SIRPG expression positively associates with an inflamed tumor microenvironment and response to PD-1 blockade.

BACKGROUND: This study aimed to investigate the relationship between signal regulatory protein gamma (SIRPG) and tumor immune microenvironment phenotypes or T cell mediated-adaptive antitumor immunity, and its predictive value for response to PD-1 blockade in cancers. METHODS: Pan-cancer analysis of SIRPG expression and immune deconvolution was performed using transcriptomic data across 33 tumor types. Transcriptomic and clinical data from 157 patients with non-small-cell lung cancer (NSCLC) and melanoma received PD-1 blockade were analyzed. Expression characteristics of SIRPG were investigated using single-cell RNA sequencing (scRNA-seq) data of 103,599 cells. The effect of SIRPG expression was evaluated via SIRPG knockdown or overexpression in Jurkat T cells. RESULTS: The results showed that most cancers with high SIRPG expression had significantly higher abundance of T cells, B cells, NK cells, M1 macrophages and cytotoxic lymphocytes and increased expression level of immunomodulatory factors regulating immune cell recruitment, antigen presentation, T cell activation and cytotoxicity, but markedly lower abundance of neutrophils, M2 macrophages, and myeloid-derived suppressor cells. High SIRPG expression was associated with favorable response to PD-1 blockade in both NSCLC and melanoma. scRNA-seq data suggested SIRPG was mainly expressed in CD8+ exhausted T and CD4+ regulatory T cells, and positively associated with immune checkpoint expression including PDCD1 and CTLA4. In vitro test showed SIRPG expression in T cells could facilitate expression of PDCD1 and CTLA4. CONCLUSION: High SIRPG expression is associated with an inflamed immune phenotype in cancers and favorable response to PD-1 blockade, suggesting it would be a promising predictive biomarker for PD-1 blockade and novel immunotherapeutic target.

Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer.

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

Salvia miltiorrhiza Bge. processed with porcine cardiac blood inhibited GLRX5-mediated ferroptosis alleviating cerebral ischemia-reperfusion injury.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) is a destructive adverse reaction of ischemic stroke, leading to high disability and mortality rates. Salvia miltiorrhiza Bge. (Danshen, DS) processed with porcine cardiac blood (PCB-DS), a characteristic processed product, has promising anti-ischemic effects. However, the underlying mechanism of PCB-DS against CIRI remains unclear. PURPOSE: Ferroptosis is demonstrated to be involved in CIRI. The aim of this study was to explore the molecular mechanism underlying PCB-DS inhibited GLRX5-mediated ferroptosis alleviating CIRI, which was different from DS. METHODS: Quality evaluation of PCB-DS and DS was conducted by UPLC. Pharmacological activities of PCB-DS and DS against CIRI were compared using neurobehavioral scores, infarct volume, proinflammatory factors, and pathological examinations. Proteomics was employed to explore the potential specific mechanism of PCB-DS against CIRI, which was different from DS. Based on the differential protein GLRX5, ferroptosis-related iron, GSH, MDA, SOD, ROS, liperfluo, and mitochondrial morphology were analyzed. Then, the proteins of GLRX5-mediated iron-starvation response and SLC7A11/GPX4 were analyzed. Finally, OGD/R-induced SH-SY5Y cells upon GLRX5 silencing were constructed to demonstrate that PCB-DS improved CIRI by GLRX5-mediated ferroptosis. RESULTS: PCB-DS better alleviated CIRI through decreasing neurological score, reducing the infarct volume, and suppressing the release of inflammatory cytokines than DS. Proteomics suggested that PCB-DS may ameliorate CIRI by inhibiting GLRX5-mediated ferroptosis, which was different from DS. PCB-DS reversed the abnormal mitochondrial morphology, iron, GSH, MDA, SOD, ROS, and liperfluo to inhibit ferroptosis in vitro and in vivo. PCB-DS directly activated GLRX5 suppressing the iron-starvation response and downregulated the SLC7A11/GPX4 signaling pathway to inhibit ferroptosis. Finally, silencing GLRX5 activated the iron-starvation response in SH-SY5Y cells and PCB-DS unimproved OGD/R injury upon GLRX5 silencing. CONCLUSION: Different from DS, PCB-DS suppressed ferroptosis to alleviate CIRI through inhibiting GLRX5-mediated iron-starvation response. These findings give a comprehensive understanding of the molecular mechanism underlying the effect of PCB-DS against CIRI and provide evidence to assess the product in clinical studies.

Efficacy and safety of local ablative therapy for patients with NSCLC and coexisting interstitial lung disease.

BACKGROUND: The effective therapeutic approach is still an unmet need for patients diagnosed with both lung cancer and interstitial lung disease (ILD). This is primarily due to the possible risk of ILD exacerbation caused by surgery or radiotherapy. The current study aimed to investigate the efficacy and safety of local ablative therapy (LAT) for this specific population. METHODS: Consecutive patients with non-small cell lung cancer (NSCLC) and ILD who received LAT between January 2018 and August 2022 were enrolled, and propensity score matching (PSM) was utilized to match the non-ILD group. The primary endpoint was recurrence-free survival (RFS), and secondary endpoints included overall survival (OS), adverse events (AEs) and hospital length of stay (HLOS). RESULTS: The PSM algorithm yielded matched pairs in the ILD group (n = 25) and non-ILD group (n = 72) at a ratio of 1:3. There were no statistically significant differences in RFS (median 16.4 vs. 18 months; HR = 1.452, p = 0.259) and OS (median: not reached vs. 47.9 months; HR = 1.096, p = 0.884) between the two groups. Meanwhile, no acute exacerbation of ILD was observed in the ILD group. However, the incidence of pneumothorax, especially pneumothorax requiring chest tube drainage, was significantly higher (36.0% vs. 11.2%, p = 0.005) among patients with NSCLC and co-existing ILD, which resulted in longer HLOS (p = 0.045). CONCLUSION: Although ILD was associated with a higher incidence of pneumothorax, the efficacy of LAT for NSCLC patients with ILD was comparable to those without ILD, suggesting that LAT might be a reliable and effective treatment option for this population, particularly in the early stage.

Study on network pharmacology of Ginkgo biloba extract against ischaemic stroke mechanism and establishment of UPLC-MS/MS methods for simultaneous determination of 19 main active components.

INTRODUCTION: Ginkgo biloba extract (GBE) is an effective substance from traditional Chinese medicine (TCM) G. biloba for treating ischaemic stroke (IS). However, its active ingredients and mechanism of action remain unclear. OBJECTIVES: This study aimed to reveal the potential active component group and possible anti-IS mechanism of GBE. MATERIALS AND METHODS: The network pharmacology method was used to reveal the possible anti-IS mechanism of these active ingredients in GBE. An ultra-high-performance liquid chromatography triple quadrupole electrospray tandem mass spectrometry (UPLC-MS/MS) method was established for the simultaneous detection of the active ingredients of GBE. RESULTS: The active components of GBE anti-IS were screened by literature integration. Network pharmacology results showed that the anti-IS effect of GBE is achieved through key active components such as protocatechuic acid, bilobalide, ginkgolide A, and so on. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the possible anti-IS mechanism of GBE is regulating the PI3K-Akt signalling pathway and other signal pathways closely related to inflammatory response and apoptosis regulation combined with AKT1, MAPK, TNF, ALB, CASP3, and other protein targets. Nineteen main constituents in seven batches of GBE were successfully analysed using the established UPLC-MS/MS method, and the results showed that the content of protocatechuic acid, gallic acid, ginkgolide A, and so forth was relatively high, which was consistent with network pharmacology results, indicating that these ingredients may be the key active anti-IS ingredients of GBE. CONCLUSION: This study revealed the key active components and the anti-IS mechanism of GBE. It also provided a simple and sensitive method for the quality control of related preparations.

Early prognostication of critical patients with spinal cord injury: A machine learning study with 1485 cases.

STUDY DESIGN: A retrospective case-series. OBJECTIVE: The study aims to use machine-learning (ML) to predict the discharge destination of spinal cord injury (SCI) patients in the intensive care unit (ICU). SUMMARY OF BACKGROUND DATA: Prognostication following SCI is vital, especially for critical patients who need intensive care. METHODS: Clinical data of patients diagnosed with SCI were extracted from a publicly available ICU database. The firstly recorded data of the included patients were used to develop a total of 98 ML classifiers, seeking to predict discharge destination (e.g. death, further medical care, home). The micro-average area under the curve (AUC) was the main indicator to assess discrimination. The best average-AUC classifier and the best death-sensitivity classifier were integrated into an ensemble classifier. The discrimination of the ensemble classifier was compared with top death-sensitivity classifiers and top average-AUC classifiers. Additionally, prediction consistency and clinical utility were also assessed. RESULTS: A total of 1485 SCI patients were included. The ensemble classifier had a micro-average AUC of 0.851, which was only slightly inferior to the best average-AUC classifier (P=0.10) The best average-AUC classifier death sensitivity was much lower than that of the ensemble classifier. The ensemble classifier had a death sensitivity of 0.452, which was inferior to top 8 death-sensitivity classifiers, whose micro-average AUC were inferior to the ensemble classifier (P<0.05). Additionally, the ensemble classifier demonstrated a comparable Brier score and superior Net benefit in the decision curve analysis, when compared to the performance of the origin classifiers. CONCLUSIONS: The ensemble classifier shows an overall superior performance in predicting discharge destination considering discrimination ability, prediction consistency and clinical utility. This classifier system may aid in the clinical management of critical SCI patients in the early phase following injury. LEVEL OF EVIDENCE: 3.

Parathyroid preservation in total endoscopic thyroid surgeries via the mammary areolas approach: Real-world data from a single center.

BACKGROUND: Preserving parathyroid glands in situ is crucial to avoid surgical hypoparathyroidism, but it is also one of the greatest challenges during thyroid surgery. Magnified endoscopic imaging has been proposed as a way to improve parathyroid preservation. METHODS: 2,603 consecutive patients who underwent thyroid surgery at the First People's Hospital of Zunyi from January 2018 to July 2022 were screened. 1,355 patients were eligible, including 965 endoscopic and 390 open cases. Parathyroid hormone (PTH) loss levels and severe parathyroid injury rates were compared between endoscopic and open cases. Meanwhile, factors that contribute to parathyroid injuries were assessed, including surgical extent, tumor size, carbon nanoparticle guidance, and surgical proficiency. RESULTS: PTH loss levels were similar between endoscopic and open cases (P = 0.440). The incidence of severe parathyroid injuries was also comparable (7.8% for endoscopic vs. 6.9% for open, P = 0.592). The endoscopic group had higher rates of autologous parathyroid transplantation (39.5% vs. 24.4%, P = 0.000), while accidental parathyroidectomy rates were similar (11.4% vs. 10.8%, P = 0.739). Among patients who received the same extent of thyroid surgeries, no significant difference was found in PTH loss levels and severe parathyroid injury rates, except for a higher risk of severe parathyroid injuries in endoscopic bilateral thyroidectomy (18.52% vs. 11.52%, P = 0.033). CONCLUSIONS: Despite the magnified endoscopic imaging facilitating the identification of parathyroid tissues, endoscopic approaches are not superior to open ones for the in-situ preservation of parathyroid glands. For a bilateral thyroidectomy, open approaches are safer for parathyroid preservation.

Association of PD-L1 expression with efficacy of alectinib in advanced NSCLC patients with ALK fusion.

BACKGROUND: Programmed cell death-ligand 1 (PD-L1) expression was found to be a biomarker of inferior efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutated non-small cell lung cancer (NSCLC). However, whether PD-L1 expression could also serve as a similar biomarker in anaplastic lymphoma kinase (ALK)-positive patients, especially for those treated with front-line alectinib, remains unclear. The aim of the study is to investigate the association of PD-L1 expression and efficacy of alectinib in this setting. METHODS: From January 2018 to March 2020, 225 patients with ALK-rearranged lung cancer were consecutively collected at Shanghai Pulmonary Hospital, Tongji University. Baseline PD-L1 expression was detected using immunohistochemistry (IHC) in 56 patients of advanced ALK-rearranged lung cancer who received front-line alectinib. RESULTS: Among the 56 eligible patients, 30 (53.6%) were PD-L1 expression negative, 19 (33.9%) patients had TPS 1%-49% and 7 (12.5%) had TPS ≥ 50%.We found no statistically significant associations between PD-L1 positivity and objective response rate (ORR, 90.0% vs. 80.8%, p = 0.274) or progression-free survival (PFS, not reached vs. not reached, HR: 0.98, 95 %CI: 0.37-2.61, p = 0.97) in patients treated with alectinib. Meanwhile, patients with PD-L1 high expression (TPS ≥ 50%) had a trend of longer PFS (not reached vs. not reached, p = 0.61). CONCLUSIONS: PD-L1 expression might not serve as a predict biomarker for the efficacy of front-line alectinib in ALK-positive NSCLC patients.

Ribavirin extends the lifespan of Caenorhabditis elegans through AMPK-TOR Signaling.

Aging is a process accompanied by widespread degenerative changes which are a major cause of human disease and disability. One goal of aging research is to develop interventions or drugs that can extend organism lifespan and treat age-related diseases. Here, we report the identification of a broad spectrum anti-viral agent, ribavirin, as a potential pharmacological aging intervention. Ribavirin extended the lifespan and healthspan of Caenorhabditis elegans by inhibiting Target of Rapamycin (TOR) signaling and activating AMP-activated protein kinase (AMPK). Moreover, our data indicate that ribavirin activated AMPK by reducing the levels of adenosine triphosphate (ATP) and lysosomal v-ATPase-Ragulator-AXIN Complex. Thus, our studies successfully identify ribavirin as a potential anti-aging drug, and indicate that its anti-aging effect is mediated via AMPK-TOR signaling.

Predicting the immune landscape of invasive breast carcinoma based on the novel signature of immune-related lncRNA.

BACKGROUND: The composition of the population of immune-related long non-coding ribonucleic acid (irlncRNA) generates a signature, irrespective of expression level, with potential value in predicting the survival status of patients with invasive breast carcinoma. METHODS: The current study uses univariate analysis to identify differentially expressed irlncRNA (DEirlncRNA) pairs from RNA-Seq data from The Cancer Genome Atlas (TCGA). 36 pairs of DEirlncRNA pairs were identified. Using various algorithms to construct a model, we have compared the area under the curve and calculated the 5-year curve of Akaike information criterion (AIC) values, which allows determination of the threshold indicating the maximum value for differentiation. Through cut-off point to establish the optimal model for distinguishing high-risk or low-risk groups among breast cancer patients. We assigned individual patients with invasive breast cancer to either high risk or low risk groups depending on the cut-off point, re-evaluated the tumor immune cell infiltration, the effectiveness of chemotherapy, immunosuppressive biomarkers, and immunotherapy. RESULTS: After re-assessing patients according to the threshold, we demonstrated an effective means of distinguish the severity of the disease, and identified patients with different clinicopathological characteristics, specific tumor immune infiltration states, high sensitivity to chemotherapy,wellpredicted response to immunotherapy and thus a more favorable survival outcome. CONCLUSIONS: The current study presents novel findings regarding the use of irlncRNA without the need to predict precise expression levels in the prognosis of breast cancer patients and to indicate their suitability for anti-tumor immunotherapy.

[Ultrasound-guided local injection of dexamethasone and lidocaine into subcapsule for subacute thyroiditis].

Objective:To compare the efficacy and safety of ultrasound-guided local injection of the mixture of dexamethasone（DEX） with lidocaine and oral prednisolone（PSL） in treating patients with subacute thyroiditis. Methods:Ninety-three patients with subacute thyroiditis were divided into group A（n=48） and Group B（n=45）. Group A was treated with ultrasound-guided subcapsular injection in thyroid lesion area, while group B was treated with oral medication. The pain relief time, the duration of treatment, thyroid function recovery, recurrence rate, concurrent hypothyroidism, and drug side effects were compared between the two groups. Results:After 6 months of follow-up, the pain relief time, the duration of treatment and thyroid function recovery in group A were significantly shorter than those in group B （P<0.05）, but not the recurrence rate and hypothyroidism（P>0.05）. Conclusion:Compared with oral PSL treatment, ultrasound-guided local injection of DEX and lidocaine mixture can quickly relieve pain, shorter the duration of treatment and lower adverse reactions.

Multiomics analysis reveals CT83 is the most specific gene for triple negative breast cancer and its hypomethylation is oncogenic in breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer (BrC) subtype lacking effective therapeutic targets currently. The development of multi-omics databases facilities the identification of core genes for TNBC. Using TCGA-BRCA and METABRIC datasets, we identified CT83 as the most TNBC-specific gene. By further integrating FUSCC-TNBC, CCLE, TCGA pan-cancer, Expression Atlas, and Human Protein Atlas datasets, we found CT83 is frequently activated in TNBC and many other cancers, while it is always silenced in non-TNBC, 120 types of normal non-testis tissues, and 18 types of blood cells. Notably, according to the TCGA-BRCA methylation data, hypomethylation on chromosome X 116,463,019 to 116,463,039 is significantly correlated with the abnormal activation of CT83 in BrC. Using Kaplan-Meier Plotter, we demonstrated that activated CT83 is significantly associated with unfavorably overall survival in BrC and worse outcomes in some other cancers. Furthermore, GSEA suggested that the abnormal activation of CT83 in BrC is probably oncogenic by triggering the activation of cell cycle signaling. Meanwhile, we also noticed copy number variations and mutations of CT83 are quite rare in any cancer type, and its role in immune infiltration is not significant. In summary, we highlighted the significance of CT83 for TNBC and presented a comprehensive bioinformatics strategy for single-gene analysis in cancer.

Comparing quality of life between patients undergoing trans-areola endoscopic thyroid surgery and trans-oral endoscopic thyroid surgery.

BACKGROUND: Compared with conventional open surgery, endoscopic thyroidectomy via the oral vestibular approach (ETVOA) and endoscopic thyroidectomy via the areola approach (ETAA) avoided scarring of the skin, which may help patients achieve a better quality of life (QOL). However, the benefit of the QOL from this technique has not been adequately investigated, therefore this study compared the QOL outcomes between ETVOA and ETAA. METHODS: 131 patients were enrolled in this study. ETAA surgery and ETVOA surgery were performed in 74 patients and 57 patients, respectively. These patients were followed up at 2 weeks, 4 weeks, and 8 weeks, and their QOL was evaluated using a thyroid surgery-specific questionnaire and a short-form health survey (SF-36). RESULTS: There were no differences in clinical characteristics such as gender, age, body mass index (BMI), and tumor size between the two groups. The volume of intraoperative blood loss, cost of hospitalization, and complications between the two procedures showed no differences. Compared with ETAA, ETVOA has a longer operation time, no drainage, and shorter hospital stay. In the QOL questionnaire, several parameters in ETVOA were better. The satisfaction scores of patients undergoing ETVOA were higher. In addition, the cosmetic satisfaction in patients who received ETOVA was significantly better than that of patients who underwent ETAA. The degree of neck movement disorder in patients with ETVOA was milder. Patients who received ETVOA had higher score on the SF-36. CONCLUSIONS: The trans-oral endoscopic approach can acquire better cosmetic results and achieved high-level QOL.

Endoscopic Thyroidectomy With Level Vb Dissection Via a Chest-breast Approach: Technical Updates for Selective Lateral Neck Dissection.

OBJECTIVE: To determine the feasibility of endoscopic thyroidectomy with level Vb dissection using a chest-breast approach. METHODS: Lateral neck level Vb dissection by endoscopic surgery using a chest-breast approach was performed as an update to the previously reported endoscopic selective lateral neck dissection. The demographic data, surgical outcomes, and adverse events were analyzed. RESULTS: A total of 12 cases were performed successfully, and no patient was converted to the open procedure. The sex ratio was 16/2 (female/male). The average age and primary lesion diameter were 36.3±5.8 years old, and 1.97±0.58 cm, respectively. The average total and lateral lymph nodes dissection time of duration was 154.6±17.0 and 276.3±19.2 minutes, respectively. The lymph node ratio (mean number of metastasis/total number of dissected nodes) at levels II, III+IV, VI, and Vb were 1.6±1.4/6.8±2.0, 5.8±2.4/14.4±3.6, 3.2±1.1/6.5±1.9, and 0.8±0.9/5.8±1.6, respectively. One of 12 patients had lymphatic leakage and 2 of 12 patients had transient hypocalcemia. There was no incidence of uncontrolled bleeding, mental nerve injury, permanent hypoparathyroidism, permanent recurrent laryngeal nerve injury, skin bruise on neck, infection, asphyxia/dyspnea, large blood vessel injury or other complications like tracheal injury, esophageal injury, etc., nor was there any death or recurrence in either of the 2 groups during a short follow-up period. CONCLUSIONS: It is feasible to perform endoscopic thyroidectomy with level Vb dissection using a chest-breast approach. Such strategy represents another option for selective papillary thyroid carcinoma patients with levels II, III, IV, and Vb lymph node metastasis.

Potential toxicity of nanopolystyrene on lifespan and aging process of nematode Caenorhabditis elegans.

In the environment, nanoplastic particles, such as nanopolystyrene, potentially cause toxicity on organisms at various aspects. We here employed endpoints of lifespan and aging-related phenotypes to further investigate the possible long-term effects of nanopolystyrene (100 nm) in Caenorhabditis elegans. After exposure from L1-larvae to adult day-3, nanopolystyrene at high concentrations (100 and 1000 µg/L) reduced the lifespan. Although nanopolystyrene (1 or 10 µg/L) did not affect the lifespan, nanopolystyrene (1 or 10 µg/L) could induce the more severe intestinal reactive oxygen species (ROS) production and decrease in locomotion behavior during the aging process compared with control. Moreover, nanopolystyrene exposure could cause the severe decrease in expressions of some immune response genes, hsp-6 gene, and genes encoding manganese-superoxide dismutases (Mn-SODs) during aging process, suggesting the severe suppression in innate immune response, inhibition in antioxidation defense system, and suppression in mitochondrial unfolded protein response (mt UPR) by nanopolystyrene. Our results highlight the potential of long-term nanopolystyrene exposure in reducing longevity and in affecting health state during the aging process in environmental organisms.

Nanopolystyrene-induced microRNAs response in Caenorhabditis elegans after long-term and lose-dose exposure.

microRNAs (miRNAs) usually act post-transcriptionally to suppress the expression of many targeted genes. However, the response of miRNAs to nanoplastics is still unclear. We here employed Caenorhabditis elegans to investigate the response of miRNAs to 100 nm nanopolystyrene at a predicted environmental concentration (1 µg/L). After exposure from L1-larvae to adult day-3, we found that 7 miRNAs (4 down-regulated (mir-39, mir-76, mir-794, and mir-1830) and 3 up-regulated (mir-35, mir-38, and mir-354)) were dysregulated by nanopolystyrene. Expressions of these 7 miRNAs were dose-dependent in nematodes exposed to 1-100 µg/L nanopolystyrene. Among these 7 miRNAs, we found that only mir-35, mir-38, mir-76, mir-354, and mir-794 were involved in the regulation of response to nanopolystyrene based on phenotypic analysis of both transgenic strains and mutant nematodes. Overexpression of mir-35, mir-38, or mir-354 induced a resistance to nanopolystyrene toxicity, and overexpression of mir-76 or mir-794 induced a susceptibility to nanopolystyrene toxicity, which suggested that these 5 miRNAs mediated a protective response to nanopolystyrene. Gene ontology and KEGG analysis further implied that mir-35, mir-38, mir-76, mir-354, and mir-794 were associated with various biological processes and signaling pathways. Our results suggest the crucial role of a certain number of miRNAs in response to nanopolystyrene after long-term and low-dose exposure in organisms.

LncRNA HIF1A-AS1 contributes to ventricular remodeling after myocardial ischemia/reperfusion injury by adsorption of microRNA-204 to regulating SOCS2 expression.

Objectives: Long non-coding RNAs (lncRNAs) serve pivotal roles in heart disease, while the role of lncRNA hypoxia-inducible factor 1α-antisense RNA 1 (HIF1A-AS1) is rarely mentioned. Therefore, the objective of this study was to investigate the mechanism of lncRNA HIF1A-AS1 regulating suppressor of cytokine signaling 2 (SOCS2) expression by adsorption of microRNA-204 (miR-204) on ventricular remodeling after myocardial ischemia-reperfusion (I/R) injury in mice. Methods: The mouse model of I/R was established by left coronary artery occlusion. The expression of HIF1A-AS1, miR-204 and SOCS2 was determined. The mice were injected with HIF1A-AS1-siRNA, miR-204 mimics or their controls to investigate their effects on cardiac function and ventricular remodeling of mice after I/R injury. The binding relationship between HIF1A-AS1 and miR-204 as well as between miR-204 and SOCS2 were verified. Results: HIF1A-AS1 and SOCS2 were upregulated and miR-204 was downregulated in myocardial tissues in mice after I/R injury. LVEDD, LVEDS, LVEDP, LVMI and RVMI expression reduced while LVEF, LVFS, +dp/dt max and - dp/dt max increased through knockdown HIF1A-AS1 and upregulated miR-204. The expression of BNP, cTnI, LDH, CK, TNF-α, IL-1ß, IL-6 and ß-MHC reduced, and the expression of α-MHC increased when HIF1A-AS1 was poorly expressed and miR-204 was highly expressed. Silencing HIF1A-AS1 and upregulating miR-204 inhibited apoptosis of cells. LncRNA HIF1A-AS1 could act as ceRNA to adsorb miR-204 to suppress miR-204 expression and elevate SOCS2 expression. Conclusion: Our study provides evidence that downregulation of HIF1A-AS1 and upregulation of miR-204 could alleviate ventricular remodeling and improve cardiac function in mice after myocardial I/R injury via regulating SOCS2.

Two-way crosstalk between BER and c-NHEJ repair pathway is mediated by Pol-ß and Ku70.

Multiple DNA repair pathways may be involved in the removal of the same DNA lesion caused by endogenous or exogenous agents. Although distinct DNA repair machinery fulfill overlapping roles in the repair of DNA lesions, the mechanisms coordinating different pathways have not been investigated in detail. Here, we show that Ku70, a core protein of nonhomologous end-joining (NHEJ) repair pathway, can directly interact with DNA polymerase-ß (Pol-ß), a central player in the DNA base excision repair (BER), and this physical complex not only promotes the polymerase activity of Pol-ß and BER efficiency but also enhances the classic NHEJ repair. Moreover, we find that DNA damages caused by methyl methanesulfonate (MMS) or etoposide promote the formation of Ku70-Pol-ß complexes at the repair foci. Furthermore, suppression of endogenous Ku70 expression by small interfering RNA reduces BER efficiency and leads to higher sensitivity to MMS and accumulation of the DNA strand breaks. Similarly, Pol-ß knockdown impairs total-NHEJ capacity but only has a slight influence on alternative NHEJ. These results suggest that Pol-ß and Ku70 coordinate 2-way crosstalk between the BER and NHEJ pathways.-Xia, W., Ci, S., Li, M., Wang, M., Dianov, G. L., Ma, Z., Li, L., Hua, K., Alagamuthu, K. K., Qing, L., Luo, L., Edick, A. M., Liu, L., Hu, Z., He, L., Pan, F., Guo, Z. Two-way crosstalk between BER and c-NHEJ repair pathway is mediated by Pol-ß and Ku70.