Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because ...they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.
China is one of the countries with the highest incidence of gastric cancer. There are differences in epidemiological characteristics, clinicopathological features, tumor biological characteristics, ...treatment patterns, and drug selection between gastric cancer patients from the Eastern and Western countries. Non‐Chinese guidelines cannot specifically reflect the diagnosis and treatment characteristics for the Chinese gastric cancer patients. The Chinese Society of Clinical Oncology (CSCO) arranged for a panel of senior experts specializing in all sub‐specialties of gastric cancer to compile, discuss, and revise the guidelines on the diagnosis and treatment of gastric cancer based on the findings of evidence‐based medicine in China and abroad. By referring to the opinions of industry experts, taking into account of regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted experts’ consensus judgement on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes. This guideline uses tables and is complemented by explanatory and descriptive notes covering the diagnosis, comprehensive treatment, and follow‐up visits for gastric cancer.
There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients ...from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub‐specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow‐up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non‐metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third‐line to the first‐line of treatment for different patient groups with detailed notes are provided.
The Chinese Society of Clinical Oncology (CSCO) organized a panel of senior experts specializing in all sub‐specialties of gastric cancer to compile the clinical guideline for gastric cancer in 2016 and then renewed it every year. The 2021 CSCO Clinical Practice Guidelines for gastric cancer covered the diagnosis, treatment, follow‐up and screening.
Oxygen plays an essential role in the photodynamic therapy (PDT) of cancer. However, hypoxia inside tumors severely attenuates the therapeutic effect of PDT. To address this issue, a novel strategy ...is reported for cutting off the oxygen consumption pathway by using sub‐50 nm dual‐drug nanoparticles (NPs) to attenuate the hypoxia‐induced resistance to PDT and to enhance PDT efficiency. Specifically, dual‐drug NPs that encapsulate photosensitizer (PS) verteporfin (VER) and oxygen‐regulator atovaquone (ATO) with sub‐50 nm diameters can penetrate deep into the interior regions of tumors and effectively deliver dual‐drug into tumor tissues. Then, ATO released from NPs efficiently reduce in advance cellular oxygen consumption by inhibition of mitochondria respiratory chain and further heighten VER to generate greater amounts of 1O2 in hypoxic tumor. As a result, accompanied with the upregulated oxygen content in tumor cells and laser irradiation, the dual‐drug NPs exhibit powerful and overall antitumor PDT effects both in vitro and in vivo, and even tumor elimination. This study presents a potential appealing clinical strategy in photodynamic eradication of tumors.
A novel strategy for reducing oxygen consumption to attenuate the hypoxia‐induced resistance to photodynamic therapy (PDT) by using sub‐50 nm dual‐drug nanoparticles (ATO/VER NPs) is described. ATO has the ability of alleviating hypoxic regions and can eliminate tumors by enhancing PDT, which provides a valuable reference for research on targeted treatment of hypoxic tumor tissues.
This study explored the effect of liver resection on perioperative circulating tumor cells (CTCs) and found that the prognostic significance of surgery was associated with changes in CTC counts in ...patients with hepatocellular carcinoma (HCC).
One hundred thirty-nine patients with HCC were consecutively enrolled. The time-points for collecting blood were one day before operation and three days after operation. CTCs in the peripheral blood were detected by the CellSearch™ System.
Both CTC detection incidence and mean CTC counts showed greater increases postoperatively (54%, mean 1.54 cells) than preoperatively (43%, mean 1.13 cells). The postoperative CTC counts increased in 41.7% of patients, decreased in 25.2% of patients and did not change in 33.1% of patients. The increase in postoperative CTC counts was significantly associated with the macroscopic tumor thrombus status. Patients with increased postoperative CTC counts (from preoperative CTC < 2 to postoperative CTC ≥ 2) had significantly shorter disease-free survival (DFS) and overall survival (OS) than did patients with persistent CTC < 2. Patients with persistent CTC levels of ≥2 had the worst prognoses.
Surgical liver resection is associated with an increase in CTC counts, and increased postoperative CTC numbers are associated with a worse prognosis in patients with HCC.
Background
To reveal detailed histopathological changes, virus distributions, immunologic properties and multi‐omic features caused by SARS‐CoV‐2 in the explanted lungs from the world's first ...successful lung transplantation of a COVID‐19 patient.
Materials and methods
A total of 36 samples were collected from the lungs. Histopathological features and virus distribution were observed by optical microscope and transmission electron microscope (TEM). Immune cells were detected by flow cytometry and immunohistochemistry. Transcriptome and proteome approaches were used to investigate main biological processes involved in COVID‐19‐associated pulmonary fibrosis.
Results
The histopathological changes of the lung tissues were characterized by extensive pulmonary interstitial fibrosis and haemorrhage. Viral particles were observed in the cytoplasm of macrophages. CD3+CD4− T cells, neutrophils, NK cells, γ/δ T cells and monocytes, but not B cells, were abundant in the lungs. Higher levels of proinflammatory cytokines iNOS, IL‐1β and IL‐6 were in the area of mild fibrosis. Multi‐omics analyses revealed a total of 126 out of 20,356 significant different transcription and 114 out of 8,493 protein expression in lung samples with mild and severe fibrosis, most of which were related to fibrosis and inflammation.
Conclusions
Our results provide novel insight that the significant neutrophil/ CD3+CD4− T cell/ macrophage activation leads to cytokine storm and severe fibrosis in the lungs of COVID‐19 patient and may contribute to a better understanding of COVID‐19 pathogenesis.
The increasing antimicrobial resistance in manure-amended soil can potentially enter food chain, representing an important vehicle for antibiotic resistance genes (ARGs) transmission into human ...microbiome. However, the pathways for transmission of ARGs from soil to plant remain unclear. Here, we explored the impacts of poultry and cattle manure application on the patterns of resistome in soil and lettuce microbiome including rhizosphere, root endosphere, leaf endosphere and phyllosphere, to identify the potential transmission routes of ARGs in the soil-plant system. After 90 days of cultivation, a total of 144 ARGs were detected in all samples using high-throughput quantitative PCR. Rhizosphere soil samples harbored the most diverse ARGs compared with other components of lettuce. Cattle manure application increased the abundance of ARGs in root endophyte, while poultry manure application increased ARGs in rhizosphere, root endophyte and phyllosphere, suggesting that poultry manure may have a stronger impact on lettuce resistomes. The ARG profiles were significantly correlated with the bacterial community, and the enrichment of soil and plant resistomes was strongly affected by the bacterial taxa including Solibacteres, Chloroflexi, Acidobacteria, Gemm-1 and Gemmatimonadetes, as revealed by the network analyses. Moreover, the overlaps of ARGs between lettuce tissues and soil were identified, which indicated that plant and environmental resistomes are interconnected. Our findings provide insights into the transmission routes of ARGs from manured soil to vegetables, and highlight the potential risks of plant resistome migration to the human food chain.
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•We established a glasshouse experiment to explore the transmission pathways of ARGs in the plant-soil system.•Diverse ARGs were detected in soil and lettuce microbiomes.•Poultry manure application significantly increased the ARG abundance in root endophyte and phyllosphere of lettuce.•Two transmission routes of ARGs are proposed by identifying the shared resistome between manured soils and lettuce.
Enhanced electrochemiluminescence (ECL) aims to promote higher sensitivity and obtain better detection limit. The core–shell nanostructures, owing to unique surface plasmon resonance (SPR) enabling ...distance‐dependent strong localized electromagnetic field, have attracted rising attention in enhanced ECL research and application. However, the present structures usually with porous shell involve electrocatalytic activity from the metal core and adsorption effect from the shell, which interfere with practical SPR enhancement contribution to ECL signal. Herein, to exclude the interference and unveil exact SPR‐enhanced effect, shell‐isolated nanoparticles (SHINs) whose shell gets thicker and becomes pinhole‐free are developed by modifying pH value and particles concentration. Furthermore, allowing for the distribution of hotspots and stronger enhancement, excitation intensity and ECL reaction layer thickness are mainly investigated, and several types of SHINs‐enhanced ECL platforms are prepared to fabricate distinct hotspot distribution via electrostatic attraction (submonolayer) and a layer‐by‐layer deposition method (monolayer). Consequently, the strongest enhancement up to ≈250‐fold is achieved by monolayer SHINs with 10 nm shell, and the platform is applied in a “turn‐off” mode sensing for dopamine. The platform provides new guidelines to shell preparation, interface engineering and hotspots fabrication for superior ECL enhancement and analytical application with high performance.
Shell‐isolated nanoparticles (SHINs) with pinhole‐free silica shell can exclude the interference from electrocatalytic activity and adsorption effect, allowing for exact SPR‐enhanced effect. Moreover, several types of SHINs‐enhanced ECL platforms are established to investigate the distribution of hotspots, expecting for stronger enhancement. Consequently, the strongest ECL enhancement up to ≈250‐fold is achieved, and the platform applies in sensing for dopamine.
Ferroptosis, a newfound non-apoptotic cell death pathway, results from the accumulation of iron-dependent lipid peroxide (LPO). Recently, emerging iron-based nanomaterials have been extensively ...developed to induce Fenton reaction-dependent ferroptosis for cancer therapy. However, insufficient amount of H2O2 and limited acidity of tumor could not satisfy the optimal conditions for Fenton reaction, which extremely limited the efficacy of ferroptosis therapy. Herein, we report a novel glutathione (GSH) and iron redox couple sequentially triggered LPO generator (LPOgener) which can directly supply the Fenton reaction-independent downstream executioner of ferroptosis for cancer therapy. By harnessing GSH-mediated Fe3+ reduction and the well-established iron redox couple-mediated lipid peroxidation, LPOgener was constructed by complete ferric ammonium citrate (FAC) and unsaturated lipids-rich phosphatidylcholine, and formed as FAC loaded liposome. The Fe3+ encapsulated in LPOgener could be efficiently reduced to Fe2+ under high GSH level in tumor cells. Subsequently, the formed iron redox couple could trigger overwhelming lipid peroxidation for Fenton reaction-independent ferroptosis. Superior anticancer therapeutic effect with little systemic toxicity demonstrated that LPOgener was a potent ferroptosis-inducing agent for cancer therapy. Therefore, to directly supply the druglike, easily prepared, GSH and iron redox couple sequentially triggered LPOgener would provide a new direction in designing strategies for ferroptosis therapy.
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