The characteristics and prognosis of different disease patterns of multiple primary lung cancers categorized according to the 8th edition lung cancer staging system.

INTRODUCTION: The 8th edition lung cancer staging system was the first to describe the detailed diagnosis and staging of multiple primary lung cancers (MPLC). However, the characteristics and prognosis of MPLC categorized according to the new system have not been evaluated. METHOD: We retrospectively analyzed data from surgically treated MPLC patients in a single center from 2011 to 2013 and explored the characteristics and outcomes of different MPLC disease patterns. RESULTS: In total, 202 surgically treated MPLC patients were identified and classified into different groups according to disease categories and diagnostic time (multifocal ground glass/lepidic (GG/L) nodules: n = 139, second primary lung cancer (SPLC): n = 63, simultaneous MPLC (sMPLC): n = 171, and metachronous MPLC (mMPLC): n = 31). There were significant differences in clinical characteristics between SPLC and GG/L nodule patients and simultaneous and metachronous MPLC patients. The overall 1-, 3-, and 5-year lung cancer-specific survival rates of MPLC were 97.98%, 90.18%, and 82.81%, respectively. Five-year survival was better in patients with multiple GG/L nodules than in those with SPLC (87.94% vs. 71.29%, P < 0.05). Sex was an independent prognostic factor for sMPLC (5-year survival, female vs. male, 88.0% vs. 69.5%, P < 0.05), and in multiple tumors, the highest tumor stage was an independent prognostic factor for all categories of MPLC. CONCLUSIONS: The different disease patterns of MPLC have significantly different characteristics and prognoses. Clinicians should place treatment emphasis on the tumor with the highest stage as it is the main contributor to the prognosis of all categories of MPLC patients.

Gypenoside induces apoptosis by inhibiting the PI3K/AKT/mTOR pathway and enhances T-cell antitumor immunity by inhibiting PD-L1 in gastric cancer.

Introduction: Gypenoside is a natural extract of Gynostemma pentaphyllum (Thunb.) Makino, a plant in the Cucurbitaceae family. It has been reported to have antitumor effects on the proliferation, migration and apoptosis of various types of cancer cells. However, the use of gypenoside in the treatment of gastric cancer has not been studied. In the present study, we explored the therapeutic effect of gypenoside on gastric cancer and the potential molecular mechanism. Methods and Results: Our results showed that gypenoside induced apoptosis in HGC-27 and SGC-7901 cells in a time-dependent and dose-dependent manner. Network pharmacology analyses predicted that gypenoside exerts its therapeutic effects through the PI3K/AKT/mTOR signaling pathway. Furthermore, molecular docking and western blot experiments confirmed that gypenoside induced the apoptosis of gastric cancer cells through the PI3K/AKT/mTOR signaling pathway. In addition, network pharmacological analysis revealed that the common targets of gypenoside in gastric cancer were enriched in the immune effector process, PD-L1 expression, the PD-1 checkpoint pathway, and the Jak-STAT signaling pathway. Furthermore, molecular docking and western blot assays demonstrated that gypenoside could bind to STAT3 and reduce its phosphorylation. Thus, the transcription of PD-L1 was inhibited in gastric cancer cells. Moreover, coculture experiments of gastric cancer cells with gypenoside and primary mouse CD8+ T cells showed that gastric cancer cells treated with gypenoside could enhance the antitumor ability of T cells. Animal experiments confirmed the antitumor effect of gypenoside, and the expression of PD-L1 was significantly downregulated in the gypenoside-treated group. Conclusion: Gypenoside induced the apoptosis of gastric cancer cells by inhibiting the PI3K/AKT/mTOR pathway and simultaneously inhibited the expression of PD-L1 in gastric cancer cells, thus enhancing the antitumor immunity of T cells. This study provides a theoretical basis for applying gypenoside as a new therapeutic agent to enhance the efficacy of immunotherapy in gastric cancer.

Hemorheology and Inflammatory Marker Changes in Patients with Acute Ischemic Stroke after Intravenous Thrombolysis with Mechanical Thrombectomy.

Objective: To investigate hemorheology and inflammatory marker changes after treatment for acute ischemic stroke (AIS) using intravenous thrombolysis (IVT) with mechanical thrombectomy (MT). Methods: We retrospectively reviewed clinical records of patients with AIS (n=83) treated in The First Affiliated Hospital of Bengbu Medical College between January 2021 and December 2022 (n=83). The control group consisted of 38 patients who underwent IVT alone and the observation group consisted of 45 patients who underwent IVT with MT. We compared differences in mean variables related to hemorheology, inflammatory markers, and total efficacy between the two groups. Results: We found that hemorheology values (plasma viscosity [PV], whole blood viscosity [WBV], fibrinogen [FIB], and hematocrit [HCT]), and the levels of inflammatory markers (tumor necrosis factor ɑ [TNF-ɑ] and interleukin-6 [IL-6]) were higher in the control group than in the observation group after treatment (P<0.05). In addition, the total efficacy of the observation group (93.3%) was higher than that in the control group (76.3%; P=0.016). Conclusions: The clinical efficacy of combined IVT and MT in the treatment of AIS is superior to IVT alone, improving levels of hemorheology and inflammatory markers in patients with AIS.

Study on the association between pregnancy-associated plasma protein-A and acute cerebral infarction.

Objective: We aimed to study the correlation between pregnancy-associated plasma protein-A (PAPP-A) and acute cerebral infarction (ACI). Methods: Patients who had the symptoms of paralysis, aphasia, or sudden neurological impairment from June 2020 to October 2021 were chosen. There were 159 patients diagnosed with ACI as the experimental group and 102 patients without ACI as the control group. We collected clinical data and observed whether they have a certain impact on plasma PAPP-A levels. The ACI group was divided into two groups: mild neurological deficit group (NIHSS score < 3) and moderate and severe neurological deficit group (NIHSS score > 3). The ACI group was divided into the atherosclerotic-type group and the arteriolar occlusion-type group according to the TOAST classification. The ACI group was divided into a good prognosis group (mRS ≤ 2 points) and a poor prognosis group (mRS > 2 points) using the Modified Rankin Scale (mRS) for 90 days of follow-up. Plasma PAPP-A levels were compared between those groups. Results: (1) The plasma PAPP-A level in patients with ACI (1.840 ± 0.281) was significantly higher than that in the control group (1.690 ± 0.260). Smoking history, leukocyte count, cystatin C, homocysteine, and plasma PAPP-A levels were independently correlated with ACI. (2) The level of PAPP-A in patients with moderate and severe neurological impairment was lower than that in patients with mild neurological impairment. (3) The level of PAPP-A in patients in the arteriolar occlusion-type group was higher than that in patients in the atherosclerosis-type group. (4) The PAPP-A levels in the group with elevated low-density lipoprotein are higher than those in the group with normal low-density lipoprotein. (5) Plasma PAPP-A level was not correlated with infarction location, infarction volume, or prognosis at the 90-day follow-up. Conclusion: (1) The level of plasma PAPP-A could be the independent risk factor of ACI. It is positively correlated with triglyceride and cholesterol content. (2) PAPP-A level is positively correlated with low-density lipoprotein. (3) PAPP-A levels between different disease severities have a significant difference. (4) The level of plasma PAPP-A in the arteriolar occlusion-type group was higher than that in the atherosclerotic-type group.

Dictamnine suppresses the development of pear ring rot induced by Botryosphaeria dothidea infection by disrupting the chitin biosynthesis.

Ring rot induced by Botryosphaeria dothidea is a major cause of growth and postharvest losses in various fruits. There is an urgent need to develop green fungicides due to pesticide resistance and environmental pressure. Here, we demonstrated the efficacy of dictamnine (DIC, 4-methoxyfuro [2,3-ß] quinoline, purity 98%), a compound isolated from the stems and leaves of Clausena lansium, in effectively suppressing pear ring rot by inhibiting the mycelial growth of B. dothidea. The median effective concentration of DIC was 15.48 µg/mL. Application of DIC to B. dothidea resulted in structural disruption of the cell wall and plasma membrane, leading to mycelial deformation, breakage, and cell death. Transcriptome analysis revealed significant inhibition of the synthetic pathways for fungal cell wall and membrane components by DIC. Particularly, the expression of chitin synthase, a key enzyme of chitin synthesis, was prominently down-regulated. Moreover, the chitin content in DIC-treated B. dothidea mycelia exhibited a substantial dose-dependent reduction. Based on these results, it is promising to develop DIC as an antifungal pesticide for controlling ring rot disease in pear fruits. Our study provides new insights into the underlying mechanism through which DIC inhibits the mycelial growth of B. dothidea.

Ecological footprint model of heavy metal pollution in water environment based on the potential ecological risk index.

Social heavy metal pollution poses a significant threat to aquatic ecosystems. Heavy metals are easily adsorbed by sediments and have cumulative effects on aquatic organisms, which is different with the hypothesis of the conventional ecological footprint model that the pollutants are independently degraded by water bodies. To solve this problem, an ecological footprint for heavy metal pollution (EFHM) is constructed based on the potential ecological risk index (PERI). EFHM is defined as the sediment area to control the cumulative ecological risk of heavy metals within the allowable limit. And then, EFHM uses ecological footprint index (EFI) and ecological footprint contribution rate (EFCR) to quantify the hazard of social heavy metal load and recognize the key risk factor. EFHM is applied for assessing the heavy metal pollution of Central China. The results show that (i) the EFHM model can effectively evaluate the cumulative ecological hazards of heavy metals in sediment. (ii) The EFHM values of Central China in 2015 and 2020 are 20,764.56 and 17,358.59 km2, respectively. (iii) Compared with 2015, the EFI values of Hunan Province and Jiangxi Province in 2020 decrease from 1.53 to 0.87 to 1.23 and 0.39, respectively, both of which are improved by one grade. The EFI values of Hubei Province increases from 0.42 to 1.34, which is deteriorated by one grade. (iv) In 2020, both of the key risk factors of Hunan Province and Hubei Province are Hg, and the crucial hazard source of Jiangxi Province is Cd. (v) The mine pollution control in Central China should be further consolidated, and the wastewater treatment of electronics and machinery industries should be strengthened.

Cholesterol metabolism in T-cell aging: Accomplices or victims.

Aging has a significant impact on the function and metabolism of T cells. Cholesterol, the most important sterol in mammals, is known as the "gold of the body" because it maintains membrane fluidity, rigidity, and signal transduction while also serving as a precursor of oxysterols, bile acids, and steroid hormones. Cholesterol homeostasis is primarily controlled by uptake, biosynthesis, efflux, and regulatory mechanisms. Previous studies have suggested that there are reciprocal interactions between cholesterol metabolism and T lymphocytes. Here, we will summarize the most recent advances in the effects of cholesterol and its derivatives on T-cell aging. We will furthermore discuss interventions that might be used to help older individuals with immune deficiencies or diminishing immune competence.

LncRNA HOXA11-AS modulates the miR-148b-3p/MLPH axis to promote prostate cancer cell proliferation.

Prostate cancer refers to the epithelial malignant tumor of the prostate. It has a high incidence and mortality rate, seriously endangering the lives of men. In recent years, lncRNAs have become a hot topic for lots of scholars for their regulation functions on assorted cancers. Several lncRNAs have been proven they can take part in the regulation of prostate cancer development. Nevertheless, how HOXA11-AS (homeobox A11 antisense RNA)functioned in prostate cancer is not explained. In our research, the expression of HOXA11-AS in prostate cancer cells was evaluated through qRT-PCR. Colony formation experiments, EdU experiments, Tanswelland TUNEL experiments, as well as caspase-3 detection, were designed to test cell proliferation, migration, invasion and apoptosis. RIP, pull down and luciferase reporter experiments examined the correlations of HOXA11-AS, miR-148b-3p and MLPH. We discovered a high level of HOXA11-AS in prostate cancer cells.HOXA11-AS silence could restrain the mentioned cell malignant behavior. Mechanically, HOXA11-AS could sponge miR-148b-3p to target MLPH. MLPH was positively associated with HOXA11-AS and overexpressed it accelerated the progression of prostate cancer. Taken together, HOXA11-AS elevated MLPH expression by sponging miR-148b-3p and accelerated prostate cancer cell proliferation.

Guillain-Barre syndrome after myocardial infarction: a case report and literature review.

BACKGROUND: Guillain-Barre syndrome after myocardial infarction occurs infrequently, and its occurrence following percutaneous coronary intervention is extremely rare. Due to the high mortality rate of myocardial infarction and the disability of Guillain-Barre syndrome, early identification of Guillain-Barre syndrome after myocardial infarction and early intervention can decrease the mortality rate, lead to early recovery, and provide a better outcome. CASE PRESENTATION: Herein, we reported a rare case of Guillain-Barre syndrome after myocardial infarction treated with percutaneous coronary intervention. The patient was a 75-year-old woman from China who was admitted to hospital due to sudden loss of consciousness. Electrocardiography showed acute myocardial infarction in the right ventricle and inferior and posterior walls. The patient underwent emergency percutaneous intervention of the posterior collateral artery of the right coronary artery. Soon after, her condition worsened resulting in limb weakness and numbness. Unfortunately, she continued to develop respiratory failure, and treated with intravenous immunoglobulin and ventilator-assisted breathing. A physical examination showed hypotonia of all four limbs, complete quadriplegia, bulbar palsy, dysarthria, and tendon areflexia. Serum immunoglobulin (Ig) G anti-ganglioside antibody analysis was positive with anti-GT1a antibodies (+ +), anti-GM1 antibodies ( +), anti-GM2 antibodies ( +), and anti-GM4 antibodies ( +), and he was diagnosed with Guillain-Barre syndrome after myocardial infarction. She was discharged due to poor response to treatment. The patient died two days after being discharged. CONCLUSIONS: Myocardial infarction and/or percutaneous coronary intervention may activate immune-mediated response and cause severe complications. Clinician should be alert to Guillain-Barre syndrome after myocardial infarction and/or percutaneous coronary intervention.

Microbial gradual shifts during the process of species replacement in Taihang Mountain.

Introduction: Understanding microbial gradual shifts along species replacement can help elucidate the mechanisms driving secondary succession, and predict microbial responses to changing environments. However, how climate-induced species replacement alters microbial processes, and whether microbial shifts follow predictable assembly trajectories remain unclear. Methods: Using space-for-time substitution approach, we studied shifts in bacterial and fungal communities in the succession from Leptodermis oblonga to Vitex negundo var. heterophylla shrubland in Taihang Mountain. Results and Discussion: Species replacement, induced by climate related environmental change, significantly increased the above-ground biomass of shrublands, and TP and TK contents in topsoil. The succession from L. oblonga to V. negundo var. heterophylla communities resulted in the gradually replacement of cold-tolerant microbes with warm-affinity ones, and alterations of microbial communities involved in soil biogeochemical processes. Soil and plant variables, such as above-ground biomass, soil pH, total phosphorus, and total potassium, well explained the variations in microbial communities, indicating that the coordinated changes in plant communities and soil properties during secondary succession caused accompanied shifts in microbial diversity and composition.

Case report: Long-read sequencing identified a novel 14.9-kb deletion of the α-globin gene locus in a family with α-thalassemia in China.

Background: Thalassemia is a hereditary blood disease resulting from globin chain synthesis impairment because of α- and/or ß-globin gene variants. α-thalassemia is characterized by non-deletional and deletional variants in the HBA gene locus, of which rare deletional variants are difficult to detect by conventional polymerase chain reaction (PCR)-based methods. Case report: We report the case of a one-month-old boy, who and his mother had abnormal hematological parameters, while his father had normal hematology. Conventional PCR-reverse dot blot (RDB) was performed for all family members to analyze the 23 most common thalassemia variants in China, but did not identify any pathologic variants. Single-molecule real-time (SMRT) long-read sequencing (LRS) technology was then performed and identified an unreported 14.9-kb large deletion (hg38 chr16:168,803-183,737) of the α-globin gene locus, which disrupted both HBA1 and HBA2 genes in the proband and his mother. The exact breakpoints of the deletion were confirmed by gap-PCR and Sanger sequencing. Conclusion: We have detected a novel large deletion in α-globin gene locus in China, which not only enriches the variant spectrum of thalassemia, but also demonstrates the accuracy and efficiency of LRS in detecting rare and novel deletions.

PLGA Nanoparticles Containing VCAM-1 Inhibitor Succinobucol and Chemotherapeutic Doxorubicin as Therapy against Primary Tumors and Their Lung Metastases.

The treatment of malignant tumors is usually accompanied by poor prognosis due to metastasis of tumor cells. Hence, it is crucial to enhance anti-metastasis efficacy when anti-tumor treatments are conducted. It has been reported that the vascular cell adhesion molecule-1 (VCAM-1) is highly expressed on the surface of tumor cells and plays an essential role in the metastasis of tumor cells. Thus, reducing VCAM-1 expression offers hope for inhibiting the metastasis of tumor cells. Evidence has shown that succinobucol (Suc) can selectively and efficiently inhibit VCAM-1 expression. Inspired by these, we designed dual drug-loaded PLGA nanoparticles (Co-NPs) to co-deliver VCAM-1 inhibitor Suc and the chemotherapeutic doxorubicin (Dox) which could both effectively suppress primary melanoma and its lung metastases. Co-NPs were composed of PLGA encapsulated Suc and Dox as hydrophobic cores and DSPE-mPEG2000 as surface modification materials. With an appropriate particle size (122.4 nm) and a negatively charged surface (-6.77 mV) we could achieve prolonged blood circulation. The in vitro experiments showed that Co-NPs had potent cytotoxicity against B16F10 cells and could significantly inhibit VCAM-1 expression and migration of B16F10 cells. Additionally, the in vivo experiments showed that Co-NPs could efficiently suppress not only primary melanoma but also its lung metastases. In conclusion, PLGA nanoparticles containing VCAM-1 inhibitor Suc and chemotherapeutic Dox as therapy against primary tumors and their lung metastases provides a promising drug delivery strategy for the treatment of metastatic malignant tumors.

Mechanism of vascular endothelial cell-derived exosomes modified with vascular endothelial growth factor in steroid-induced femoral head necrosis.

Steroid-induced avascular necrosis of the femoral head (SANFH) is an intractable orthopedic disease. This study investigated the regulatory effect and molecular mechanism of vascular endothelial cell (VEC)-derived exosomes (Exos) modified with vascular endothelial growth factor (VEGF) in osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in SANFH. VECs were culturedin vitroand transfected with adenovirus Adv-VEGF plasmids. Exos were extracted and identified.In vitro/vivoSANFH models were established and treated with VEGF-modified VEC-Exos (VEGF-VEC-Exos). The internalization of Exos by BMSCs, proliferation and osteogenic and adipogenic differentiation of BMSCs were determined by the uptake test, cell counting kit-8 (CCK-8) assay, alizarin red staining, and oil red O staining. Meanwhile, the mRNA level of VEGF, the appearance of the femoral head, and histological analysis were assessed by reverse transcription quantitative polymerase chain reaction and hematoxylin-eosin staining. Moreover, the protein levels of VEGF, osteogenic markers, adipogenic markers, and mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinases (ERK) pathway-related indicators were examined by Western blotting, along with evaluation of the VEGF levels in femur tissues by immunohistochemistry. Glucocorticoid (GC) induced adipogenic differentiation of BMSCs and inhibited osteogenic differentiation. VEGF-VEC-Exos accelerated the osteogenic differentiation of GC-induced BMSCs and inhibited adipogenic differentiation. VEGF-VEC-Exos activated the MAPK/ERK pathway in GC-induced BMSCs. VEGF-VEC-Exos promoted osteoblast differentiation and suppressed adipogenic differentiation of BMSCs by activating the MAPK/ERK pathway. VEGF-VEC-Exos accelerated bone formation and restrained adipogenesis in SANFH rats. VEGF-VEC-Exos carried VEGF into BMSCs and motivated the MAPK/ERK pathway, thereby promoting osteoblast differentiation of BMSCs in SANFH, inhibiting adipogenic differentiation, and alleviating SANFH.

Recent Advances of Circular RNAs as Biomarkers for Osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumor in young adult, which is prone to early metastasis and poor prognosis. The current treatment methods need to be improved. Circular RNA is a covalently blocked circular, non-coding RNA that plays an essential role in the occurrence, development, clinical diagnosis, and treatment of various diseases. Recently, an increasing number of circRNAs have been identified in osteosarcoma. Understanding its role in osteosarcoma is conducive to the early detection, diagnosis, and treatment of osteosarcoma. In this paper, we reviewed the mechanism of action of circular RNA in the occurrence and development of osteosarcoma and its clinical application in recent years.

Long-term Incidence Rates of Esophageal Squamous Cell Carcinoma in Chinese Patients With Low-grade Intraepithelial Neoplasia and Association of Surveillance Endoscopy With Incidence.

Importance: Surveillance endoscopy is recommended for patients with low-grade intraepithelial neoplasia (LGIN); high-quality evidence about the use of surveillance endoscopy and esophageal squamous cell carcinoma (ESCC) incidence in patients with LGIN is important but limited. Objective: To estimate long-term ESCC incidence rates in patients with LGIN and the association between surveillance endoscopy and ESCC incidence. Design, Setting, and Participants: This community-based, multicenter, prospective cohort study in 9 regions in rural China included patients with LGIN diagnosed by endoscopic screening between July 1, 2007, and December 31, 2016; all participants were followed up until December 31, 2021. Main Outcomes and Measures: The primary outcome was ESCC incidence. The ESCC standardized incidence ratio (SIR) was estimated using sex- and age-specific incidence in the general population of rural China in 2010 and hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards models. Results: A total of 3258 patients with LGIN were included; 1772 (54.39%) were men, with a mean (SD) age of 58.21 (6.97) years. Among them, 1378 patients (42.30%) underwent at least 1 surveillance endoscopy (surveillance group) and 1880 (57.70%) did not undergo any surveillance endoscopy (nonsurveillance group). During the follow-up period (median, 7.96 years; IQR, 6.08-10.54 years), 170 ESCC cases were diagnosed, with a cumulative incidence of 6.28 per 1000 person-years. A higher incidence of ESCC (incidence rate, 7.07 per 1000 person-years) was observed in the nonsurveillance group than in the surveillance group (incidence rate, 5.14 per 1000 person-years). Patients with LGIN in the surveillance group had a lower SIR (SIR, 4.07; 95% CI, 1.13-10.34) than those in the nonsurveillance group (SIR, 5.65; 95% CI, 2.00-12.58); however, patients with LGIN in both groups had a higher risk of ESCC than the general population. Patients in the surveillance group had a 31% decreased risk of ESCC incidence (HR, 0.69; 95% CI, 0.50-0.95) compared with those in the nonsurveillance group, after adjusting for baseline risk factors. Conclusions and Relevance: In this prospective cohort study, patients with LGIN had a higher risk of developing ESCC than the general population, and endoscopic surveillance was associated with a decrease in ESCC incidence in these patients.

Colorectal cancer burden, trends and risk factors in China: A review and comparison with the United States.

Objective: China and the United States (the U.S.) have the heaviest colorectal cancer (CRC) burden with considerable variations in temporal trends. This study aims to analyze the temporal patterns of CRC burden and its risk factors in China and the U.S. across the past three decades. Methods: Data were extracted from the Global Burden of Disease (GBD) Study in 2019, including cases, deaths, disability-adjusted life-years (DALYs), age-standardized rate (ASR), and summary exposure value (SEV) of CRC in China and the U.S. between 1990 and 2019. Annual average percentage changes (AAPCs) of CRC burden were calculated using the Joinpoint regression model. The mortality in CRC attributable to potential risk factors was characterized by countries, gender, and age groups. Results: In 2019, there were 607,900 and 227,241 CRC cases, and 261,777 and 84,026 CRC deaths in China and the U.S., respectively. The age-standardized incidence rate (ASIR) was 30.55 per 100,000 in China and 41.86 per 100,000 in the U.S., and the age-standardized mortality rate (ASMR) was 13.86 per 100,000 in China and 14.77 per 100,000 in the U.S. CRC incidence, mortality, and DALY rate in the U.S. showed downward trends in the past three decades (AAPC=-0.47, -1.06, and -0.88, respectively), while upward trends were observed in China (AAPC=3.11, 1.05, and 0.91, respectively). Among the cause of CRC, the leading risk factor contributing to CRC death was low milk in China and smoking in the U.S., respectively. Conclusions: From 1990 to 2019, the burden of CRC in China increased dramatically, particularly for males and middle-aged and elderly people. The management of the major risk factors associated with the high burden of CRC should be enhanced.

Exosomal RNF157 mRNA from prostate cancer cells contributes to M2 macrophage polarization through destabilizing HDAC1.

Background: Exosomes have been identified to mediate the transmission of RNAs among different cells in tumor microenvironment, thus affecting the progression of different diseases. However, exosomal messenger RNAs (mRNAs) have been rarely explored. RNF157 mRNA has been found to be up-regulated in PCa patients' exosomes, but the role of exosomal RNF157 mRNA in PCa development remains unclear. Methods: Online databases were utilized for predicting gene expression and binding correlation between different factors. RT-qPCR and western blot assays were respectively done to analyze RNA and protein expressions. Flow cytometry analysis was implemented to analyze M2 polarization. Results: RNF157 expression was high in PCa tissues and cells. M2 polarization of macrophages was enhanced after co-culture with PCa cells or with exosomes released by PCa cells. Upon RNF157 knockdown in PCa cells, the extracted exosomes could not lead to the facilitated M2 polarization. Mechanistically, RNF157 could bind to HDAC1 and contribute to HDAC1 ubiquitination, which led to HDAC1 degradation and resulting in promoting M2 polarization of macrophages. Animal experiments validated that exosomal RNF157 accelerated PCa tumor growth through facilitating macrophage M2 polarization. Conclusion: Exosome-mediated RNF157 mRNA from PCa cells results in M2 macrophage polarization via destabilizing HDAC1, consequently promoting PCa tumor progression.

Cognition-enhancing effect of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in the 5 × FAD transgenic mouse model of Alzheimer's pathology.

BACKGROUND: Intracerebral translocator protein 18 kDa (TSPO) mediates the transport of cholesterol from cytoplasm to mitochondria and activation of microglia. The change of TSPO and the dysfunction of microglia are closely related to the pathogenesis of Alzheimer's disease (AD). AIMS: This study aimed to investigate the effects of microglial TSPO and its selective ligand YL-IPA08 on the cognitive function of transgenic mice in 5 × familial Alzheimer's disease (FAD) mouse model of AD. METHODS: The TSPO knockout 5 × FAD transgenic mice were bred, and tested by Morris water maze. The effects of YL-IPA08 on cognitive abilities and expression of Aß in 5 × FAD mice were also explored into. RESULTS: The latency of escape by TSPO knockout 5 × FAD mice was significantly prolonged compared with the 5 × FAD group, indicating that the cognitive impairment of mice aggravated. With the attenuated phagocytic ability of microglia, the deposition of Aß in prefrontal cortex of TSPO knockout 5 × FAD mice increased, and the expression of proinflammatory factors (IL-1ß, TNF-α, IL-6) were upregulated. In addition, YL-IPA08 significantly reduced the latency of escape by 5 × FAD mice, increased the number of times of crossing over the platform by mice, and inhibited the deposition of Aß in the prefrontal cortex of 5 × FAD mice without affecting the cleavage of APP. CONCLUSION: Our findings suggested that TSPO knockout in 5 × FAD mice inhibited microglial phagocytosis, promoted Aß deposition and neuroinflammation, and aggravated cognitive dysfunction in AD mice. YL-IPA08 had a significant cognition-enhancing effect in 5 × FAD transgenic mice, which might provide a new basis for potential drug candidates in AD treatment.

The Effect of Intraoperative Fentanyl Consumption on Prognosis of Colorectal Liver Metastasis treated by Simultaneous Resection: A Propensity Score Matching Analysis.

Background: No previous studies have reported the effect of intraoperative opioid consumption in colorectal liver metastasis (CRLM). Methods: Medical records of patients who received simultaneous resection of CRLM were retrospectively reviewed. Patients with epidural anesthesia, intraoperative morphine, or intraoperative oxycodone were excluded. Patients were separated into high- and low-dose groups by median intraoperative equianalgesic fentanyl dose. Short-term outcomes, progression-free surcical (PFS) and overall survival (OS) were compared between groups before and after 1:1 propensity score matching (PSM). Univariable and multivariable Cox regression analysis were performed to identify independent predictors of survival. Results: The final study population included 343 patients. Patients were separated into the low dose group (n=172) and the high dose group (n=171) by median intraoperative equianalgesic fentanyl dose (8.33 µg/kg). After PSM, 55 patients in the low dose group were matched to 55 patients in the high dose group and the baseline characteristics of the two groups were balanced. The two groups had no statistically significance difference in severity and categories of postoperative complications before and after PSM. Before PSM, the two groups had similar PFS (median 10.2 vs. 12.4 months, P=0.54) and OS (median 59.0 vs. 58.3 months, P=0.76). Univariate and multivariate Cox regression analyses revealed no statistically significant association between intraoperative equianalgesic fentanyl and PFS (multivariate HR=0.852, 95% CI 0.655-1.11, P=0.235) and OS (multivariate HR=1, 95% CI 0.68-1.49, P = 0.981). After PSM, the two groups also had similar PFS (median 9.2 vs. 10.7 months, P=0.98) and OS (median 51.0 vs. 46.0 months, P=0.39). Univariate and multivariate Cox regression analyses revealed no statistically significant association between intraoperative equianalgesic fentanyl and PFS (multivariate HR=1.05, 95% CI 0.632-1.73, P=0.861) and OS (multivariate HR=1.74, 95% CI 0.892-3.38, P = 0.105). Conclusion: Intraoperative opioids consumption was not correlated with outcomes of CRLM patients treated with simultaneous resection.