Emerging polymeric materials for treatment of oral diseases: design strategy towards a unique oral environment.

Oral diseases are prevalent but challenging diseases owing to the highly movable and wet, microbial and inflammatory environment. Polymeric materials are regarded as one of the most promising biomaterials due to their good compatibility, facile preparation, and flexible design to obtain multifunctionality. Therefore, a variety of strategies have been employed to develop materials with improved therapeutic efficacy by overcoming physicobiological barriers in oral diseases. In this review, we summarize the design strategies of polymeric biomaterials for the treatment of oral diseases. First, we present the unique oral environment including highly movable and wet, microbial and inflammatory environment, which hinders the effective treatment of oral diseases. Second, a series of strategies for designing polymeric materials towards such a unique oral environment are highlighted. For example, multifunctional polymeric materials are armed with wet-adhesive, antimicrobial, and anti-inflammatory functions through advanced chemistry and nanotechnology to effectively treat oral diseases. These are achieved by designing wet-adhesive polymers modified with hydroxy, amine, quinone, and aldehyde groups to provide strong wet-adhesion through hydrogen and covalent bonding, and electrostatic and hydrophobic interactions, by developing antimicrobial polymers including cationic polymers, antimicrobial peptides, and antibiotic-conjugated polymers, and by synthesizing anti-inflammatory polymers with phenolic hydroxy and cysteine groups that function as immunomodulators and electron donors to reactive oxygen species to reduce inflammation. Third, various delivery systems with strong wet-adhesion and enhanced mucosa and biofilm penetration capabilities, such as nanoparticles, hydrogels, patches, and microneedles, are constructed for delivery of antibiotics, immunomodulators, and antioxidants to achieve therapeutic efficacy. Finally, we provide insights into challenges and future development of polymeric materials for oral diseases with promise for clinical translation.

The immune factors have complex causal regulation effects on kidney stone disease: a mendelian randomization study.

PURPOSE: Previous studies have reported the potential impact of immune cells on kidney stone disease (KSD), but definitive causal relationships have yet to be established. The purpose of this paper is to elucidate the potential causal association between immune cells and KSD by Mendelian randomization (MR) analysis. METHODS: In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between immune cell traits and kidney stone disease. We included a total of four immune traits (median fluorescence intensity (MFI), relative cellular (RC), absolute cellular (AC), and morphological parameters (MP)), which are publicly available data. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results. RESULTS: After FDR correction, the CD8 on HLA DR + CD8br (OR = 0.95, 95% CI = 0.93-0.98, p-value = 7.20 × 10- 4, q-value = 0.088) was determined to be distinctly associated with KSD, and we also found other 25 suggestive associations between immune cells and KSD, of which 13 associations were suggested as protective factors and 12 associations were suggested as risk factors. There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our Cochrane Q-test, MR Egger's intercept test, and MR-PRESSO, which were all > 0.05. CONCLUSIONS: Our study has explored the potential causal connection between immune cells and KSD by Mendelian randomization analysis, thus providing some insights for future clinical studies.

Saliva - a new opportunity for fluid biopsy.

Saliva is a complex biological fluid with a variety of biomolecules, such as DNA, RNA, proteins, metabolites and microbiota, which can be used for the screening and diagnosis of many diseases. In addition, saliva has the characteristics of simple collection, non-invasive and convenient storage, which gives it the potential to replace blood as a new main body of fluid biopsy, and it is an excellent biological diagnostic fluid. This review integrates recent studies and summarizes the research contents of salivaomics and the research progress of saliva in early diagnosis of oral and systemic diseases. This review aims to explore the value and prospect of saliva diagnosis in clinical application.

Nanocomposite Hydrogels in Regenerative Medicine: Applications and Challenges.

Regenerative medicine is a highly regarded multidisciplinary field that aims to transform the future of clinical medicine through curative strategies rather than palliative therapies. As an emerging field, the development of regenerative medicine cannot be achieved without multifunctional biomaterials. Among the various bioscaffold materials, hydrogels are one of the materials of interest in bioengineering and medical research because of their similarity to the natural extracellular matrix and good biocompatibility. However, conventional hydrogels have simple internal structures and single cross-linking modes, which require improvement in a single function and structural stability. Introducing multifunctional nanomaterials into 3D hydrogel networks physically or chemically avoids their disadvantages. Nanomaterials (NMs) are materials in the size range of 1-100 nm with distinct physical and chemical properties that differ from that of the macroscopic size and enable hydrogels to exhibit multifunctionality. Although regenerative medicine and hydrogels have been well researched in their respective fields, the connection between nanocomposite hydrogels (NCHs) and regenerative medicine has not been elaborated. Therefore, this review briefly describes the preparation and design requirements of NCHs and discusses their applications and challenges in regenerative medicine, hoping to clarify the relationship between the two.

Extensive generation and characterization of ion clusters by silicopolyoxometalate anions under matrix-assisted laser desorption/ionization conditions in the gas phase.

RATIONALE: The research area of ion clusters has helped to enrich the study of chemical bonding theory, clarify the crystal nucleation process and investigate the cluster ion-molecule reactions. The mass spectrometry (MS) technique, especially high-resolution MS, is an important method for investigating ion clusters in the gas phase. As polyoxometalates (POMs) have been attracting considerable interest in biochemistry, medicine and materials science due to their excellent structural and electronic features it is important to characterize these clusters by MS. METHODS: Singly negatively charged molybdenum-containing and tungsten-containing ion clusters with different matrices were produced by Keggin-type silicopolyoxometalate anions under matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICR MS) conditions. RESULTS: The matrices displayed an obvious influence on the formation of ion clusters. It was found that the molybdenum-containing ion species [(HSiO3 )(MoO3 )n ]- , [(SiO2 )m (MoO3 )n (H2 O)x ] -• , [(OH)(MoO3 )n ]-• , [(MoO3 )n ]-• , and [Hx SiMoy Oz ]- were the main ion series in the mass spectra. For the tungsten-containing ion clusters, [(HSiO3 )(WO3 )n ]- , [(C8 H5 Om )(WO3 )n (H2 O)x ]- , [(OH)(WO3 )n ]- , and [(WO3 )n ]-• were the main ion species in the mass spectra, and a series of organic-inorganic hybrid tungsten-containing ion clusters [(C8 H5 Om )(WO3 )n (H2 O)x ]- were generated by the interaction of DHAP and THAP matrices with tungstate anions. Furthermore, the most abundant species (magic number) in each ion series indicated that they might adopt more stable structures than other relevant clusters. CONCLUSIONS: Keggin-type silicopolyoxometalate anions can produce several series of singly charged molybdenum-containing/tungsten-containing ion clusters in negative-ion generating mode under MALDI conditions. It is proposed that the "Lucky Survivors" hypothesis may be used to illustrate the generation of ion clusters in the gas phase during the early stages of plume expansion. In addition, clear evidence of hydrogen transfer and electron capture to POMs was found in the obtained MALDI mass spectra. These results highlight the utility of the MALDI-FT method for obtaining novel ion clusters and also show the stability of these clusters.

Struvite-type AMgPO4·6H2O (A = NH4, K): Two Natural Deep-Ultraviolet Transparent Nonlinear Optical Crystals.

Deep-ultraviolet (DUV) nonlinear optical (NLO) materials play vital roles in diverse fields. Unfortunately, only the KBe2BO3F2 crystal has found commercial applications so far. Therefore, the discovery of new DUV NLO crystals is still urgent. As we all know, digging into the properties of existing crystals is also an effective way to obtain new NLO crystals. Herein, two natural asymmetric orthophosphates AMgPO4·6H2O (A = NH4, K) are proposed. Although their structures and some properties such as infrared spectra, thermal properties, and dielectric properties have been previously characterized, their NLO properties have not been reported. Thus, in this work, these two natural DUV transparent orthophosphates NH4MgPO4·6H2O (NMP) and KMgPO4·6H2O (KMP) were successfully acquired by a simple slow evaporation method. The single-crystal X-ray diffraction data indicate that NMP and KMP are isomorphic and that both belong to the Pmn21 space group of the orthorhombic system. Remarkably, NMP and KMP possess short cutoff edges below 190 nm, and their second-harmonic generation (SHG) efficiencies are 0.62 and 0.80 times that of KH2PO4(KDP), respectively; furthermore, they can achieve type-I phase matching at 1064 nm.

Upregulation of CASP9 through NF-κB and Its Target MiR-1276 Contributed to TNFα-promoted Apoptosis of Cancer Cells Induced by Doxorubicin.

：Under some conditions, nuclear factor-κB (NF-κB) has a pro-apoptotic role, but the mechanisms underlying this function remain unclear. This study demonstrated that NF-κB directly binds to CASP9 and miR1276 in tumor necrosis factor α (TNFα)-treated HeLa and HepG2 cells. NF-κB upregulated CASP9 expression, whereas downregulated miR1276 expression in the TNFα-treated cells. The miR1276 repressed CASP9 expression in both cells. As a result, a typical NF-κB-mediated coherent feed-forward loop was formed in the TNFα-treated cells. It was proposed that the NF-κB-mediated loop may contribute to cell apoptosis under certain conditions. This opinion was supported by the following evidence: TNFα promoted the apoptosis of HeLa and HepG2 cells induced by doxorubicin (DOX). CASP9 was significantly upregulated and activated by TNFα in the DOX-induced cells. Moreover, a known inhibitor of CASP9 activation significantly repressed the TNFα promotion of apoptosis induced by DOX. These findings indicate that CASP9 is a new mediator of the NF-κB pro-apoptotic pathway, at least in such conditions. This study therefore provides new insights into the pro-apoptotic role of NF-κB. The results also shed new light on the molecular mechanism underlying TNFα-promotion of cancer cells apoptosis induced by some anticancer drugs such as DOX.

Polarization switching realized in the continuous-wave and acousto-optic Q-switched pulse Er:Yb:LaMgB5O10 lasers at 1556 and 1568 nm.

By using the natural birefringence of crystalline quartz, the switching of a 1568 nm laser with polarization parallel to the Z optical indicatrix axis to a 1556 nm laser with polarization parallel to the Y optical indicatrix axis was observed in both continuous-wave and acousto-optic Q-switched pulse lasers based on an X-cut Er:Yb:LaMgB5O10 crystal, when the alignment of the output mirror in a 976 nm diode-end-pumped plano-concave resonator was precisely tilted. For the continuous-wave regime, a 1568 nm laser with a maximum output power of 500 mW and slope efficiency of 16%, as well as a 1556 nm laser with a maximum output power of 400 mW and slope efficiency of 13.5% were realized, respectively. For the Q-switched regime, a 1568 nm pulse laser with an energy of 144 µJ and width of 300 ns, as well as a 1556 nm pulse laser with an energy of 168 µJ and width of 270 ns, were obtained respectively by precisely tilting the alignment of the output mirror, when the absorbed pump power was 4.0 W and pulse repetition frequency was 0.5 kHz.

Efficient continuous-wave diode-pumped Er3+:Yb3+:LaMgB5O10 laser with sapphire cooling at 1.57 µm.

Efficient 1.57 µm continuous-wave laser was demonstrated in an X-cut, 2.0 mm-thick Er3+:Yb3+:LaMgB5O10 crystal with sapphire cooling end-pumped by a 976 nm laser diode. In a plano-concave cavity, a laser with a maximum output power of 0.61 W and a slope efficiency of 23% was realized at an absorbed pump power of 4.0 W. A continuous-wave 1566 nm micro-laser with a maximum output power of 0.47 W and a slope efficiency of 16% was also obtained. The lasers were totally linear polarization parallel to the crystalline Z axis. The results show that the Er3+:Yb3+:LaMgB5O10 crystal with high thermal conductivity may be a good gain medium for laser around 1.55 µm.

Efficient orthogonally polarized dual-wavelength Nd:LaMgB5O10 laser.

We reported an efficient, continuous-wave, diode-pumped, orthogonally polarized dual-wavelength laser working at 1051.8 and 1081.4 nm in a new neodymium-doped borate crystal, Nd:LaMgB5O10, which was grown by the top-seeded solution growth method. A maximum output power of 5.1 W was obtained with an absorbed pump power of 14.8 W, corresponding to an optical-to-optical conversion efficiency of 34.5% and a slope efficiency of 42.5%. By slightly tilting the laser cavity output mirror, the balanced dual-wavelength emissions were obtained with the total output power as high as 4.2 W. This new efficient dual-wavelength laser may be a promising light source for terahertz generation with a rarely large frequency difference of 7.8 THz through difference frequency generation.

Efficacy of erlotinib in previously treated patients with advanced non-small cell lung cancer: analysis of the Chinese subpopulation in the TRUST study.

OBJECTIVE: This study is to analyze the data of Chinese subpopulation in the Tarceva Lung Cancer Survival Treatment Study (TRUST-China) which was a global Phase IV study designed to provide erlotinib to previously treated patients with Stage IIIB/IV non-small cell lung cancer. METHODS: Patients with pathologically confirmed, unresectable Stage IIIB/IV non-small cell lung cancer who were previously failed on or unsuitable for chemotherapy or radiotherapy were given erlotinib (150 mg/day, oral) until disease progression, intolerable toxicity or death. Efficacy and toxicity of the agent were evaluated. RESULTS: In total, 519 patients Chinese patients were analyzed. The TRUST-China had similar baseline characteristics to TRUST-Global except the greater percentage of adenocarcinoma and non-smoker cases. The response rate and disease control rate were 24.7 and 75.3%, respectively. Median progression-free survival and overall survival were 6.4 and 15.4 months in the general Chinese population in the TRUST, and 10.2 and 18.9 months in non-smokers with adenocarcinoma (n = 254). Median progression-free survival and overall survival were significantly longer in non-smokers with adenocarcinoma than those in other groups (P ≤ 0.0001 and P ≤ 0.0001, respectively). Eastern Cooperative Oncology Group Performance Status (≥ 2 vs. ≤ 1, hazard ratio = 1.746, P < 0.0001) and histology (squamous cell carcinoma vs. adenocarcinoma, hazard ratio = 1.595, P = 0.0008) were independent risk factors that affected survival according to Cox regression multivariate analysis. CONCLUSIONS: We confirmed the efficacy and safety of erlotinib in Chinese patients. Non-smoking patients with adenocarcinoma histology had the best clinical benefits. (NCT00949910).

The risk factors for tuberculosis in liver or kidney transplant recipients.

BACKGROUND: Liver or kidney transplant recipients are at a higher risk of developing tuberculosis (TB) than general population. We aimed to clarify the incidence density of and risk factors for TB in liver or kidney transplant recipients in the present study. METHODS: All patients with TB following liver or kidney transplantation were investigated retrospectively at the Third Xiangya Hospital, Central South University, Changsha, China. The incidence density of TB was calculated. We performed a nested case-control study (1:1) to investigate by univariate and multivariate logistic regression analysis the potential risk factors for TB. RESULTS: From January 2000 to August 2013, 1748 kidney and 166 liver transplant recipients were performed at a university teaching hospital. Among the 1914 recipients, 45 cases (2.4%) of TB were reported. The incidence density was 506 cases per 105 patient-years in kidney or liver transplant recipients, which was 7 times higher than in the general Chinese population (around 70 cases per 105 person-years). The median time to develop TB was 20.0 months (interquartile ratio: 5.0-70.0). The receipt of a graft from a cadaveric donor (odds ratio [OR] = 3.7; 95% confidence interval [CI] = 1.4-10.0; P = 0.010) and the preoperative evidence of latent TB (OR = 6.8; 95% CI = 2.0-22.7; P = 0.002) were identified as two risk factors for developing TB in liver or kidney transplant recipients. CONCLUSIONS: The incidence density of TB among liver or kidney transplant recipients was much higher than in the general Chinese population. Recipients receiving a graft from a cadaveric donor and the preoperative evidence of latent TB were two major risk factors for developing TB in liver or kidney transplant recipients.

[Efficacies of gefitinib versus paclitaxel/carboplatin for patients with advanced pulmonary adenocarcinoma].

OBJECTIVE: To compare the clinical efficacies of gefitinib versus paclitaxel/carboplatin in patients with advanced pulmonary adenocarcinoma. METHODS: A total of 51 advanced pulmonary adenocarcinoma patients were recruited from Guangdong General Hospital during October 2006 to September 2007. Eligible patients were ≥ 18 years old, either non-smokers or former light smokers and receiving no prior chemotherapy or biological/immunological therapy. According to performance status, smoking status and gender, they were selected with dynamic equilibrium randomized method 1: 1 to receive first-line gefitinib (250 mg/d) in gefitinib arm or carboplatin/paclitaxel (carboplatin, area under the curve 5 mg × ml⁻¹ × min⁻¹, 21-day cycle; paclitaxel, 200 mg/m², 21-day cycle in chemotherapy arm. The primary endpoint was progression free survival (PFS). And the secondary endpoints were objective response rate (ORR) and overall survival (OS). RESULTS: They were randomized into gefitinib arm (n = 25) and paclitaxel/carboplatin arm (n = 26). The median PFS was 4.2 months in gefitinib arm and 8.3 months in paclitaxel/carboplatin arm (P = 0.422); ORR 36.0% in gefitinib arm and 42.3% in paclitaxel/carboplatin arm (P = 0.645); Median OS 14.4 months in gefitinib arm and 15.0 months in paclitaxel/carboplatin arm (P = 0.290). Multifactorial Cox regression analysis showed that age (P = 0.004), epidermal growth factor receptor (EGFR) gene mutation status (P = 0.012) and subsequent treatments (platinum-based chemotherapy, P = 0.001; EGFR-tyrosine kinase inhibitors (TKI), P = 0.005) were the significant predictors of OS. CONCLUSIONS: No significant differences exist in terms of efficacy and survival between first-line gefitinib and paclitaxel/carboplatin for Chinese patients with pulmonary adenocarcinoma who are non-smokers or former light smokers. And age, EGFR gene mutation status and subsequent treatments are significant predictor of OS. However, first-line gefitinib should not be recommended for advanced non-small cell lung cancer (NSCLC) patients only based on clinical factors, due to a very small sample-size in our study.

Novel ferroptosis signature for improving prediction of prognosis and indicating gene targets from single-cell level in oral squamous cell carcinoma.

Background: Oral squamous cell carcinoma (OSCC) is one of the most prevalent kinds of cancers. Therefore, there is a pressing need to create a new risk scoring model to personalize the prognosis of OSCC patients and screen for patient-specific therapeutic agents and molecular targets. Methods: Firstly, A series of bioinformatics was performed to construct a novel ferroptosis-related prognostic model; Further, drug sensitivity analysis was used to screen for specific therapeutic agents for OSCC; Single-cell analysis was employed to investigate the enrichment of FRDEGs (ferroptosis-related differentially expressed genes) in the OSCC microenvironment; Finally, various experiments were conducted to screen and validate molecular therapeutic targets for OSCC. Results: In this study, we constructed a novel 10-FRDEGs risk scoring model. Base on the risk scoring model, we founded three potential chemotherapeutic agents for OSCC: 5Z)-7-Oxozeaenol, AT-7519, KIN001-266; In addition, FRDEGs were enriched in the epithelial cells of OSCC. Finally, we found that CA9 and CAV1 could regulate OSCC proliferation, migration and ferroptosis in vitro. Conclusion: A novel 10-FRDEGs risk scoring model can predict the prognosis of patients with OSCC.Further,5Z)-7-Oxozeaenol, AT-7519, KIN001-266 are potential chemotherapeutic agents for OSCC.Moreover, we identified CA9、CAV1 as potential molecular target for the treatment of OSCC.Our findings provide new directions for prognostic assessment and precise treatment of oral cell squamous carcinoma.

Effects of collagen-based coating with chitosan and ε-polylysine on sensory, texture, and biochemical changes of refrigerated Nemipterus virgatus fillets.

In order to evaluate the effects of chitosan, ε-polylysine, and collagen on the preservation properties of refrigerated Nemipterus virgatus, samples were tested with different treatments for 10 days, namely chitosan, ε-polylysine and collagen (CH + ε-PL + CA), chitosan and ε-polylysine (CH + ε-PL), chitosan and collagen (CH + CA), ε-polylysine and collagen (ε-PL + CA), and the uncoated sample (CK). The results demonstrated that the bio-coating exhibited better preservation effects. The CH + ε-PL + CA, CH + ε-PL, CH + CA, ε-PL + CA treatments could significantly inhibit bacterial growth and retard the increase of total volatile base nitrogen (TVB-N), 2-thiobarbituric acid (TBA), K-value, and total viable counts (TVC) in N. virgatus fillets. The pH of all samples decreased and reached its lowest value on day 6, then increased significantly at the end of the experiment (p < .05). Water-holding capacity (WHC) of all the groups decreased continuously throughout storage, and CK reached 66.03% on day 6, which is significantly lower than CH + ε-PL + CA, CH + ε-PL, CH + CA, and ε-PL + CA (p < .05). On the contrary, the sensory scores of CH + ε-PL + CA, CH + ε-PL, CH + CA, and ε-PL + CA were significantly higher than the control, and the score of CH + ε-PL + CA (p < .05) was the best among all the groups. In terms of texture, CH + PL + CA also showed less cell shrinkage and tighter muscle fiber arrangement compared to other treatments. To sum up, the CH + PL + CA bio-coating proved to be a promising method for maintaining the storage quality of N. virgatus under refrigerated storage conditions.

Engineered microorganisms: A new direction in kidney stone prevention and treatment.

Numerous studies have shown that intestinal and urinary tract flora are closely related to the formation of kidney stones. The removal of probiotics represented by lactic acid bacteria and the colonization of pathogenic bacteria can directly or indirectly promote the occurrence of kidney stones. However, currently existing natural probiotics have limitations. Synthetic biology is an emerging discipline in which cells or living organisms are genetically designed and modified to have biological functions that meet human needs, or even create new biological systems, and has now become a research hotspot in various fields. Using synthetic biology approaches of microbial engineering and biological redesign to enable probiotic bacteria to acquire new phenotypes or heterologous protein expression capabilities is an important part of synthetic biology research. Synthetic biology modification of microorganisms in the gut and urinary tract can effectively inhibit the development of kidney stones by a range of means, including direct degradation of metabolites that promote stone production or indirect regulation of flora homeostasis. This article reviews the research status of engineered microorganisms in the prevention and treatment of kidney stones, to provide a new and effective idea for the prevention and treatment of kidney stones.

The effect and safety assessment of monitoring ethanol concentration in exhaled breath combined with intelligent control of renal pelvic pressure on the absorption of perfusion fluid during flexible ureteroscopic lithotripsy.

PURPOSE: Previously, we designed a ureteral access sheath with the capability of renal pelvic pressure (RPP) measurement and a medical perfusion and aspiration platform, allowing for the intelligent control of RPP. However, the effect of different RPP levels on perfusion fluid absorption remains unclear. This randomized controlled trial aimed to investigate the effects of exhaled ethanol concentration monitoring and intelligent pressure control on perfusion fluid absorption during flexible ureteroscopic lithotripsy. METHODS: Eighty patients scheduled for flexible ureteroscopic lithotripsy were randomly divided into four groups. In groups A, B, and C, the RPPs were set at 0, - 5, and - 10 mmHg, respectively. Group D was regarded as the controls with unfixed RPP. Isotonic saline containing 1% ethanol was used as the irrigation fluid, with an average irrigation flow rate of 100 mL/min. The primary outcome of this study was the absorption of perfusion fluid that was calculated based on the exhaled ethanol concentration. The secondary outcomes included duration of operation and amounts of perfusion fluid used. Postoperative complications, pre- and postoperative renal function, infection markers, and blood gas analysis were also recorded for safety assessment. RESULTS: In all, 76 patients were involved in this study, whose demographic characteristics and preoperative conditions were comparable among groups. Under the same perfusion flow rate, the groups with fixed RPP exhibited reduced absorption of perfusion fluid, duration of operation, and perfusion volume. In particular, the lowest values were observed in group C (RPP = - 10 mmHg). In contrast to the unfixed RPP group, no considerable difference were observed in levels of BUN, Scr, WBC, CRP, and blood gas values among the fixed RPP groups. Moreover, postoperative complications showed no significant difference among groups. CONCLUSION: In flexible ureteroscopic lithotripsy, the groups with fixed RPP had less absorption of perfusion fluid and perfusion volume, shorter duration of surgery, and higher safety than the unfixed group.

Inflammatory cytokines and their potential role in kidney stone disease: a Mendelian randomization study.

PURPOSE: Previous studies have reported a complex relationship between inflammatory cytokines and kidney stone disease (KSD). The purpose of this paper is to investigate the potential causal impact of inflammatory cytokines on KSD by Mendelian randomization (MR) analysis. METHODS: In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between inflammatory cytokines and kidney stone disease. Utilizing GWAS summary data of inflammatory cytokines and KSD, we performed the first two-sample MR analysis. Genetic variants in GWASs related to inflammatory cytokines were employed as instrumental variables (IVs). The data on cytokines were derived from 14,824 participants and analyzed by utilizing the Olink Target-96 Inflammation Panel. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Reverse MR analysis, Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results. RESULTS: 91 cytokines were enrolled in the MR analysis after strict quality control of IV. The IVW analysis revealed 2 cytokines as risk factors for KSD: Cystatin D (OR 1.06, 95% CI 1.01-1.11), Fibroblast growth factor 5 (OR 1.06, 95% CI 1.00-1.12), suggesting they are positively associated with the occurrence of kidney stones. We also found 3 protective associations between cytokines and KSD: Artemin (OR 0.86, 95% CI 0.78-0.96), T-cell surface glycoprotein CD6 isoform (OR 0.92, 95% CI 0.88-0.98), STAM-binding protein (OR 0.83, 95% CI 0.69-0.99). There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our MR Egger's intercept test, Cochrane Q-test, and MR-PRESSO, which were all > 0.05. CONCLUSIONS: Our study explored a variety of inflammatory cytokines related to KSD through MR analysis, which validated several previous findings and provided some new potential biomarkers for KSD. However, the findings require further investigation to validate their exact functions in the pathogenesis and evolution of KSD.

Nab-paclitaxel, cisplatin, and capecitabine versus cisplatin and gemcitabine as first line chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma: randomised phase 3 clinical trial.

OBJECTIVE: To compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment option for recurrent or metastatic nasopharyngeal carcinoma. DESIGN: Phase 3, open label, multicentre, randomised trial. SETTING: Four hospitals located in China between September 2019 and August 2022. PARTICIPANTS: Adults (≥18 years) with recurrent or metastatic nasopharyngeal carcinoma. INTERVENTIONS: Patients were randomised in a 1:1 ratio to treatment with either nab-paclitaxel (200 g/m2 on day 1), cisplatin (60 mg/m2 on day 1), and capecitabine (1000 mg/m2 twice on days 1-14) or gemcitabine (1 g/m2 on days 1 and 8) and cisplatin (80 mg/m2 on day 1). MAIN OUTCOME MEASURES: Progression-free survival was evaluated by the independent review committee as the primary endpoint in the intention-to-treat population. RESULTS: The median follow-up was 15.8 months in the prespecified interim analysis (31 October 2022). As assessed by the independent review committee, the median progression-free survival was 11.3 (95% confidence interval 9.7 to 12.9) months in the nab-TPC cohort compared with 7.7 (6.5 to 9.0) months in the gemcitabine and cisplatin cohort. The hazard ratio was 0.43 (95% confidence interval 0.25 to 0.73; P=0.002). The objective response rate in the nab-TPC cohort was 83% (34/41) versus 63% (25/40) in the gemcitabine and cisplatin cohort (P=0.05), and the duration of response was 10.8 months in the nab-TPC cohort compared with 6.9 months in the gemcitabine and cisplatin cohort (P=0.009). Treatment related grade 3 or 4 adverse events, including leukopenia (4/41 (10%) v 13/40 (33%); P=0.02), neutropenia (6/41 (15%) v 16/40 (40%); P=0.01), and anaemia (1/41 (2%) v 8/40 (20%); P=0.01), were higher in the gemcitabine and cisplatin cohort than in the nab-TPC cohort. No deaths related to treatment occurred in either treatment group. Survival and long term toxicity are still being evaluated with longer follow-up. CONCLUSION: The nab-TPC regimen showed a superior antitumoural efficacy and favourable safety profile compared with gemcitabine and cisplatin for recurrent or metastatic nasopharyngeal carcinoma. Nab-TPC should be considered the standard first line treatment for recurrent or metastatic nasopharyngeal carcinoma. Longer follow-up is needed to confirm the benefits for overall survival. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900027112.