The gut microbiota contributes to methamphetamine-induced reproductive toxicity in male mice.

Methamphetamine (METH) is a psychostimulant drug belonging to the amphetamine-type stimulant class, known to exert male reproductive toxicity. Recent studies suggest that METH can disrupt the gut microbiota. Furthermore, the gut-testis axis concept has gained attention due to the potential link between gut microbiome dysfunction and reproductive health. Nonetheless, the role of the gut microbiota in mediating the impact of METH on male reproductive toxicity remains unclear. In this study, we employed a mouse model exposed to escalating doses of METH to assess sperm quality, testicular pathology, and reproductive hormone levels. The fecal microbiota transplantation method was employed to investigate the effect of gut microbiota on male reproductive toxicity. Transcriptomic, metabolomic, and microbiological analyses were conducted to explore the damage mechanism to the male reproductive system caused by METH. We found that METH exposure led to hormonal disorders, decreased sperm quality, and changes in the gut microbiota and testicular metabolome in mice. Testicular RNA sequencing revealed enrichment of several Gene Ontology terms associated with reproductive processes, as well as PI3K-Akt signaling pathways. FMT conveyed similar reproductive damage from METH-treated mice to healthy recipient mice. The aforementioned findings suggest that the gut microbiota plays a substantial role in facilitating the reproductive toxicity caused by METH, thereby highlighting a prospective avenue for therapeutic intervention in the context of METH-induced infertility.

Research trends and perspective of low-intensity pulsed ultrasound in orthopedic rehabilitation treatment based on Web of Science: A bibliometric analysis.

BACKGROUND: Ultrasound has a long history as a diagnostic and therapeutic tool. Low-intensity pulsed ultrasound (LIPUS), whose intensity is below 300 mW/cm2, has been widely used in orthopedic rehabilitation treatment. However, the detailed bioeffects and underlying mechanisms of LIPUS treatment need to be explored. OBJECTIVE: To make a comprehensive view of the field, bibliometric and visualization analysis was used to reveal the global research trends of LIPUS in orthopedics and rehabilitation treatment between 1994 and 2023. METHODS: All literature data on LIPUS were retrieved from the Web of Science Core Collection database. VOSviewer and CiteSpace were applied for the bibliometric and visualization analysis. RESULTS: A total of 760 publications were included. The distribution of publications generally showed an unstable rising trend. China had the highest number of publications (28.0%), and Chong Qing Medical University was the organization with the highest number of publications (5.8%). Ultrasound in Medicine and Biology had the highest number of publications (8.8%), while BMJ-British Medical Journal had the highest impact factor among the retrieved journals. Ling Qin from the Chinese University of Hong Kong was the most active researcher. Our overlay visualization map showed that the keywords such as pain, knee osteoarthritis, apoptosis, chondrocytes, cartilage, and autophagy, which link to osteoarthritis, have becoming the new research trends and hotspots. CONCLUSION: LIPUS is a popular and increasingly important area of orthopedic rehabilitation, and collaboration of authors from different countries should be further strengthened. Predictably, clinical application of LIPUS on chronic inflammation-related diseases and regenerative medicine, and in-depth biological mechanisms are the orientations of LIPUS in orthopedic rehabilitation treatment.

Inulin alleviates perinatal 2-ethylhexyl diphenyl phosphate (EHDPHP) exposure-induced intestinal toxicity by reshaping the gut microbiota and suppressing the enteric-origin LPS/TLR4/NF-κb pathway in dams and pups.

Organophosphorus flame retardants (OPFRs), such as 2-ethylhexyl diphenyl phosphate (EHDPHP), are ubiquitously used, leading to pervasive environmental contamination and human health risks. While associations between EHDPHP and health issues such as disruption of hormones, neurotoxic effects, and toxicity to reproduction have been recognized, exposure to EHDPHP during perinatal life and its implications for the intestinal health of dams and their pups have largely been unexplored. This study investigated the intestinal toxicity of EHDPHP and the potential for which inulin was effective. Dams were administered either an EHDPHP solution or a corn oil control from gestation day 7 (GD7) to postnatal day 21 (PND21), with inulin provided in their drinking water. Our results indicate that inulin supplementation mitigates damage to the intestinal epithelium caused by EHDPHP, restores mucus-secreting cells, suppresses intestinal hyperpermeability, and abates intestinal inflammation by curtailing lipopolysaccharide leakage through reshaping of the gut microbiota. A reduction in LPS levels concurrently inhibited the inflammation-associated TLR4/NF-κB pathway. In conclusion, inulin administration may ameliorate intestinal toxicity caused by EHDPHP in dams and pups by reshaping the gut microbiota and suppressing the LPS/TLR4/NF-κB pathway. These findings underscore the efficacy of inulin as a therapeutic agent for managing health risks linked to EHDPHP exposure.

Bone regeneration with hydroxyapatite particles loaded in photo-cross-linkable hydrogel: An experimental study.

This study explores the use of in situ cross-linked hyaluronic acid methacryloyl (HAMA) and hydroxyapatite particles (HAP) for bone defect repair. Human periodontal ligament stem cells (PDLSCs) were isolated and co-cultured with the HAMA-HAP composite. Osteogenic differentiation was evaluated using Alizarin Red staining, alkaline phosphatase activity quantification, and polymerase chain reaction (PCR). A cranial defect was induced in Sprague-Dawley rats. This defect was then filled with the HAMA-HAP composite and cross-linked using UV light exposure. Bone formation was assessed through radiographic and histological analyses. The HAMA-HAP composite was found to promote cell viability similarly to pure HAP. It also enhanced gene expression of ALP, OPN, and Runx2, and increased ALP activity and mineralized nodule formation in vitro. Micro-CT scans showed defect restoration in the HAMA-HAP and HAP groups compared to the control group. The HAMA-HAP group exhibited higher Tb.N, Tb.Sp, Tb.Th, and BV/TV. Masson staining showed the HAMA-HAP composite restored the defect site, with new bone formation thicker than in the HAP group. The HAMA-HAP composite showed excellent biocompatibility and promoted osteogenic differentiation of PDLSCs. It effectively repaired cranial defects, indicating its potential for clinical use in bone defect repair.

Prevalence and associated factors of frailty in patients with chronic kidney disease: a cross-sectional analysis of PEAKING study.

AIM:  Frailty is common and is reported to be associated with adverse outcomes in patients with chronic diseases in Western countries. However, the prevalence of frailty remains unclear in individuals with chronic kidney disease (CKD) in China. We examined the prevalence of frailty and factors associated with frailty in patients with CKD. METHODS:  This was a cross-sectional analysis of 177 adult patients (mean age 54 ± 15 years, 52% men) with CKD from the open cohort entitled Physical Evaluation and Adverse outcomes for patients with chronic Kidney disease IN Guangdong (PEAKING). Frailty at baseline were assessed by FRAIL scale which included five items: fatigue, resistance, ambulation, illnesses, and loss of weight. Potential risk factors of frailty including age, sex, body mass index, and daily step counts recorded by ActiGraph GT3X + accelerometer were analyzed by multivariate logistic regression analysis. RESULTS: The prevalence of prefrailty and frailty was 50.0% and 11.9% in patients with stages 4-5 CKD, 29.6% and 9.3% in stage 3, and 32.1% and 0 in stages 1-2. In the multivariate logistic regression analysis, an increase of 100 steps per day (OR = 0.95, 95% CI 0.91-0.99, P = 0.01) and an increase of 5 units eGFR (OR = 0.82, 95% CI 0.68-0.99, P = 0.045) were inversely associated with being frail; higher BMI was associated with a higher likelihood of being frail (OR = 1.52, 95% CI 1.11-2.06, P = 0.008) and prefrail (OR = 1.25, 95% CI 1.10-1.42, P = 0.001). CONCLUSION:  Frailty and prefrailty were common in patients with advanced CKD. A lower number of steps per day, lower eGFR, and a higher BMI were associated with frailty in this population.

Gut microbiota-derived short-chain fatty acids ameliorate methamphetamine-induced depression- and anxiety-like behaviors in a Sigmar-1 receptor-dependent manner.

Methamphetamine (Meth) abuse can cause serious mental disorders, including anxiety and depression. The gut microbiota is a crucial contributor to maintaining host mental health. Here, we aim to investigate if microbiota participate in Meth-induced mental disorders, and the potential mechanisms involved. Here, 15 mg/kg Meth resulted in anxiety- and depression-like behaviors of mice successfully and suppressed the Sigma-1 receptor (SIGMAR1)/BDNF/TRKB pathway in the hippocampus. Meanwhile, Meth impaired gut homeostasis by arousing the Toll-like receptor 4 (TLR4)-related colonic inflammation, disturbing the gut microbiome and reducing the microbiota-derived short-chain fatty acids (SCFAs). Moreover, fecal microbiota from Meth-administrated mice mediated the colonic inflammation and reproduced anxiety- and depression-like behaviors in recipients. Further, SCFAs supplementation optimized Meth-induced microbial dysbiosis, ameliorated colonic inflammation, and repressed anxiety- and depression-like behaviors. Finally, Sigmar1 knockout (Sigmar1-/-) repressed the BDNF/TRKB pathway and produced similar behavioral phenotypes with Meth exposure, and eliminated the anti-anxiety and -depression effects of SCFAs. The activation of SIGMAR1 with fluvoxamine attenuated Meth-induced anxiety- and depression-like behaviors. Our findings indicated that gut microbiota-derived SCFAs could optimize gut homeostasis, and ameliorate Meth-induced mental disorders in a SIGMAR1-dependent manner. This study confirms the crucial role of microbiota in Meth-related mental disorders and provides a potential preemptive therapy.

Photoredox-Catalyzed Phosphonocarboxylation of Allenes with Phosphine Oxides and CO2.

Phosphonocarboxylation of allenes with diarylphosphine oxides and CO2 via visible-light photoredox catalysis was developed for the first time. This work provided practical and sustainable access to highly valuable but otherwise difficult-to-access linear allylic ß-phosphonyl carboxylic acids in moderate yields with exclusive regio- and stereoselectivity. This method was also characterized by step and atom economy and transition-metal free and mild conditions. Preliminary mechanistic studies suggested that allyl-methyl carbanion species are the key intermediates.

Multi-Omics Analysis Reveals the Role of Sigma-1 Receptor in a Takotsubo-like Cardiomyopathy Model.

Takotsubo syndrome (TTS) is a stress-induced cardiomyopathy that presents with sudden onset of chest pain and dyspneic and cardiac dysfunction as a result of extreme physical or emotional stress. The sigma-1 receptor (Sigmar1) is a ligand-dependent molecular chaperone that is postulated to be involved in various processes related to cardiovascular disease. However, the role of Sigmar1 in TTS remains unresolved. In this study, we established a mouse model of TTS using wild-type and Sigmar1 knockout mice to investigate the involvement of Sigmar1 in TTS development. Our results revealed that Sigmar1 knockout exacerbated cardiac dysfunction, with a noticeable decrease in ejection fraction (EF) and fractional shortening (FS) compared to the wild-type model. In terms of the gut microbiome, we observed regulation of Firmicutes and Bacteroidetes ratios; suppression of probiotic Lactobacillus growth; and a rise in pathogenic bacterial species, such as Colidextribacter. Metabolomic and transcriptomic analyses further suggested that Sigmar1 plays a role in regulating tryptophan metabolism and several signaling pathways, including MAPK, HIF-1, calcium signaling, and apoptosis pathways, which may be crucial in TTS pathogenesis. These findings offer valuable insight into the function of Sigmar1 in TTS, and this receptor may represent a promising therapeutic target for TTS.

The prognostic value of tumor-associated macrophages in glioma patients.

Glioma is a complex tumor composed of both neoplastic and non-neoplastic cells, including tumor-infiltrating leukocytes (TILs), and each cell type contributes to tumor formation and malignant progression. Among TILs, tumor-associated macrophages (TAMs) are of great importance and play a key role in the immune response to cancer. In this study, 22 types of adaptive and innate TILs were evaluated in gliomas. TAMs, which account for 38.7% of all these cells, are the most abundant immune infiltrates in the tumor microenvironment. In addition, we observed different immune cell patterns in low-grade glioma and glioblastoma. Our research indicated that there was a connection between TILs, and 13 of 22 TILs were significantly associated with patient outcomes. Finally, the prognosis and diagnostic value of TAMs were revealed using Kaplan-Meier analysis. We identified the optimal cutoff point of TAMs at an infiltrating level of 0.47 to predict patient prognosis, with a median overall survival of 448 days in patients with higher TAM infiltration levels and 2660 days in patients with lower TAM infiltration levels. These findings provide a new idea for glioma to regulate tumor-specific immunity, clarify the potential effects of TAMs on disease pathology, and provide a theoretical basis for immune intervention treatment of gliomas.

Inulin alleviates neuroinflammation and oxidative stress induced by perinatal 2-ethylhexyl diphenyl phosphate (EHDPHP) exposure in female mice and offspring.

Organophosphorus flame retardants (OPFRs), including 2-ethylhexyl diphenyl phosphate (EHDPHP), are prevalent in everyday life due to their broad usage in fields such as healthcare, electronics, industry, and sports. These compounds, added to polymers through physical mixing, can leach into the environment, posing a risk to humans through direct contact or the food chain. Despite known associations with health issues like endocrine disruption, neurotoxicity, and reproductive toxicity, the implications of perinatal EHDPHP exposure on both mothers and offspring are still unclear. This study aimed to investigate the neuroinflammatory effects of EHDPHP and the potential mitigating role of inulin. Pregnant C57 mice were administered either a corn oil control or an EHDPHP solution (300 µg/kg bw/d) from gestation day 7 (GD7) to postnatal day 21 (PND21). Concurrently, mice were provided either regular drinking water or water supplemented with 1% inulin. We found that EHDPHP significantly increased the serum levels of IL-1ß, IL-6, and MDA, but decreased SOD levels in both mothers and pups. These effects were reversed by inulin supplementation. RNA-sequencing revealed that EHDPHP induced inflammation and oxidative stress through the TLR4/NF-κB pathway, which was mitigated by inulin. In conclusion, inulin ameliorated EHDPHP-induced neuroinflammation and oxidative stress in both mothers and offspring, highlighting its potential therapeutic role.

Epigallocatechin-3-gallate ameliorates polystyrene microplastics-induced anxiety-like behavior in mice by modulating gut microbe homeostasis.

Polystyrene microplastics (PS-MPs) have emerged as a concerning pollutant in modern society due to their widespread production and usage. Despite ongoing research efforts, the impact of PS-MPs on mammalian behavior and the mechanisms driving these effects remain incompletely elucidated. Consequently, effective strategies for prevention have yet to be developed. To fill these gaps, C57BL/6 mice were orally administered with 5 µm PS-MPs for 28 consecutive days in this study. The open-field test and the elevated plus-maze test were performed to evaluate the anxiety-like behavior, 16S rRNA sequencing and untargeted metabolomics analysis were used to detect the changes of gut microbiota and serum metabolites. Our results indicated that PS-MPs exposure activated hippocampal inflammation and induced anxiety-like behavior in mice. Meanwhile, PS-MPs disturbed the gut microbiota, impaired the intestinal barrier, and aroused peripheral inflammation. Specifically, PS-MPs increased the abundance of pathogenic microbiota Tuzzerella, while lowered the abundance of probiotics Faecalibaculum and Akkermansia. Interestingly, eliminating the gut microbiota protected against the deleterious effects of PS-MPs on intestinal barrier integrity, reduced the levels of peripheral inflammatory cytokines, and ameliorated anxiety-like behavior. Additionally, green tea's primary bioactive constituent, epigallocatechin-3-gallate (EGCG), optimized gut microbial composition, improved intestinal barrier function, reduced peripheral inflammation, and exerted anti-anxiety effects by inhibiting the hippocampal TLR4/MyD88/NF-κB signaling cascade. EGCG also remodeled serum metabolism, especially modulated purine metabolism. These findings suggested that gut microbiota participates in PS-MPs-induced anxiety-like behavior by modulating the gut-brain axis, and that EGCG could serve as a potential preventive strategy.

Microbial community succession in the intestine of mice with deep partial-thickness burns.

Introduction: Burn injury has been shown to lead to changes in the composition of the gut microbiome and cause other damage in patients. However, little is known about how the gut microbial community evolves in individuals who have recovered from burn injury. Methods: In this study, we established a model of deep partial-thickness burn in mice and collected fecal samples at eight time points (pre-burn, 1, 3, 5, 7, 14, 21, and 28 days post-burn) for 16S rRNA amplification and high-throughput sequencing. Results: The results of the sequencing were analyzed using measures of alpha diversity, and beta diversity and taxonomy. We observed that the richness of the gut microbiome declined from day 7 post-burn and that the principal component and microbial community structure varied over time. On day 28 after the burn, the microbiome composition largely returned to the pre-burn level, although day 5 was a turning point for change. Some probiotics, such as the Lachnospiraceae_NK4A136_group, decreased in composition after the burn but were restored in the later recovery period. In contrast, Proteobacteria showed an opposite trend, which is known to include potential pathogenic bacteria. Conclusion: These findings demonstrate gut microbial dysbiosis after burn injury and provide new insights into the burn-related dysbiosis of the gut microbiome and strategies for improving the treatment of burn injury from the perspective of the microbiota.

A Photosensitizer for N-O Bond Activation: 2,7-Br-4CzIPN-Catalyzed Difunctionalization of Alkenes with Oxime Esters.

We developed 2,4,5,6-tetrakis(2,7-dibromo-9H-carbazol-9-yl)isophthalonitrile (2,7-Br-4CzIPN) as a new photosensitizer for the energy-transfer-driven N-O bond dissociation of oxime esters. In the presence of 2,7-Br-4CzIPN, difunctionalization of alkenes with oxime esters, including oxyimination, aminocarboxylation, and amidylimination, could afford a variety of versatile molecules in good yields with excellent regioselectivity, which widely occur in natural products and drugs. Our theoretical investigations and experiments have demonstrated that 2,7-Br-4CzIPN has unique photophysical properties, favorable triplet energy, and excellent photocatalytic activity.

IgG4-related kidney disease complicated with retroperitoneal fibrosis: A case report.

BACKGROUND: IgG4-related disease (IgG4-RD) is a chronic fibrotic disease mediated by immunity recognized by clinicians in recent years. When the kidney is involved, it is called IgG4-related kidney disease (IgG4-RKD). IgG4-related tubulointerstitial nephritis (IgG4-TIN) is a representative manifestation of IgG4-RKD. IgG4-TIN can cause obstructive nephropathy complicated by retroperitoneal fibrosis (RPF). Cases of IgG4-TIN complicated with RPF are rare. Glucocorticoids are the first-line therapeutic medication for IgG4-RD and can significantly improve renal function. CASE SUMMARY: Herein, we report the case of a 56-year-old man with IgG4-RKD complicated with RPF. The patient presented to the hospital with complaints of elevated serum creatinine (Cr), nausea, and vomiting. During hospitalization, Cr was 1448.6 µmol/L, and serum IgG4 was increased. A total abdominal computed tomography (CT) scan and enhanced CT scan obviously indicated RPF. Although this patient had a long course and renal insufficiency, we performed a kidney biopsy. Renal biopsy showed that the renal tubulointerstitium had focal plasma cell infiltration and increased lymphocyte infiltration accompanied by fibrosis. After combining the biopsy results with immunohistochemistry, it was found that the absolute number of positive IgG4+ cells per high power field exceeded 10, and the ratio of IgG4/IgG was over 40%. Finally, the patient was diagnosed with IgG4-TIN complicated with RPF and given glucocorticoids as long-term maintenance therapy, helping him keep out of dialysis. After a follow-up of 19 mo, the patient had recovered well. Previous literature on IgG4-RKD and RPF was retrieved from PubMed to characterize the clinical and pathological features and to identify the diagnosis and treatment of IgG4-RKD. CONCLUSION: Our case report demonstrates the clinical characteristics of IgG4-RKD complicated with RPF. Serum IgG4 is a favorable indicator for screening. Performing renal biopsy actively plays a vital role in diagnosis and treatment, even if the patient has a long course and manifests with renal insufficiency. It is remarkable to treat IgG4-RKD with glucocorticoids. Hence, early diagnosis and targeted therapy are essential for reversing renal function and improving extrarenal manifestations in patients with IgG4-RKD.

Synergistic adsorption and oxidation of trivalent antimony from groundwater using biochar supported magnesium ferrite: Performances and mechanisms.

Antimony (Sb) pollution is considered an environmental problem, since Sb is toxic and carcinogenic to humans. Here, a novel biochar supported magnesium ferrite (BC@MF) was adopted for Sb(III) removal from groundwater. The maximum adsorption capacity was 77.44 mg g-1. Together with characterization, batch experiments, kinetics, isotherms, and thermodynamic analyses suggested that inner-sphere complexation, H-bonding, and electrostatic interactions were the primary mechanisms. C-C/CC, C-O, and O-CO groups and Fe/Mg oxides might have acted as adsorption sites. The adsorbed Sb(III) was oxidized to Sb(V). The generation of reactive oxygen species, iron redox reaction, and oxidizing functional groups all contributed to Sb(III) oxidation. Furthermore, the fixed-bed column system demonstrated a satisfactory Sb removal performance; BC@MF could treat ∼6060 BV of simulated Sb-polluted groundwater. This research provides a promising approach to sufficiently remove Sb(III) from contaminated groundwater, providing new insights for the development of innovative strategies for heavy metal removal.

Bessel acoustic-beam acoustic lens for extending the depth of field of detection in optical-resolution photoacoustic microscopy.

As an important part of optical-resolution photoacoustic microscopy, the acoustic lens is responsible for efficient collection of photoacoustic signals. The spherical focused acoustic lens is commonly used in photoacoustic microscopy because of its efficient detection of the photoacoustic signal in the focus area. However, the narrow depth of field of the spherical focused acoustic lens limits the expansion of the depth of field of the photoacoustic microscopy. To solve this problem, a Bessel acoustic-beam acoustic lens is proposed. The Bessel acoustic-beam acoustic lens replaces the spherical concave surface with a conical concave surface to generate a Bessel acoustic beam with non-diffraction. Using the simulation model of Bessel acoustic-beam acoustic lens constructed by COMSOL Multiphysics, it is verified theoretically that the Bessel acoustic-beam acoustic lens can improve the depth of field of detection by ∼2 times. The Bessel acoustic-beam acoustic lens can further promote the capability of high-speed and large volumetric imaging of optical-resolution photoacoustic microscopy and will be helpful in the acquisition of physiological and pathological processes.

Self-passivated edges of ZnO nanoribbons: a global search.

The edge structure of two-dimensional (2D) materials plays a critical role in controlling their growth kinetics and morphological evolution, electronic structures and functionalities. However, until now, the accurate edge reconstruction of ZnO nanoribbons remains absent. Here, we present results of a global search of ZnO edge structures having used the CALYPSO program combined with the density functional theory (DFT) method. In addition to a database of all the possible edge reconstructed structures of ZnO nanoribbons, the most stable edge reconstructed structures of armchair (ZnOAC), O-enriched zigzag (OZZ) and Zn-enriched zigzag edges (ZnZZ) have been confirmed based on molecular dynamics (MD) simulation and bonding configuration analysis of atoms near the edges. The edge formation energies show that their stabilities depend on the chemical potential (µO) and the concentrations (ρO) of oxygen atoms. Interestingly, a highly stable ZnZZ edge exhibits a novel nanotube-like structure and metallic characteristics, while the most stable reconstructed OZZ edge, resembling the letter "T", exhibits a narrow direct band-gap. It is almost certain that their electronic properties are determined by the edge states.

Structures and Electronic and Hydrogen Storage Properties of Magnesium Scandium Hydrides.

MgH2 is well known as a potential hydrogen storage material. However, its high thermodynamic stability, high dissociation temperature, slow absorption, and desorption kinetics severely limit its application. Aiming at these shortcomings, we try to improve the hydrogen storage property of MgH2 by doping with transition metal Sc atoms. The structures and electronic and hydrogen storage properties of Mg-Sc-H systems have been systematically studied by combining the crystal structure analysis by particle swarm optimization and density functional theory method. The results show that the structure of MgScH8 with the R3 space group is the most stable one, which is proved to be a wide-band gap (2.96 eV) semiconductor. The possible decomposition pathways, which are crucial for the applicability of R3-MgScH8 as a hydrogen storage material, are studied, and the pathway of MgScH8 → ScH6 + Mg + H2 is found to be the most favorable one under 107.8 GPa pressure, while above 107.8 GPa, MgScH8 → Mg + Sc + 4H2 becomes the most thermodynamically stable pathway and releases the maximum amount of hydrogen. Based on the root mean square deviation calculation, it is found that R3-MgScH8 begins to melt at 400 K. The result of ab initio molecular dynamics simulations shows that the hydrogen release capacity (4.04 wt %) can be easily achieved at 500 K, thus making MgScH8 a potential hydrogen storage material.

Performance of different methods for detecting T790M mutation in the plasma of patients with advanced NSCLC after developing resistance to first-generation EGFR-TKIs in a real-world clinical setting.

Several approaches to the detection of T790M mutations in patient plasma or tissue samples have been implemented to date. The present study was designed to assess the ability of different technologies to detect the T790M mutation in plasma samples and to evaluate the relative rates of re-biopsy and subsequent patient management in a clinical setting. Data from patients with advanced NSCLC who visited the Department of Respiratory Medicine of the First Hospital Affiliated to Wenzhou Medical University between December 2014 and July 2018 were retrospectively collected. Following re-biopsy, these patients were evaluated for the presence of the T790M mutation via next-generation sequencing (NGS), amplification refractory mutation system or Roche Cobas z480 (Cobas) analyses of tissue samples. T790M mutation status in tumor tissue samples was calculated as a standard reference used to establish the sensitivity, specificity and concordance of three circulating tumor DNA detection approaches, including NGS, droplet digital PCR (ddPCR) and super amplification refractory mutation system (SuperARMS). Subsequent patient management was also recorded. In total, 287 patients with advanced non-small cell lung cancer were evaluated, of whom 55.4% (159/287) underwent tissue re-biopsy, 76.7% (122/159) underwent sequencing analysis of plasma and/or tissue samples, and 59.0% (72/122) were found to harbor the T790M mutation. The rates of plasma sample T790M detection via NGS, ddPCR and SuperARMS were 60.0, 59.3 and 60.0%, respectively. Only 32 patients with T790M mutations (44.4%, 32/72) were treated with third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), while 19 continued treatment with first-generation TKIs, 13 underwent chemotherapy, 1 switched to treatment with anlotinib, 4 succumbed to pericardial or brain metastases, and 3 were lost to follow-up. Additionally, 2 patients exhibited histological transformation from adenocarcinoma to small cell lung cancer, while 17/97 patients who were evaluated for brain metastases during treatment exhibited intracranial progression. Of these, 8 patients had been treated with osimertinib. In this study of a real-world clinical setting, fewer patients than expected underwent re-biopsy and gene sequencing. Of the tools available for the analysis of plasma samples, NGS exhibited the highest sensitivity and concordance with the results of tissue-based T790M detection strategies. It was additionally found that only a subset of patients harboring the T790M mutation were ultimately treated using third-generation EGFR-TKIs.

A Self-Serviced-Track 3D DNA Walker for Ultrasensitive Detection of Tumor Exosomes by Glycoprotein Profiling.

Sensitive and accurate analysis of low-concentration of tumor-derived exosomes (Exos) in biofluids is essential for noninvasive cancer diagnosis but is still challenging due to the lack of high-sensitive methods with low-cost and easy-operation. Herein, exploiting target Exos as a three-dimensional (3D) track for the first time, we developed a self-serviced-track DNA walker (STDW) for wash-free detection of tumor Exos using exosomal glycoprotein, which was enabled by split aptamer-recognition-initiated autonomous running powered by a catalytic hairpin assembly (CHA). Benefiting from high selectivity and sensitivity of the STDW assay, direct detection of tumor Exos in cell culture medium and serum could also be realized. Furthermore, this method exhibited high accuracy in clinical sample analysis, offering the potential for early cancer diagnosis and postoperative response prediction.