[Knockdown mitochondrial transcription factor A (TFAM) inhibits autophagy, proliferation, invasion and migration in human cervical cancer and osteosarcoma cells].

Objective To investigate the effects of mitochondrial transcription factor A (TFAM) on mitochondrial function, autophagy, proliferation, invasion, and migration in cervical cancer HeLa cells and osteosarcoma U2OS cells. Methods TFAM small-interfering RNA (si-TFAM) was transfected to HeLa and U2OS cells for downregulating TFAM expression. Mito-Tracker Red CMXRos staining combined with laser confocal microscopy was used to detect mitochondrial membrane potential (MMP). MitoSOXTM Red labeling was used to test mitochondrial reactive oxygen species (mtROS) levels. The expression of mitochondrial DNA (mtDNA) was detected by real-time quantitative PCR. Changes in the number of autophagosomes were detected by immunofluorescence cytochemistry. Western blot analysis was used to detect the expressions of TFAM, autophagy microtubule associated protein 1 light chain 3A/B (LC3A/B), autophagy associated protein 2A (ATG2A), ATG2B, ATG9A, zinc finger transcription factor Snail, matrix metalloproteinase 2 (MMP2) and MMP9. CCK-8 assay and plate clony formation assay were used to detect cell proliferation, while TranswellTM assay and scratch healing assay were used to detect changes in cell invasion and migration. Results The downregulation of TFAM expression resulted in a decrease in MMP and mtDNA copy number, but an increase in mtROS production. The protein content of LC3A/B decreased significantly compared to the control group and the number of autophagosomes in the cytoplasm decreased significantly. The expressions of ATG2B and ATG9A in the early stage of autophagy were significantly reduced. The expressions of Snail, MMP2 and MMP9 proteins in HeLa and U2OS cells were also decreased. The proliferation, invasion and migration ability of HeLa and U2OS cells were inhibited after being interfered with TFAM expression. Conclusion Downregulation of TFAM expression inhibits mitochondrial function, delays autophagy process and reduces the proliferation, invasion and migration ability of cervical cancer cells and osteosarcoma cells.

ML365 ameliorates postoperative cognitive impairment in aged mice by inhibiting NLRP3 inflammasome activation in the hippocampus.

The aim of this study was to examine the effects of ML365, a two-pore potassium channel (K2P) inhibitor, on postoperative cognitive impairment (POCD). A mouse model of POCD was constructed by subjecting aged C57BL/6 mice to exploratory laparotomy. Changes in cognitive function were assessed using the Morris water maze test. Western blotting and qPCR were used to detect hippocampal NLRP3, Caspase-1 and IL-1ß expression levels on days 3 and 7 post-surgery. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) expression level was also assessed by western blotting. Pathological changes and nerve damage in the hippocampal CA1 and CA3 regions were detected by H&E staining, while the concentration of malondialdehyde (MDA) in the plasma was measured. We found that pretreatment with ML365 (administered intraperitoneally at a dose of 10 mg/kg) 30 min prior to exploratory laparotomy effectively ameliorated POCD in mice. ML365 pretreatment also reduced NLRP3, Caspase-1, ASC and IL-1ß expression levels in the hippocampus, improved POCD-induced pathological changes in the hippocampal CA1 and CA3 areas of aged mice, and decreased levels of plasma MDA and oxidative stress. Together, our findings indicate that ML365 can alleviate POCD in mice by inhibiting NLRP3 inflammasome activation in the hippocampus.

Effects of biodegradable and conventional microplastics on the intestine, intestinal community composition, and metabolic levels in tilapia (Oreochromis mossambicus).

Despite growing interest in conventional microplastics (CMPs) and their toxicological effects on aquatic species, little is known about biodegradable microplastics (BMPs) and their corresponding implications for aquatic life. Here, tilapia (Oreochromis mossambicus) were semi-statically exposed for 14 days to the bio-based plastic polylactic acid (PLA, 100 µg/L, 2.52 ± 0.46 µm) and the petroleum-based plastic polyvinyl chloride (PVC, 100 µg/L, 1.58 ± 0.36 µm). The results showed that ingesting the above two types of microplastics (MPs) led to oxidative stress in the fish gut, and damage to gut tissues and organelles, and PLA resulted in more obvious gut tissue edema than PVC. Furthermore, PLA caused increased levels of gut microbiota dysbiosis and a decrease in the abundance of the genus Cetobacterium, which is linked to vitamin B-12 synthesis, whereas an opposite relationship was observed on PVC. Metabolomic analysis indicated that PVC caused a significant down-regulation of orotic acid, co-metabolite of folic acid with vitamin B-12, while PLA did not affect orotic acid, which may lead to the accumulation of folic acid in fish. The joint analysis found that MPs disturbed gut metabolism homeostasis, implying that abnormal gut microbiota metabolites may be a key mechanism for MPs to induce tissue damage and oxidative stress in the gut. Overall, this study systematically illustrates the differential toxic effects of BMPs and CMPs on tilapia through gut microbiota and metabolite interactions, which will contribute to assessing the risks of BMPs to organismal health.

Denosumab Improves Glycaemic Parameters in Postmenopausal Osteoporosis Patients with Combined Type 2 Diabetes Mellitus.

This study aimed to determine whether RANKL inhibitors in postmenopausal osteoporosis patients with combined type 2 diabetes mellitus (T2DM) could improve their glucose metabolism index. First of all, 84 patients affected with postmenopausal osteoporosis with combined T2DM attending the Department of Endocrinology at the Third Hospital of Hebei Medical University were selected and randomized into two groups of 42 patients each. One group was given Denosumab 60 mg once every six months (denosumab group, D.G.), and the other group was given 2 mg ibandronate once every three months (ibandronate group, I.G.). Blood glucose parameters were compared before and after treatment in both groups and serum active GLP-1 levels and DPP-4 levels were also assessed. After treatment, there was no significant difference in fasting glucose between the two groups, but there was a significant decrease in fasting glucose in the Denosumab Group (D.G.) compared to before treatment. There was a significant difference in 2-hour postprandial glucose (2hPG) between the two groups after treatment, with the D.G. being lower than the ibandronate group (I.G.). Glycosylated haemoglobin (HbA1c) was lower in the D.G. than in the I.G. after treatment, but the difference between them was insignificant. In the D.G., serum active GLP-1 levels increased after treatment, and serum DPP-4 levels decreased. Serum GLP-1 and DPP-4 levels in the I.G. did not change compared with those before treatment. In conclusion, In the clinical management of postmenopausal osteoporosis patients with combined T2DM, the choice of RANKL inhibitors as anti-osteoporosis therapy may benefit their glycaemic parameters by elevating serum active GLP-1 levels and decreasing serum DPP-4 levels.

[miR-497 inhibits the growth and metastasis of SGC-7901 human gastric cancer anoikis resistant cells via blocking Wnt/ß-catenin signaling pathway].

Objective To investigate the effects of microRNA497 (miR-497) on the metastasis of gastric cancer and its possible molecular mechanism. Methods SGC-7901 gastric cancer parent cells were cultured in an ultra-low adhesion environment, and the anoikis resistance model of SGC-7901 cells was created after re-adhesion. Clone formation assay, flow cytometry, TranswellTM test and scratch healing test were used to detect the differences of biological behavior compared with their parent cells. Fluorescence quantitative PCR was performed to detect the expression of miR-497. Western blot analysis was used to detect the changes of key proteins of Wnt/ß-catenin signaling pathway and epithelial mesenchymal transformation (EMT) related proteins such as vimentin and E-cadherin. Parent cells and anoikis resistant SGC-7901 cells were transfected with miR-497 inhibitor or miR-497 mimic, and CCK-8 assay was used to detect the proliferation activity. TranswellTM invasion assay was performed to detect the invasion ability of cells. TranswellTM migration test and scratch healing assay was used to determine the migration ability. Western blot analysis was used to detect the expressions of Wnt1, ß-catenin, vimentin and E-cadherin. By transfecting miR-497 mimic into the anoikis resistance SGC-7901 cells and inoculating them subcutaneously in nude mice, the changes in the volume and mass of tumor tissues were measured and recorded. Western blot analysis was used to determine the expressions of Wnt1, ß-catenin, vimentin and E-cadherin of tumor tissues. Results Compared with the parent cells, the anoikis resistance SGC-7901 gastric cancer cells had faster proliferation rate, stronger colony formation, lower apoptosis rate, stronger invasion and migration ability. The expression of miR-497 was significantly decreased. After down-regulation of miR-497, the proliferation ability, invasion and migration ability were significantly enhanced. The expressions of Wnt1, ß-catenin and vimentin increased significantly, while E-cadherin decreased notably. The results of up-regulation miR-497 were the opposite. The tumor growth rate, tumor volume and mass of miR-497 overexpression group were significantly lower than those of control group. The expressions of Wnt1, ß-catenin and vimentin decreased significantly, while the expression of E-cadherin increased significantly. Conclusion The expression of miR-497 is low in the anoikis resistance SGC-7901 cells. miR-497 can inhibit the growth and metastasis of gastric cancer cells by blocking Wnt/ß-catenin signaling pathway and EMT.

Cuproptosis-related LINC01711 promotes the progression of kidney renal clear cell carcinoma.

This study utilized The Cancer Genome Atlas (TCGA) database to identify cuproptosis-related long non-coding RNAs (CRlncRNAs) in patients with kidney renal clear cell carcinoma (KIRC) which was further applied to construct risk signatures. All KIRC patients were divided into the training and the validation sets at a ratio of 7:3. Lasso regression analysis identified two prognosis-associated CRlncRNAs (LINC01204 and LINC01711), and prognostic risk signatures were constructed in both the training and the validation sets. Kaplan-Meier survival curves showed that patients with high-risk scores had significantly shorter overall survival (OS) than those with low-risk scores both in both the training and the validation sets. The area under the curve (AUC) of the prognostic nomogram generated based on age, grade, stage and risk signature to predict the 1-, 3- and 5-year OS were 0.84, 0.81 and 0.77, respectively, and the calibration curves also showed the high accuracy of the nomogram. In addition, we constructed the LINC01204/LINC01711-miRNA-mRNA ceRNA network graph. Finally, we experimentally investigated the function of LINC01711 by knocking down LINC01711 and revealed that knockdown of LINC01711 inhibited the proliferation, migration and invasion of KIRC cells. Hence, in this study, we developed a signature of prognostic risk-associated CRlncRNAs that could accurately predict the prognosis of KIRC patients and constructed a related ceRNA network to shed light on the mechanistic study of KIRC. LINC01711 might serve as a potential biomarker for the early diagnosis and prognosis of KIRC patients.

Heterogeneous aggregation between microplastics and microalgae: May provide new insights for microplastics removal.

Existing studies have shown that microplastics (MPs) as artificial surfaces can be colonized by plankton microorganisms. However, systematic research on exploring the aggregation formation process of MPs and microalgae is still lacking and particularly the influencing factors of aggregation remain to be elucidated. Therefore, this study investigated the heterogeneous aggregation process between various microalgal species (i.e., Chlorella vulgaris, Scenedesmus obliquus, Tetraselmis subcordiformis, Chaetoceros müelleri and Streptococcus westermani) and MPs (i.e., mPS and mPLA) with different sizes (i.e., 74 µm and 613 µm), concentrations (i.e., 0.1 g/L, 1 g/L and 2 g/L) and shapes (i.e., the particle and sheet). The results showed that microalgae can first attach to the holes or protrusions of MPs and highly accumulate in the local region, and then multi-layer aggregation can be formed subsequently. The aggregation degree between MPs and microalgae was closely related to the MPs shape and size, and was less related to the MPs concentration. The aggregation speed of small-sized MPs (e.g., 74 µm) was faster than the large-sized ones (e.g., 613 µm). The MPs in a shape of sheet were more obvious than those in particle on their aggregation with microalgae. The density of aggregates was increased compared with pristine MPs, which is related to the cell density and cell number of attached microalgae. For the same type of MPs, the aggregation degree for the tested microalgae was as follows: Scenedesmus obliquus > C. vulgaris > T. subcordiformis > C. müelleri > S. westermani. Meanwhile, MPs inhibited cell growth of microalgae, particularly under the circumstance of their aggregation, by limiting the gas and mass transfer between microalgal cells and the extracellular environment. The heterogeneous aggregation of MPs and microalgae may provide new ideas for treatment and controlling of MPs in the environment.

Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines, anti-PD-1 and poly I:C.

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

[Acteoside promotes autophagy and apoptosis of hepatoma cells by regulating JNK signaling pathway].

This study explored the molecular mechanism of acteoside against hepatoma 22(H22) tumor in mice through c-Jun N-terminal kinase(JNK) signaling pathway. H22 cells were subcutaneously inoculated in 50 male BALB/c mice, and then the model mice were classified into model group, low-dose, medium-dose, and high-dose acteoside groups, and cisplatin group. The administration lasted 2 weeks for each group(5 consecutive days/week). The general conditions of mice in each group, such as mental status, diet intake, water intake, activity, and fur were observed. The body weight, tumor volume, tumor weight, and tumor-inhibiting rate were compared before and after administration. Morphological changes of liver cancer tissues were observed based on hematoxylin and eosin(HE) staining, and the expression of phosphorylated(p)-JNK, JNK, B-cell lymphoma-2(Bcl-2), Beclin-1, and light chain 3(LC3) in each tissue was detected by immunohistochemistry and Western blot. qRT-PCR was performed to detect the mRNA expression of JNK, Bcl-2, Beclin-1, and LC3. The general conditions of mice in model and low-dose acteoside groups were poor, while the general conditions of mice in the remaining three groups were improved. The body weight of mice in medium-dose acteoside group, high-dose acteoside group, and cisplatin group was smaller than that in model group(P<0.01). The tumor volume in model group was insignificantly different from that in low-dose acteoside group, and the volume in cisplatin group showed no significant difference from that in high-dose acteoside group. Tumor volume and weight in medium-dose and high-dose acteoside groups and cisplatin group were lower than those in the model group(P<0.001). The tumor-inhibiting rates were 10.72%, 40.32%, 53.79%, and 56.44% in the low-dose, medium-dose, and high-dose acteoside groups and cisplatin group, respectively. HE staining showed gradual decrease in the count of hepatoma cells and increasing sign of cell necrosis in the acteoside and cisplatin groups, and the necrosis was particularly obvious in the high-dose acteoside group and cisplatin group. Immunohistochemical results suggested that the expression of Beclin-1, LC3, p-JNK, and JNK was up-regulated in acteoside and cisplatin groups(P<0.05). The results of immunohistochemistry, Western blot, and qRT-PCR indicated that the expression of Bcl-2 was down-regulated in the medium-dose and high-dose acteoside groups and cisplatin group(P<0.01). Western blot showed that the expression of Beclin-1, LC3, and p-JNK was up-regulated in acteoside and cisplatin groups(P<0.01), and there was no difference in the expression of JNK among groups. qRT-PCR results showed that the levels of Beclin-1 and LC3 mRNA were up-regulated in the acteoside and cisplatin groups(P<0.05), and the level of JNK mRNA was up-regulated in medium-dose and high-dose acteoside groups and cisplatin group(P<0.001). Acteoside promotes apoptosis and autophagy of H22 cells in mice hepatoma cells by up-regulating the JNK signaling pathway, thus inhibiting tumor growth.

TFAM knockdown undermines SQSTM1 mRNA stability but retards autophagy flux and inhibits tumor cells proliferation under starvation conditions.

Although starvation stress can alter the homeostasis of mitochondria and promote autophagy, there is still a lack of research focusing on the connection between them. In this study, we found that, accompanied by the upregulation of autophagy flux, the membrane mitochondrial potential (MMP), the content of reactive oxygen species (ROS), the production of ATP, and the copy number of mitochondrial DNA (mt-DNA) were changed when limiting amino acids supply. We screened and analyzed altered genes related to mitochondrial homeostasis under starvation stress and verified that the expression of mitochondrial transcription factor A (TFAM) was prominently upregulated. Inhibition of TFAM led to the change of mitochondrial function and homeostasis, caused the decrease of SQSTM1 mRNA stability and ATG101 protein level and restricted the autophagy process of cells under amino acid deficient conditions. In addition, the TFAM knockdown and starvation treatment aggravated the DNA damage and reduced proliferation rate of tumor cells. Therefore, our data shows the correlation between mitochondria homeostasis and autophagy, reveals the effect of TFAM on autophagy flux under starvation stress and provides experimental basis for the combined starvation therapy targeting mitochondria to inhibit tumor growth.

Microplastics leachate may play a more important role than microplastics in inhibiting microalga Chlorella vulgaris growth at cellular and molecular levels.

The leaching of microplastics (MPs) additives and their negative effects on aquatic organisms remain to be systematically elucidated. In this study, the toxicological effects of MPs leachate (micro-sized polyethylene (mPE) and micro-sized polyvinyl chloride (mPVC) acceleratedly leached by UVA for 15, 90, and 180 days in seawater) on microalga Chlorella vulgaris in terms of cell growth inhibition, oxidative stress, and transcriptomes were investigated. The leachate components of MPs aged for 90 days were further identified to elucidate the corresponding toxicity mechanisms of MPs on microalgal cells. The results revealed that both leachates of mPE and mPVC inhibited cell growth and increased oxidative stress in C. vulgaris, accompanied by a growth inhibition rate to microalgal cells of 4.0%-36.2% and 7.1%-48.2%, respectively. At the same mass concentration, the toxicological effects on C. vulgaris followed the order of mPVC leachate > mPE > mPE leachate > mPVC, whereas MPs leaching time indicated no change in MPs leaching toxicity. Furthermore, the gene functions of "translation, ribosomal structure and biogenesis" were mostly affected by MPs leachate. Compared to mPE leachate and pure MPs, the stronger inhibitory effects of mPVC leachate on microalgal cells may be attributed to the fact that more substances were leached from the polymer of mPVC, including Zn, farnesol isomer a, 2,6-di-tert-butyl-4-methylphenol, and acetyl castor oil methyl ester. In summary, this study provides a better understanding of the ecotoxicological influences of MPs and MPs leachate, and offers a warning on the ecological risk caused by plastic additives.

Impacts of microplastic-petroleum pollution on nutrient uptake, growth, and antioxidative activity of Chlorella vulgaris.

As one of the emerging pollutants, microplastics (MPs; <5 mm) can interact with co-contaminants such as petroleum in marine aquatic systems, and their combined toxicity has not been fully investigated. Therefore, this study focused on pollutants such as micro-sized polyethylene (mPE) and petroleum, aiming to explore their single and combined toxicities to microalga Chlorella vulgaris in terms of the cell growth, antioxidative enzymes, and nutrients utilization. The results showed that the MPs alone (particle sizes (i.e., 13, 165, 550 µm), concentrations (i.e., 0.01, 0.1, and 1 g/L), and aging degrees (i.e., aged for 0 d and 90 d under UVA)), and petroleum alone (5% water accommodated fraction, WAF), and their combinations (i.e., 5% WAF + 165 µm-0.1 g/L-aged 0 d mPE, 5% WAF + 165 µm-0.1 g/L-aged 90 d mPE) all posed toxicities risk to C. vulgaris, following an increase in oxidative stress. The cellular utilization of elements such as Fe, Si, Ca, and Mg was inhibited, whereas the uptake of Mn, NO3--N, and PO43--P increased as compared to the control experiments. Furthermore, the relationship between nutrients and growth indicators was analyzed using a structural equation model. The results indicated that Fe and Mn directly affected the indirect NO3--N absorption by C. vulgaris, which indirectly affected the dry cell weight (DCW) of the microalgae. The path coefficient of Fe and Mn affecting nitrate was 0.399 and 0.388, respectively. The absorption of N was the key step for C. vulgaris resist stress. This study provides a novel analysis of the effects of MPs on the growth of microalgae from the perspective of nutrient elements, thereby providing a useful basis for further exploration of the associated mechanisms.

Recent progress in the treatment of intractable sialolithiasis / 北京大学学报(医学版)

Sialolithiasis occurs in approximately 0.45% to 1.20% of the general population. The typical clinical symptom manifests as a painful swelling of the affected glands after a meal or upon salivary stimulation, which extremely affects the life quality of the patients. With the development of sialendoscopy and lithotripsy, most sialoliths can be successfully removed with preservation of the gland. However, sialoliths in the deep hilar-parenchymal submandibular ducts and impacted parotid stones located in the proximal ducts continue to pose great challenges. Our research center for salivary gland diseases (in Peking University School and Hospital of Stomatology) has used sialendoscopy for 17 years and treated >2 000 patients with salivary gland calculi. The success rate was approximately 92% for submandibular gland calculi and 95% for parotid calculi. A variety of minimally invasive surgical techniques have been applied and developed, which add substantial improvements in the treatment of refractory sialolithiasis. Further, the radiographic positioning criteria and treatment strategy are proposed for these intractable stones. Most of the hilar-parenchymal submandibular stones are successfully removed by a transoral approach, including transoral duct slitting and intraductal basket grasping, while a small portion of superficial stones can be removed by a mini-incision in submandibular area. Impacted stones located in the distal third of parotid gland ducts are removed via "peri-ostium incision", which is applied to avoid a cicatricial stenosis from a direct ostium incision. Impacted parotid stones located in the middle and proximal third of the Stensen's duct are removed via a direct mini-incision or a peri-auricular flap. A direct transcutaneous mini-incision is commonly performed under local anesthesia with an imperceptible scar, and is indicated for most of impacted stones located in the middle third, hilum and intraglandular ducts. By contrast, a peri-auricular flap is performed under general anesthesia with relatively larger operational injury of the gland parenchyma, and should be best reserved for deeper intraglandular stones. Laser lithotripsy has been applied in the treatment of sialolithiasis in the past decade, and holmium ∶YAG laser is reported to have the best therapeutic effects. During the past 3 years, our research group has performed laser lithotripsy for a few cases with intractable salivary stones. From our experiences, withdrawal of the endoscopic tip 0.5-1.0 cm away from the extremity of the laser fiber, consistent saline irrigation, and careful monitoring of gland swelling are of vital importance for avoidance of injuries of the ductal wall and the vulnerable endoscope lens during lithotripsy. Larger calculi require multiple treatment procedures. The risk of ductal stenosis can be alleviated by endoscopic dilation. In summary, appropriate use of various endoscopy-assisted lithotomy helps preserve the gland function in most of the patients with refractory sialolithiasis. Further studies are needed in the following aspects: Transcervical removal of intraglandular submandibular stones, intraductal laser lithotripsy of impacted parotid stones and deep submandibular stones, evaluation of long-term postoperative function of the affected gland, et al.

Role of Preoperative Peripheral Blood Inflammatory Parameters and Postoperative Lymph-node Ratio in Prognosis of Patients with Gastric Cancer Undergoing Chemotherapy / 肿瘤防治研究

Objective To analyze the role of preoperative peripheral blood inflammatory parameters and postoperative lymph-node ratio (LNR) in the prognosis of gastric cancer patients treated with chemotherapy. Methods The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune inflammatory response index (SII), lymphocyte-to-monocyte ratio (LMR), Onodera prognostic nutritional index (OPNI), and LNR of 108 patients with gastric cancer were classified into high and low groups to analyze their prognostic value on the overall survival (OS) of gastric cancer patients treated with chemotherapy. The independent prognostic indicators were plotted in columns to predict the survival rate of gastric cancer patients. Results NLR was statistically significant in the prognostic assessment of gastric cancer patients treated with chemotherapy (P < 0.001). Moreover, the high PLR group, high SII group, high LNR group, N3 stage, TNM (Ⅲ-Ⅳ) stage, nerve invasion, and carcinoembryonic antigen (CEA) were independent risk factors for the prognosis of gastric cancer (all P < 0.05). These findings indicated that in predicting the prognosis of gastric cancer, the combination of LNR, PLR, and SII (AUC=0.875) was better than that of LNR, PLR, and SII alone or in pairwise combination. Conclusion Elevated NLR, LNR, PLR, and SII are associated with significantly reduced survival of patients. LNR, PLR, and SII could be used as independent risk factors for the prognosis of gastric cancer patients treated with chemotherapy, and their combination can predict the survival of gastric cancer patients.

Research progress on aspiration in patients with dysphagia after ischemic stroke / 中国基层医药

Based on the research results of aspiration in patients with dysphagia after ischemic stroke at home and abroad, this paper reviews the definition, detection methods, and risk factors of aspiration and emphasizes the incidence rate and severity of this disease. The authors conclude that preventing aspiration can decrease the incidence rate of aspiration pneumonia, change the clinical outcome of patients, and thereby save medical resources.

Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines,anti-PD-1 and poly I:C / 药物分析学报

Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immu-notherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histo-compatibility complex(MHC)class Ⅰ and Ⅱ antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4+and CD8+T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

The role of advanced glycation end products in fracture risk assessment in postmenopausal type 2 diabetic patients.

Objective: The objective of this study was to analyze the quantitative association between advanced glycation end products (AGEs) and adjusted FRAX by rheumatoid arthritis (FRAX-RA) in postmenopausal type 2 diabetic (T2D) patients. The optimal cutoff value of AGEs was also explored, which was aimed at demonstrating the potential value of AGEs on evaluating osteoporotic fracture risk in postmenopausal T2D patients. Methods: We conducted a cross-sectional study including 366 postmenopausal participants (180 T2D patients [DM group] and 186 non-T2D individuals [NDM group]). All the subjects in each group were divided into three subgroups according to BMD. Physical examination, dual-energy x-ray absorptiometry (DXA), and serum indicators (including serum AGEs, glycemic parameters, bone turnover markers and inflammation factors) were examined. The relationship between FRAX-RA, serum laboratory variables, and AGEs were explored. The optimal cutoff value of AGEs to predict the risk of osteoporotic fracture was also investigated. Results: Adjusting the FRAX values with rheumatoid arthritis (RA) of T2D patients reached a significantly increased MOF-RA and an increasing trend of HF-RA. AGEs level was higher in the DM group compared to the NDMs, and was positively correlated with MOF-RA (r=0.682, P<0.001) and HF-RA (r=0.677, P<0.001). The receiver operating characteristic curve analysis revealed that the area under the curve was 0.804 (P<0.001), and the optimal AGEs cut-off value was 4.156mmol/L. Subgroup analysis for T2D patients revealed an increase in TGF-ß, IL-6 and SCTX in the osteoporosis group, while a decreased PINP in the osteoporosis group compared to the other two subgroups. AGEs were positively associated with FBG, HbA1c, HOMA-IR, S-CTX, IL-6 and TGF-ß in T2D patients, and negatively associated with PINP. Conclusions: RA-adjusted FRAX is a relevant clinical tool in evaluating fracture risk of postmenopausal T2D patients. Our study analyzed the relationship between AGEs and FRAX-RA, and explored the threshold value of AGEs for predicting fracture risk in postmenopausal T2D patients. AGEs were also associated with serum bone turnover markers and inflammation factors, indicating that the increasing level of AGEs in postmenopausal T2D patients accelerated the expression of inflammatory factors, which led to bone metabolism disorders and a higher risk of osteoporotic fractures.

Aucubin Impeded Preosteoclast Fusion and Enhanced CD31hi EMCNhi Vessel Angiogenesis in Ovariectomized Mice.

Osteogenesis is tightly correlated with angiogenesis during the process of bone development, regeneration, and remodeling. In addition to providing nutrients and oxygen for bone tissue, blood vessels around bone tissue also secrete some factors to regulate bone formation. Type H vessels which were regulated by platelet-derived growth factor-BB (PDGF-BB) were confirmed to couple angiogenesis and osteogenesis. Recently, preosteoclasts have been identified as the most important source of PDGF-BB. Therefore, inhibiting osteoclast maturation, improving PDGF-BB secretion, stimulating type H angiogenesis, and subsequently accelerating bone regeneration may be potent treatments for bone loss disease. In the present study, aucubin, an iridoid glycoside extracted from Aucuba japonica and Eucommia ulmoides, was found to inhibit bone loss in ovariectomized mice. We further confirmed that aucubin could inhibit the fusion of tartrate-resistant acid phosphatase (TRAP)+ preosteoclasts into mature osteoclasts and indirectly increasing angiogenesis of type H vessel. The underlying mechanism is the aucubin-induced inhibition of MAPK/NF-κB signaling, which increases the preosteoclast number and subsequently promotes angiogenesis via PDGF-BB. These results prompted that aucubin could be an antiosteoporosis drug candidate, which needs further research.

Elucidating the negatively influential and potentially toxic mechanism of single and combined micro-sized polyethylene and petroleum to Chlorella vulgaris at the cellular and molecular levels.

Although microplastics (MPs; <5 mm) may interact with co-contaminants (e.g., petroleum) in marine aquatic systems, little is known about their combined toxicity. Therefore, this study explored the toxicities and their mechanisms of micro-sized polyethylene (mPE) and their combination with petroleum to Chlorella vulgaris. The single MPs at various particle sizes, concentrations, and aging degree, single petroleum, and their combinations, were found to pose toxicities to C. vulgaris. This study also found the microcosm's microbial diversity changed. The microbial communities in the C. vulgaris biotopes were altered under exposure to mPE and petroleum, and were disturbed by external factors such as MPs particle size, concentration, aging time, and the combination with petroleum. Furthermore, as compared with the toxicity of petroleum on microalgal transcriptional function, mPE caused less toxic to C. vulgaris, and only impact the posttranslational modification, protein turnover, and signal transduction processes. Most importantly, mPE reduced petroleum toxicity in C. vulgaris via regulating the ABC transporter, eukaryotic ribosome synthesis, and the citrate cycle metabolic pathways. Overall, our findings could fundamentally provide insights into the joint ecotoxicological effects of MPs and petroleum, and highlight the potential risks of co-exsiting pollutants.

Secondary microplastics formation and colonized microorganisms on the surface of conventional and degradable plastic granules during long-term UV aging in various environmental media.

Recently, biodegradable plastics (BPs) as an alternative of conventional plastics have been widely advocated and applied. However, there is still a large research gap between the formation of secondary microplastics (MPs) and colonized microorganisms on their surface under long-term aging in different environments. In this study, the generation of secondary MPs and the formation of surface biofilms on the micro-sized (3-5 mm) biodegradable plastic poly (butyleneadipate-co-terephthalate) (BP-PBAT) and conventional plastic polyvinyl chloride (CP-PVC) under long-term UV aging was investigated. The results showed that hundreds and even thousands of MPs (185.53 ± 85.73 items/g - 1473.27 ± 143.67 items/g) were generated by BP-PBAT and CP-PVC after aged for 90 days, and the abundance of MPs produced by BP-PBAT was significantly higher than that of CP-PVC. Moreover, the α diversities and detected OTU number of biofilm communities formed on MPs increased with MPs-aging. The genes related to the formation of biofilms was significantly expressed on aged MPs and the genes related to human pathogens and diseases were also detected in enriching on MPs surface. Overall, BPs may lead to greater ecological risks as it releases thousands of secondary MPs after being aged, and their environmental behavior needs to be further explored.