmentally friendly industries. We propose a two-echelon supply chain with one supplier and two competing retailers over a single period and investigate ordering, sales, and financing decisions simultaneously under competition. Retailers constrained by financial considerations may secure GSCF or traditional bank financing (BF) loans. This study investigates the influence of competition on pricing and sales strategies during the selling season. The results demonstrate that retailers select between clearance and responsive selling strategies based on the level of market competition. During the ordering season, retailers share the product market equally when interest rates are uniform, and the supplier formulates a supply chain contract while considering the financing interest rate. In the presence of differential interest rates, retailers may not always opt for the GSCF, even when they offer an interest rate advantage, due to the comprehensive impacts of operational and financial strategies. Remarkably, competitive retailers do not choose the GSCF when their initial green investment capital surpasses a certain threshold.