Comparison of two ablation procedures combined with high ligation and foam sclerotherapy and compression therapy for patients with venous leg ulcers.

AIM: To compare the ablation techniques' efficacy of endovenous microwave ablation (EMA) combined with high ligation (HL), foam sclerotherapy (FS) and compression therapy (CT) and endovenous laser ablation (EVLA) combined with HL-FS-CT in the treatment of VLUs. METHOD: 301 consecutive patients with VLUs from 2013 to 2022 in a 3200-bed hospital were intervened by EMA combined with HL-FS-CT and EVLA combined with HL-FS-CT were retrospectively compared. RESULTS: One hundred thirty-four patients underwent EMA+HL-FS-CT and 167 patients underwent EVLA+HL-FS-CT. The primary outcome of the ulcer healing time was 1.45(0.75-1.5) months and 1.86(0.5-2.5) months, respectively, in the two groups (HR for ulcer healing was 1.26, 95% CI [0.96-1.66], p = 0.097). Secondary outcomes included that no significant difference was found in ulcer recurrence and GSV recanalization and complications between the two groups, and the postoperative VCSS and AVVQ were significantly lower than the baseline values in the respective groups (p = 0.0001). CONCLUSION: EMA+HL-FS-CT and EVLA+HL-FS-CT are both effective at treating VLUs. Both of the two comprehensive treatments were beneficial to the healing of ulcers, but no evidence showed which one was superior in the ulcer healing time.

New clinical trial design in precision medicine: discovery, development and direction.

In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional "one-size-fits-all" trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the "Precision Pro", "Dynamic Precision", and "Intelligent Precision". This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.

A quantitative survey of the blueberry (Vaccinium spp.) culturable nectar microbiome: variation between cultivars, locations, and farm management approaches.

Microbes in floral nectar can impact both their host plants and floral visitors, yet little is known about the nectar microbiome of most pollinator-dependent crops. In this study, we examined the abundance and composition of the fungi and bacteria inhabiting Vaccinium spp. nectar, as well as nectar volume and sugar concentrations. We compared wild V. myrsinites with two field-grown V. corymbosum cultivars collected from two organic and two conventional farms. Differences in nectar traits and microbiomes were identified between V. corymbosum cultivars but not Vaccinium species. The microbiome of cultivated plants also varied greatly between farms, whereas management regime had only subtle effects, with higher fungal populations detected under organic management. Nectars were hexose-dominant, and high cell densities were correlated with reduced nectar sugar concentrations. Bacteria were more common than fungi in blueberry nectar, although both were frequently detected and co-occurred more often than would be predicted by chance. "Cosmopolitan" blueberry nectar microbes that were isolated in all plants, including Rosenbergiella sp. and Symmetrospora symmetrica, were identified. This study provides the first systematic report of the blueberry nectar microbiome, which may have important implications for pollinator and crop health.

The maize PLASTID TERMINAL OXIDASE (PTOX) locus controls the carotenoid content of kernels.

Carotenoids perform a broad range of important functions in humans; therefore, carotenoid biofortification of maize (Zea mays L.), one of the most highly produced cereal crops worldwide, would have a global impact on human health. PLASTID TERMINAL OXIDASE (PTOX) genes play an important role in carotenoid metabolism; however, the possible function of PTOX in carotenoid biosynthesis in maize has not yet been explored. In this study, we characterized the maize PTOX locus by forward- and reverse-genetic analyses. While most higher plant species possess a single copy of the PTOX gene, maize carries two tandemly duplicated copies. Characterization of mutants revealed that disruption of either copy resulted in a carotenoid-deficient phenotype. We identified mutations in the PTOX genes as being causal of the classic maize mutant, albescent1. Remarkably, overexpression of ZmPTOX1 significantly improved the content of carotenoids, especially ß-carotene (provitamin A), which was increased by ~threefold, in maize kernels. Overall, our study shows that maize PTOX locus plays an important role in carotenoid biosynthesis in maize kernels and suggests that fine-tuning the expression of this gene could improve the nutritional value of cereal grains.

Macrophage KLF15 prevents foam cell formation and atherosclerosis via transcriptional suppression of OLR-1.

BACKGROUND: Macrophage-derived foam cells are a hallmark of atherosclerosis. Scavenger receptors, including lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (OLR-1), are the principal receptors responsible for the uptake and modification of LDL, facilitating macrophage lipid load and the uptake of oxidized LDL by arterial wall cells. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates the expression of genes by binding to the promoter during transcription. Therefore, this study aimed to investigate the precise role of macrophage KLF15 in atherogenesis. METHODS: We used two murine models of atherosclerosis: mice injected with an adeno-associated virus (AAV) encoding the Asp374-to-Tyr mutant version of human PCSK9, followed by 12 weeks on a high-fat diet (HFD), and ApoE-/-- mice on a HFD. We subsequently injected mice with AAV-KLF15 and AAV-LacZ to assess the role of KLF15 in the development of atherosclerosis in vivo. Oil Red O, H&E, and Masson's trichome staining were used to evaluate atherosclerotic lesions. Western blots and RT-qPCR were used to assess protein and mRNA levels, respectively. RESULTS: We determined that KLF15 expression was downregulated during atherosclerosis formation, and KLF15 overexpression prevented atherosclerosis progression. KLF15 expression levels did not affect body weight or serum lipid levels in mice. However, KLF15 overexpression in macrophages prevented foam cell formation by reducing OLR-1-meditated lipid uptake. KLF15 directly targeted and transcriptionally downregulated OLR-1 levels. Restoration of OLR-1 reversed the beneficial effects of KLF15 in atherosclerosis. CONCLUSION: Macrophage KLF15 transcriptionally downregulated OLR-1 expression to reduce lipid uptake, thereby preventing foam cell formation and atherosclerosis. Thus, our results suggest that KLF15 is a potential therapeutic target for atherosclerosis.

Novel androgen receptor inhibitors for metastatic hormone-sensitive prostate cancer: Current application and future perspectives.

Androgen receptor (AR) signaling is essential in prostate cancer treatment. For many years, androgen deprivation therapy (ADT) has been primarily applied to manage advanced prostate cancer. However, most individuals with metastatic hormone-sensitive prostate cancer (mHSPC) administered ADT alone are at risk of developing metastatic castration-resistant prostate cancer (mCRPC) in less than two years. New approaches employing novel AR inhibitors (ARi) as intensified upfront systemic treatment in mHSPC have recently demonstrated substantial benefits in delaying disease progression and prolonging overall survival. Administration of novel ARi has become the new standard of care in mHSPC. The new landscape simultaneously makes treatment choice more challenging. This review provides comprehensive data on molecular structure, pharmaceutical properties, and efficacy and safety profiles reported by pivotal clinical trials. We also discuss future directions with ongoing Phase III trials of novel ARi in mHSPC. Considering these biological and clinical insights, this review aimed to provide a comprehensive understanding of differences in the development and applications of novel ARi for mHSPC, which may be helpful in designing strategies for first-line treatment choices.

Analysis of volatile organic compounds and potential odour compounds in food contact paperboard using headspace two-dimensional GC-QTOF-MS.

The objective was to establish a robust and reliable approach for the characterisation of volatile organic compounds (VOCs) present in food contact paperboard. This was achieved through the utilisation of headspace solid-phase microextraction in tandem with comprehensive two-dimensional (2D) gas chromatography (GC) and quadrupole time-of-flight mass spectrometry (HS-SPME-GC × GC-QTOF-MS). The experimental parameters were optimised, involving the use of a DVB/C-WR/PDMS fibre at a temperature of 80 °C for a duration of 30 min. A total of 344 VOCs comprising aldehydes, ketones, alcohols, ethers, esters, alkanes and aromatic compounds, were tentatively identified in the samples. Twelve compounds believed to be from biogenic sources had a high odour impact making them major contributors to potential taint from the paperboard samples. Significant attention should be devoted to five compounds namely, 2-methylnaphthalene, 2-pentyl-furan, furfural, 1-octen-3-one and 1-octen-3-ol due to their potential adverse impact on the organoleptic qualities of packaged food items and their potential toxicity.Abbreviations: C-WR: carbon wide range; DVB: divinylbenzene; GC-MS: gas chromatography - mass spectrometry; GCxGC-QTOF-MS: comprehensive two-dimensional gas chromatography coupled to quadrupole-time-of-flight - mass spectrometry; HS-SPME: headspace - solid phase microextraction; LOD: limit of detection; LOQ: limit of quantification; OAV: odor activity values; PDMS: polydimethylsiloxane; RI: retention index; TTC: threshold of toxicological concern; VOC: volatile organic compound.

The Protective Role of Dietary Polyphenols in Urolithiasis: Insights into Antioxidant Effects and Mechanisms of Action.

Urolithiasis is a common urological disease with increasing prevalence and high recurrence rates around the world. Numerous studies have indicated reactive oxygen species (ROS) and oxidative stress (OS) were crucial pathogenic factors in stone formation. Dietary polyphenols are a large group of natural antioxidant compounds widely distributed in plant-based foods and beverages. Their diverse health benefits have attracted growing scientific attention in recent decades. Many literatures have reported the effectiveness of dietary polyphenols against stone formation. The antiurolithiatic mechanisms of polyphenols have been explained by their antioxidant potential to scavenge free radicals and ROS, modulate the expression and the activity of endogenous antioxidant and prooxidant enzymes, regulate signaling pathways associated with OS, and maintain cell morphology and function. In this review, we first describe OS and its pathogenic effects in urolithiasis and summarize the classification and sources of dietary polyphenols. Then, we focus on the current evidence defining their antioxidant potential against stone formation and put forward challenges and future perspectives of dietary polyphenols. To conclude, dietary polyphenols offer potential applications in the treatment and prevention of urolithiasis.

A Thermo-Electro-Viscoelastic Model for Dielectric Elastomers.

Dielectric elastomers (DEs) are a class of electro-active polymers (EAPs) that can deform under electric stimuli and have great application potential in bionic robots, biomedical devices, energy harvesters, and many other areas due to their outstanding deformation abilities. It has been found that stretching rate, temperature, and electric field have significant effects on the stress-strain relations of DEs, which may result in the failure of DEs in their applications. Thus, this paper aims to develop a thermo-electro-viscoelastic model for DEs at finite deformation and simulate the highly nonlinear stress-strain relations of DEs under various thermo-electro-mechanical loading conditions. To do so, a thermodynamically consistent continuum theoretical framework is developed for thermo-electro-mechanically coupling problems, and then specific constitutive equations are given to describe the thermo-electro-viscoelastic behaviors of DEs. Furthermore, the present model is fitted with the experimental data of VHB4905 to determine a temperature-dependent function of the equilibrium modulus. A comparison of the nonlinear loading-unloading curves between the model prediction and the experimental data of VHB4905 at various thermo-electro-mechanical loading conditions verifies the present model and shows its ability to simulate the thermo-electro-viscoelastic behaviors of DEs. Simultaneously, the results reveal the softening phenomena and the instant pre-stretch induced by temperature and the electric field, respectively. This work is conducive to analyzing the failure of DEs in functionalities and structures from theoretical aspects at various thermo-electro-mechanical conditions.

Inhibition of AT1R/IP3/IP3R-mediated Ca2+ release protects against calcium oxalate crystals-induced renal oxidative stress.

Calcium oxalate (CaOx) stones are the most prevalent type of kidney stones. CaOx crystals can stimulate reactive oxygen species (ROS) generation and induce renal oxidative stress to promote stone formation. Intracellular Ca2+ is an important signaling molecule, and an elevation of cytoplasmic Ca2+ levels could trigger oxidative stress. Our previous study has revealed that upregulation of Ang II/AT1R promoted renal oxidative stress during CaOx exposure. IP3/IP3R/Ca2+ signaling pathway activated via Ang II/AT1R is involved in several diseases, but its role in stone formation has not been reported. Herein, we focus on the role of AT1R/IP3/IP3R-mediated Ca2+ release in CaOx crystals-induced oxidative stress and explore whether inhibition of this pathway could alleviate renal oxidative stress. NRK-52E cells were exposed to CaOx crystals pretreated with AT1R inhibitor losartan or IP3R inhibitor 2-APB, and glyoxylic acid monohydrate-induced CaOx stone-forming rats were treated with losartan or 2-APB. The intracellular Ca2+ levels, ROS levels, oxidative stress indexes, and the gene expression of this pathway were detected. Our results showed that CaOx crystals activated AT1R to promote IP3/IP3R-mediated Ca2+ release, leading to increased cytoplasmic Ca2+ levels. The Ca2+ elevation was able to stimulate NOX2 and NOX4 to generate ROS, induce oxidative stress, and upregulate the expression of stone-related proteins. 2-APB and losartan reversed the referred effects, reduced CaOx crystals deposition and alleviated tissue injury in the rat kidneys. In summary, our results indicated that CaOx crystals promoted renal oxidative stress by activating the AT1R/IP3/IP3R/Ca2+ pathway. Inhibition of AT1R/IP3/IP3R-mediated Ca2+ release protected against CaOx crystals-induced renal oxidative stress. 2-APB and losartan might be promising preventive and therapeutic agents for the treatment of kidney stone disease.

Authentication of recycled and virgin polyethylene terephthalate based on UPLC-Q-TOF-MS using non-volatile organic compounds and chemometrics.

Plastic packaging waste, such as polyethylene terephthalate (PET) has increased significantly in recent decades, arousing a considerable and serious public concern regarding the environment, economy, and policy. Plastic recycling is a useful tool to mitigate this issue. Here, a feasible study was performed to investigate the potential of a novel method for identifying virgin and recycled PET. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was combined with various chemometrics, as a simple and reliable method that achieved a high discrimination rate for 105 batches of virgin PET (v-PET) and recycled PET (r-PET) based on 202 non-volatile organic compounds (NVOCs). Making use of orthogonal partial least-squares discrimination analysis (OPLS-DA) together with non-parametric tests, 26 marker compounds (i.e. 12 intentionally added substances (IAS) and 14 non-intentionally added substances (NIAS) as well as 31 marker compounds (i.e. 11 IAS and 20 NIAS) obtained from positive and combination of positive and negative ionization modes of UPLC-Q-TOF-MS, respectively, were successfully identified. Moreover, 100% accuracy was obtained using a decision tree (DT). Cross-discrimination based on misclassified samples using various chemometrics allowed the prediction accuracy to be improved and to identify a large sample set, thus greatly enhancing the application scope of this method. The possible origins of these detected compounds can be the plastic itself, as well as contamination from food, medicine, pesticides, industry-related substances, and degradation and polymerization products. As many of these compounds are toxic, especially those pesticide related, this indicates an urgent requirement for closed loop recycling. Overall, this analytical method provides a quick, accurate, and robust way to distinguish virgin from recycled PET and thus addresses the issue of potential virgin PET adulteration thereby detecting fraud in the area of PET recycling.

Pan-cancer efficacy and safety of anlotinib plus PD-1 inhibitor in refractory solid tumor: A single-arm, open-label, phase II trial.

The combination of immunotherapy and antiangiogenic agents for the treatment of refractory solid tumor has not been well investigated. Thus, our study aimed to evaluate the efficacy and safety of a new regimen of anlotinib plus PD-1 inhibitor to treat refractory solid tumor. APICAL-RST is an investigator-initiated, open-label, single-arm, phase II trial in patients with heavily treated, refractory, metastatic solid tumor. Eligible patients experienced disease progression during prior therapy without further effective regimen. All patients received anlotinib and PD-1 inhibitor. The primary endpoints were objective response and disease control rates. The secondary endpoints included the ratio of progression-free survival 2 (PFS2)/PFS1, overall survival (OS) and safety. Forty-one patients were recruited in our study; 9 patients achieved a confirmed partial response and 21 patients had stable disease. Objective response rate and disease control rate were 22.0% and 73.2% in the intention-to-treat cohort, and 24.3% and 81.1% in the efficacy-evaluable cohort, respectively. A total of 63.4% (95% confidence interval [CI]: 46.9%-77.4%) of the patients (26/41) presented PFS2/PFS1 >1.3. The median OS was 16.8 months (range: 8.23-24.4), and the 12- and 36-month OS rates were 62.8% and 28.9%, respectively. No significant association was observed between concomitant mutation and efficacy. Thirty-one (75.6%) patients experienced at least one treatment-related adverse event. The most common adverse events were hypothyroidism, hand-foot syndrome and malaise. This phase II trial showed that anlotinib plus PD-1 inhibitor exhibits favorable efficacy and tolerability in patients with refractory solid tumor.

Bioinformatics analysis reveals the potential role of matrix metalloproteinases in immunity and urolithiasis.

Background: The pathogenesis of urolithiasis remains unclear, making the development of medications for treatment and prevention stagnant. Randall's plaques (RPs) begin as interstitial calcium phosphate crystal deposits, grow outward and breach the renal papillary surface, acting as attachment for CaOx stones. Since matrix metalloproteinases (MMPs) can degrade all components of extracellular matrix (ECM), they might participate in the breach of RPs. Besides, MMPs can modulate the immune response and inflammation, which were confirmed to be involved in urolithiasis. We aimed to investigate the role of MMPs in the development of RPs and stone formation. Methods: The public dataset GSE73680 was mined to identify differentially expressed MMPs (DEMMPs) between normal tissues and RPs. WGCNA and three machine learning algorithms were performed to screen the hub DEMMPs. In vitro experiments were conducted for validation. Afterwards, RPs samples were classified into clusters based on the hub DEMMPs expression. Differentially expressed genes (DEGs) between clusters were identified and functional enrichment analysis and GSEA were applied to explore the biological role of DEGs. Moreover, the immune infiltration levels between clusters were evaluated by CIBERSORT and ssGSEA. Results: Five DEMMPs, including MMP1, MMP3, MMP9, MMP10, and MMP12, were identified between normal tissues and RPs, and all of them were elevated in RPs. Based on WGCNA and three machine learning algorithms, all of five DEMMPs were regarded as hub DEMMPs. In vitro validation found the expression of hub DEMMPs also increased in renal tubular epithelial cells under lithogenic environment. RPs samples were divided into two clusters and cluster A exhibited higher expression of hub DEMMPs compared to cluster B. Functional enrichment analysis and GSEA found DEGs were enriched in immune-related functions and pathways. Moreover, increased infiltration of M1 macrophages and enhanced levels of inflammation were observed in cluster A by immune infiltration analysis. Conclusion: We assumed that MMPs might participate in RPs and stone formation through ECM degradation and macrophages-mediated immune response and inflammation. Our findings offer a novel perspective on the role of MMPs in immunity and urolithiasis for the first time, and provide potential biomarkers to develop targets for treatment and prevention.

Targeted therapy for intractable cancer on the basis of molecular profiles: An open-label, phase II basket trial (Long March Pathway).

Purpose: We evaluated he effects of molecular guided-targeted therapy for intractable cancer. Also, the epidemiology of druggable gene alterations in Chinese population was investigated. Materials and methods: The Long March Pathway (ClinicalTrials.gov identifier: NCT03239015) is a non-randomized, open-label, phase II trial consisting of several basket studies examining the molecular profiles of intractable cancers in the Chinese population. The trial aimed to 1) evaluate the efficacy of targeted therapy for intractable cancer and 2) identify the molecular epidemiology of the tier II gene alterations among Chinese pan-cancer patients. Results: In the first stage, molecular profiles of 520 intractable pan-cancer patients were identified, and 115 patients were identified to have tier II gene alterations. Then, 27 of these 115 patients received targeted therapy based on molecular profiles. The overall response rate (ORR) was 29.6% (8/27), and the disease control rate (DCR) was 44.4% (12/27). The median duration of response (DOR) was 4.80 months (95% CI, 3.33-27.2), and median progression-free survival (PFS) was 4.67 months (95% CI, 2.33-9.50). In the second stage, molecular epidemiology of 17,841 Chinese pan-cancer patients demonstrated that the frequency of tier II gene alterations across cancer types is 17.7%. Bladder cancer had the most tier-II alterations (26.1%), followed by breast cancer (22.4%), and non-small cell lung cancer (NSCLC; 20.2%). Conclusion: The Long March Pathway trial demonstrated a significant clinical benefit for intractable cancer from molecular-guided targeted therapy in the Chinese population. The frequency of tier II gene alterations across cancer types supports the feasibility of molecular-guided targeted therapy under basket trials.

Acquired EML4-ALK fusion and EGFR C797S in cis mutation as resistance mechanisms to osimertinib in a non-small cell lung cancer patient with EGFR L858R/T790M.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) dramatically improve the clinical outcomes of non-small cell lung cancer (NSCLC) patients harboring EGFR -sensitive mutations. Despite the remarkable efficacy of first-and second-generation EGFR TKIs, disease relapse is inevitable. EGFR T790M mutation is a primary contributor to the acquired resistance to first- and second-generation EGFR TKIs. Osimertinib, which is an irreversible third-generation EGFR TKI, was designed for EGFR -activating mutations as well as the EGFR T790M mutation in patients with advanced NSCLC and has demonstrated a convincing efficacy. However, acquired resistance to osimertinib after treatment inevitably occurs. The acquired resistance mechanisms to osimertinib are highly complicated and not fully understood, encompassing EGFR -dependent as well as EGFR -independent mechanisms. Treatment approaches for patients progressing from osimertinib have not been established. We present a case of a stage IV lung adenocarcinoma patient harboring EGFR L858R, acquired T790M after treatment with first-line gefitinib. She then acquired a new EML4-ALK gene fusion after treatment with osimertinib. A combination targeted therapy of osimertinib plus alectinib was initiated, with a progression-free survival of 5 months without any serious adverse reaction. After disease progression, EGFR C797S in cis was detected with a loss of the EML4-ALK fusion by targeted next-generation sequencing. Then therapy was changed to pemetrexed combined with bevacizumab plus camrelizumab, but no obvious effect was observed. The patient had achieved an overall survival of 31 months. As far as we know, this was the first reported case that an EGFR -mutant NSCLC patient-acquired ALK fusion mediating resistance to osimertinib, and sequential EGFR C797S mutation mediating resistance to combined targeted therapy with osimertinib and alectinib. Our case shows that EML4-ALK fusion is a rare but critical resistance mechanism to osimertinib, and C797S mutation in cis may be an underlying mechanism of acquired resistance mutation in double TKIs therapy. Furthermore, molecular detection and rebiopsy play important roles in the selection of therapeutic strategies when the disease progresses.

Research progress of integrated traditional Chinese and Western medicine in the treatment of advanced gastric cancer.

Gastric cancer (GC) is a malignant tumor originating from the gastric epithelium, and its incidence and mortality rates rank third among all malignant tumors worldwide. It is also one of the most common cancers in China and is treated predominantly by Western medicine in clinical practice. However, with the advancements in medical technology and informatics, the values of traditional Chinese medicine (TCM) in preventing and treating GC and improving prognosis have increasingly been recognized. According to TCM, clinical manifestations of GC can be divided into Yege (dysphagia), regurgitation, stomach pain, and Zhengxia (abdominal mass). Due to the unbalanced distribution of health care resources in China, most GC patients already have progressive or advanced-stage disease at the first diagnosis. As a result, most GC patients have poor physical function, and surgery or chemotherapy alone will aggravate the impairment to the immune function and seriously affect the quality of life. In contrast, TCM therapies have shown promising efficacy in the management of these patients. Here we review the role of the integrated TCM and Western medicine in treating advanced GC.

The role of microbiome: a novel insight into urolithiasis.

Urolithiasis, referred to as the formation of stones in the urinary tract, is a common disease with growing prevalence and high recurrence rate worldwide. Although researchers have endeavoured to explore the mechanism of urinary stone formation for novel effective therapeutic and preventative measures, the exact aetiology and pathogenesis remain unclear. Propelled by sequencing technologies and culturomics, great advances have been made in understanding the pivotal contribution of the human microbiome to urolithiasis. Indeed, there are diverse and abundant microbes interacting with the host in the urinary tract, overturning the dogma that urinary system, and urine are sterile. The urinary microbiome of stone formers was clearly distinct from healthy individuals. Besides, dysbiosis of the intestinal microbiome appears to be involved in stone formation through the gut-kidney axis. Thus, the human microbiome has potential significant implications for the aetiology of urolithiasis, providing a novel insight into diagnostic, therapeutic, and prognostic strategies. Herein, we review and summarize the landmark microbiome studies in urolithiasis and identify therapeutic implications, challenges, and future perspectives in this rapidly evolving field. To conclude, a new front has opened with the evidence for a microbial role in stone formation, offering potential applications in the prevention, and treatment of urolithiasis.

Analysis of microplastics released from plastic take-out food containers based on thermal properties and morphology study.

Plastic take-out food containers may release microplastics (MPs) into food and pose a potential risk to food safety and human health. Here, after being subjected to hot water treatment, MPs released from three types of plastic food containers (polypropylene, PP; polyethylene, PE; expanded polystyrene, EPS) were identified by micro-Raman spectroscopy. The results showed that the size of released MPs ranged from 0.8-38 µm and over 96% MPs were smaller than 10 µm. Various MPs concentrations were found from the three types of containers, that is, 1.90 × 104, 1.01 × 105, and 2.82 × 106 particles/L on average from PP, PE, and EPS, respectively. Moreover, based on thermal and morphology analysis, we discovered that both relaxations of the polymer chains in the rubbery state and defects caused by processing techniques might contribute to the release of MPs. Thus, such release can be reduced by increasing the thermal stability of the materials and mitigating the defects generated during production.

Low-dose anti-VEGFR2 therapy promotes anti-tumor immunity in lung adenocarcinoma by down-regulating the expression of layilin on tumor-infiltrating CD8+T cells.

PURPOSE: Our study intended to explore how low-dose anti-angiogenic drugs affected anti-tumor immunity of tumor-infiltrating exhausted CD8+T cells and achieved better clinical response when combined with immunotherapy. We set out to find potential targets or predictive biomarker on CD8+T cells for immunotherapy. METHODS: We tested different doses of anti-VEGFR2 antibody combined with anti-PD1 antibody to treat LUAD in vivo and analyzed tumor-infiltrating CD8+T cells by flow cytometry. CD8+T cells overexpressing LAYN were co-cultured with LA795 cell lines to identify the function of LAYN in CD8+T cells. We also analyzed clinical samples from advanced LUAD patients treated with anti-angiogenesis therapy combined with immunotherapy. RESULTS: Low-dose anti-VEGFR2 antibody combined with anti-PD1 antibody treatment delayed tumor growth and prolonged the survival time of tumor-bearing mice. The number of tumor-infiltrating CD8+T cells was reduced and the expression of LAYN was down-regulated in tumor-infiltrating CD8+T cells in the low-dose anti-VEGFR2 combination group. It was found that LAYN inhibited the killing function of CD8+T cells. In patients with advanced LUAD who received anti-angiogenesis therapy combined with immunotherapy, the LAYN+CD8+T cell subpopulation in good responders was significantly higher than that in poor responders. Furthermore, we demonstrated the expression of LAYN was regulated by upstream transcription factor NR4A1. CONCLUSION: Low-dose anti-VEGFR2 antibody combined with anti-PD1 antibody therapy promoted anti-tumor immunity and the downregulation of LAYN in tumor-infiltrating CD8+T cells played an important role in this process. These findings had implications for improving the efficacy of immune checkpoint blockade therapy and further optimized clinical treatment guidelines in advanced LUAD.