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Abstract Background High expression of ubiquitin ligase MDM2 is a primary cause of p53 inactivation in many tumors, making it a promising therapeutic target. However, MDM2 inhibitors have failed in clinical trials due to p53-induced feedback that enhances MDM2 expression. This underscores the urgent need to find an effective adaptive genotype or combination of targets. Methods Kinome-wide CRISPR/Cas9 knockout screen was performed to identify genes that modulate the response to MDM2 inhibitor using TP53 wild type cancer cells and found ULK1 as a candidate. The MTT cell viability assay, flow cytometry and LDH assay were conducted to evaluate the activation of pyroptosis and the synthetic lethality effects of combining ULK1 depletion with p53 activation. Dual-luciferase reporter assay and ChIP-qPCR were performed to confirm that p53 directly mediates the transcription of GSDME and to identify the binding region of p53 in the promoter of GSDME. ULK1 knockout / overexpression cells were constructed to investigate the functional role of ULK1 both in vitro and in vivo. The mechanism of ULK1 depletion to activate GSMDE was mainly investigated by qPCR, western blot and ELISA. Results By using high-throughput screening, we identified ULK1 as a synthetic lethal gene for the MDM2 inhibitor APG115. It was determined that deletion of ULK1 significantly increased the sensitivity, with cells undergoing typical pyroptosis. Mechanistically, p53 promote pyroptosis initiation by directly mediating GSDME transcription that induce basal-level pyroptosis. Moreover, ULK1 depletion reduces mitophagy, resulting in the accumulation of damaged mitochondria and subsequent increasing of reactive oxygen species (ROS). This in turn cleaves and activates GSDME via the NLRP3-Caspase inflammatory signaling axis. The molecular cascade makes ULK1 act as a crucial regulator of pyroptosis initiation mediated by p53 activation cells. Besides, mitophagy is enhanced in platinum-resistant tumors, and ULK1 depletion/p53 activation has a synergistic lethal effect on these tumors, inducing pyroptosis through GSDME directly. Conclusion Our research demonstrates that ULK1 deficiency can synergize with MDM2 inhibitors to induce pyroptosis. p53 plays a direct role in activating GSDME transcription, while ULK1 deficiency triggers upregulation of the ROS-NLRP3 signaling pathway, leading to GSDME cleavage and activation. These findings underscore the pivotal role of p53 in determining pyroptosis and provide new avenues for the clinical application of p53 restoration therapies, as well as suggesting potential combination strategies.

Background: Heart failure (HF) is a condition caused by a malfunction of the heart's pumping function. The single-point insulin sensitivity estimator (SPISE) index is a novel indicator for assessing insulin resistance in humans. However, the connection between the SPISE index and the risk of HF in the elderly is unknown. Therefore, our study aims to evaluate the connection between the SPISE index and HF in older adults. Methods: The study was based on data collected from the 1999–2020 National Health and Nutrition Examination Survey database and included 6165 participants aged ≥60 years. The multivariable linear regression model and the smooth fitting curve model were applied to investigate the connection between the SPISE index and HF in the elderly. Furthermore, the subgroup analysis was performed to investigate the interactive factors. Results: In this study, the mean age of the population was 69.38 years. After adjusting for all covariates, we observed that the SPISE index was inversely related to the prevalence of HF (OR = 0.87, 95 % CI = 0.80–0.94, P

Abstract Endocrine‐resistant ER+HER2– breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine‐resistant BC remain elusive. Here, analysis of the RNA‐sequencing data from ER+HER2– BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine‐resistant BC cells, not immune cells. Indeed, compared with endocrine‐sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS‐STING pathway is attenuated in endocrine‐resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS–STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2– BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine‐resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine‐resistant BC.

A novel species of Mucor was identified as the causal agent of a brown rot of Prunus domestica (European plum), widely grown in the south of Xinjiang, China. This disease first appears as red spots after the onset of the fruits. With favorable environmental conditions, fruit with infected spots turn brown, sag, expand, wrinkle, and harden, resulting in fruit falling. Fungal species were isolated from infected fruits. A phylogenetic analysis based on internal transcribed spacer (ITS) regions and the large subunit (LSU) of the nuclear ribosomal RNA (rRNA) gene regions strongly supported that these isolates made a distinct evolutionary lineage in Mucor (Mucoromycetes, Mucoraceae) that represents a new taxonomic species, herein named as Mucor xinjiangensis. Microscopic characters confirmed that these strains were morphologically distinct from known Mucor species. The pathogenicity of M. xinjiangensis was confirmed by attaching an agar disk containing mycelium on fruits and re-isolation of the pathogen from symptomatic tissues. Later, fourteen fungicides were selected to determine the inhibitory effect on the pathogen. Further, results showed that difenoconazole had the best effect on the pathogen and the strongest toxicity with the smallest half maximal effective concentration (EC50) value, followed by a compound fungicide composed of difenoconazole with azoxystrobin, mancozeb, prochloraz with iprodione, pyraclostrobin with tebuconazole, and trifloxystrobin with tebuconazole and ethhylicin. Present study provides the basis for the prevention and control of the novel plum disease and its pathogen.

Abstract Background Previous studies have demonstrated that trans fatty acids (TFAs) intake was linked to an increased risk of chronic diseases. As a novel systemic inflammatory biomarker, the clinical value and efficacy of the systemic immune-inflammation index (SII) have been widely explored. However, the association between TFAs and SII is still unclear. Therefore, the study aims to investigate the connection between TFAs and SII in US adults. Methods The study retrieved data from the National Health and Nutrition Examination Survey (NHANES) for the years 1999–2000 and 2009–2010. Following the exclusion of ineligible participants, the study encompassed a total of 3047 individuals. The research employed a multivariate linear regression model to investigate the connection between circulating TFAs and SII. Furthermore, the restricted cubic spline (RCS) model was utilized to evaluate the potential nonlinear association. Subgroup analysis was also conducted to investigate the latent interactive factors. Results In this investigation, participants exhibited a mean age of 47.40 years, with 53.91% of them being female. Utilizing a multivariate linear regression model, the independent positive associations between the log2-transformed palmitelaidic acid, the log2 transformed-vaccenic acid, the log2-transformed elaidic acid, the log2-transformed linolelaidic acid, and the log2-transformed-total sum of TFAs with the SII (all P 0.05). For the stratified analysis, the relationship between the circulating TFAs and the SII differed by the obesity status and the smoking status. Conclusions A positive association was investigated between three types of TFA, the sum of TFAs, and the SII in the US population. Additional rigorously designed studies are needed to verify the results and explore the potential mechanism.

Abstract Background This study aimed to evaluate whether coffee consumption and caffeine intake are independently associated with periodontitis infection. Methods Coffee consumption was categorized into binary and continuous variables, serving as the exposure factor alongside caffeine intake, with periodontitis infection as the outcome variable. Other covariables were regarded as potential confounders. The cross‐sectional study was conducted based on the national health and nutrition examination survey, with multivariate regression models, subgroup analyses, smooth fitting curves, and threshold effect examinations conducted to pursue a definite correlation between exposures and the outcome. Results Negative associations were discovered between binary coffee consumption (OR = 0.81, 95% CI = (0.71, 0.92), p‐value = 0.001) and caffeine intake (Q3: OR = 0.77, 95% CI = (0.66, 0.91), p‐value = 0.002; Q4: OR = 0.76, 95% CI = (0.64, 0.90), p‐value = 0.001) with periodontitis infection, respectively, with all confounders adjusted. In subgroup analyses stratified by gender, diabetes mellitus status, and hypertension status, interaction, and threshold effects were observed, which were intuitively revealed by smooth‐fitting curves. Conclusions Significant negative associations between binary consumption and caffeine intake and periodontitis infection separately were indicated, with no evidence suggesting a credible correlation between continuous coffee consumption and infection risk of periodontitis. The benefits of the behavior of consuming coffee and caffeine were more obvious among males and individuals who did not suffer from diabetes or hypertension.

Abstract Background Observational studies have suggested an association between endometriosis and glycemic traits, but causality remains unclear. We used bidirectional and multivariate Mendelian randomization (MR) to examine the causal effect of glycemic traits on endometriosis and vice versa. Methods We obtained genome-wide association studies summary data of endometriosis and glycemic traits in our study. Inverse variance weighted (IVW), Weighted median, MR-Egger and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were applied in bidirectional two-sample MR analyses. MVMR was implemented to estimate the causal effect for fasting insulin (FI), fasting glucose (FG), and glycosylated hemoglobin A1c (HbA1c) on endometriosis. To test the validity of our findings, a number of sensitivity analyses were conducted. Results The risk of endometriosis was significantly increased by genetically predicted T1DM (OR = 1.02, 95% CI 1.00-1.04, p = 0.0171, q = 0.0556) and GDM (OR = 1.01, 95% CI 1.01–1.02, p = 1.34 × 10− 8, q = 1.74 × 10− 7). Endometriosis had a suggestive association with HbA1c (Beta = 0.04, 95% CI 0.00-0.08, p = 0.0481, q = 0.1251). Using multivariate Mendelian randomization (MVMR), a significant causal effect of FI on genetically predicted endometriosis was found (OR = 2.18, 95% CI 1.16–4.09, p = 0.0154, q = 0.0547). Moreover, no causal associations between endometriosis and other glycemic traits were detected. Conclusion Our findings supported the significant causal associations of T1DM, GDM and FI with endometriosis, respectively. Additionally, a suggestive association was found of endometriosis on HbA1c. Importantly, our study may shed light on etiology studies and clinical management of endometriosis.

IntroductionThe burden of colorectal cancer (CRC) plays a pivotal role in the global cancer epidemic. Our study reported the incidence trends in CRC and the associated effects of age, period, and birth cohort in 204 countries and territories over the past 30 years.MethodsThe incidence data of CRC were extracted from the Global Burden of Disease Study (GBD) 2019. We performed the age–period–cohort (APC) model to estimate the overall annual percentage change (net drift) in the incidence rate, the annual percentage change by age group (local drift), and the relative risk (period and cohort effects) of the period and cohort in CRC during 1990–2019. This approach allows examining and distinguishing age, period, and cohort effects in incidence and potentially distinguishing colorectal cancer gaps in prevention and screening.ResultsIn 2019, the incidence of CRC was 2.17 (95% UI 2.00–2.34) million, of which China, the United States of America, and Japan had the highest incidence population, accounting for 45.9% of the global population. The age–standardized incidence rate (ASIR) was 26.7 (95% UI 28.9–24.6) per 100,000 people, of which 30 countries had an incidence rate greater than 40.0 per 100,000 people. From 1990 to 2019, the middle SDI region had the largest increase in incidence rate, with a net drift of 2.33% (95% CI 2.2–2.46%, p 2%), mostly concentrated in the middle SDI region, such as China, Mexico, and Brazil, and the risk of period and birth cohort was unfavorable.ConclusionGlobally, the incidence of CRC has shown an overall upward trend over the past 30 years, with the exception of some countries with higher SDI values. Significant age–period–cohort differences were observed in the risk of incidence in CRC worldwide. Effective prevention and control policies need to take into account the age–period–cohort effect characteristics of different regions.

Abstract Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21 −/−) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21 −/− and Ctsk-cre; Trim21 f/f mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.

Abstract Background As the most lethal gynecologic cancer, ovarian cancer (OV) holds the potential of being immunotherapy-responsive. However, only modest therapeutic effects have been achieved by immunotherapies such as immune checkpoint blockade. This study aims to propose a generalized stroma-immune prognostic signature (SIPS) to identify OV patients who may benefit from immunotherapy. Methods The 2097 OV patients included in the study were significant with high-grade serous ovarian cancer in the III/IV stage. The 470 immune-related signatures were collected and analyzed by the Cox regression and Lasso algorithm to generalize a credible SIPS. Correlations between the SIPS signature and tumor microenvironment were further analyzed. The critical immunosuppressive role of stroma indicated by the SIPS was further validated by targeting the major suppressive stroma component (CAFs, Cancer-associated fibroblasts) in vitro and in vivo. With four machine-learning methods predicting tumor immune subtypes, the stroma-immune signature was upgraded to a 23-gene signature. Results The SIPS effectively discriminated the high-risk individuals in the training and validating cohorts, where the high SIPS succeeded in predicting worse survival in several immunotherapy cohorts. The SIPS signature was positively correlated with stroma components, especially CAFs and immunosuppressive cells in the tumor microenvironment, indicating the critical suppressive stroma-immune network. The combination of CAFs’ marker PDGFRB inhibitors and frontline PARP inhibitors substantially inhibited tumor growth and promoted the survival of OV-bearing mice. The stroma-immune signature was upgraded to a 23-gene signature to improve clinical utility. Several drug types that suppress stroma-immune signatures, such as EGFR inhibitors, could be candidates for potential immunotherapeutic combinations in ovarian cancer. Conclusions The stroma-immune signature could efficiently predict the immunotherapeutic sensitivity of OV patients. Immunotherapy and auxiliary drugs targeting stroma could enhance immunotherapeutic efficacy in ovarian cancer.

Purpose: To conduct a real-world evaluation of the efficacy and safety of combined Chinese and Western medicine in treating knee osteoarthritis (KOA).Methods: A multicenter, prospective cohort study design was employed, enrolling 450 KOA patients (Kellgren-Lawrence score of 3 or less). The patients were divided into a Western medicine treatment group (WM group) and a combined Western and traditional Chinese medicine treatment group (WM-CM group). A 6-week treatment plan was administered, and follow-up visits occurred at 2 weeks, 4 weeks, and 6 weeks after initiating treatment. The primary outcome indicator was the total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score after 6 weeks of treatment. Secondary outcome indicators included WOMAC subscales for pain, stiffness, and joint function, visual analogue scale (VAS) score, physical component summary (PCS), mental component summary (MCS), and clinical effectiveness. The incidence of drug-related adverse events was used as a safety evaluation indicator.Results: A total of 419 patients were included in the final analysis: 98 in the WM group and 321 in the WM-CM group. The baseline characteristics of the two groups were comparable, except for the incidence of stiffness symptoms and stiffness scores. After 6 weeks of treatment, the WM-CM group exhibited superior results to the WM group in improving the total WOMAC score (24.71 ± 1.38 vs. 16.36 ± 0.62, p < 0.001). The WM-CM group also outperformed the WM group in WOMAC pain and joint function scores, VAS score, PCS score, MCS score, and clinical effectiveness (p < 0.05), which was consistent with the findings of the main evaluation index. Subgroup analysis indicated that the combined Chinese and Western medicine treatment showed more pronounced benefits in patients under 65 years of age and in those with a Kellgren-Lawrence (K-L) classification of 0-I. Throughout the study, no adverse effects were observed in either group.Conclusion: The combination of Chinese and Western medicine demonstrated superiority over Western medicine alone in relieving knee pain symptoms, improving knee function, and enhancing the quality of life for KOA patients with a K-L score of 3 or less. Moreover, the treatment exhibited a good safety profile.Clinical Trial Registration: (https://www.chictr.org.cn/), identifier (ChiCTR1900027175).

Ferroptosis, an iron-dependent lipid peroxidation-driven programmed cell death, is closely related to cancer therapy. The development of druggable ferroptosis inducers and their rational application in cancer therapy are critical. Here, we identified Tubastatin A, an HDAC6 inhibitor as a novel druggable ferroptosis inducer through large-scale drug screening. Tubastatin A directly bonded to GPX4 and inhibited GPX4 enzymatic activity through biotin-linked Tubastatin A putdown and LC/MS analysis, which is independent of its inhibition of HDAC6. In addition, our results showed that radiotherapy not only activated Nrf2-mediated GPX4 transcription but also inhibited lysosome-mediated GPX4 degradation, subsequently inducing ferroptosis tolerance and radioresistance in cancer cells. Tubastatin A overcame ferroptosis resistance and radioresistance of cancer cells by inhibiting GPX4 enzymatic activity. More importantly, Tubastatin A has excellent bioavailability, as demonstrated by its ability to significantly promote radiotherapy-induced lipid peroxidation and tumour suppression in a mouse xenograft model. Our findings identify a novel druggable ferroptosis inducer, Tubastatin A, which enhances radiotherapy-mediated antitumor effects. This work provides a compelling rationale for the clinical evaluation of Tubastatin A, especially in combination with radiotherapy.

Our previous study has shown that the transcription factor Krüppel-like factor 7 (KLF7) promotes peripheral nerve regeneration and motor function recovery after spinal cord injury. KLF7 also participates in traumatic brain injury, but its regulatory mechanisms remain poorly understood. In the present study, an HT22 cell model of traumatic brain injury was established by stretch injury and oxygen-glucose deprivation. These cells were then transfected with an adeno-associated virus carrying KLF7 (AAV-KLF7). The results revealed that, after stretch injury and oxygen-glucose deprivation, KLF7 greatly reduced apoptosis, activated caspase-3 and lactate dehydrogenase, downregulated the expression of the apoptotic markers B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and cleaved caspase-3, and increased the expression of βIII-tubulin and the antiapoptotic marker Bcl-2. Furthermore, KLF7 overexpression upregulated Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) phosphorylation in HT22 cells treated by stretch injury and oxygen-glucose deprivation. Immunoprecipitation assays revealed that KLF7 directly participated in the phosphorylation of STAT3. In addition, treatment with AG490, a selective inhibitor of JAK2/STAT3, weakened the protective effects of KLF7. A mouse controlled cortical impact model of traumatic brain injury was then established. At 30 minutes before modeling, AAV-KLF7 was injected into the ipsilateral lateral ventricle. The protein and mRNA levels of KLF7 in the hippocampus were increased at 1 day after injury and recovered to normal levels at 3 days after injury. KLF7 reduced ipsilateral hippocampal atrophy, decreased the injured cortex volume, downregulated Bax and cleaved caspase-3 expression, and increased the number of 5-bromo-2′-deoxyuridine-positive neurons and Bcl-2 protein expression. Moreover, KLF7 transfection greatly enhanced the phosphorylation of JAK2 and STAT3 in the ipsilateral hippocampus. These results suggest that KLF7 may protect hippocampal neurons after traumatic brain injury through activation of the JAK2/STAT3 signaling pathway. The study was approved by the Institutional Review Board of Mudanjiang Medical University, China (approval No. mdjyxy-2018-0012) on March 6, 2018.

This study was conducted to examine differences in visual attention according to sports type and sex. In total, 132 participants [open-skill sport athletes (basketball players), closed-skill sport athletes (swimmers), and non-athletes; n = 22 men and 22 women each] aged 19–24 years performed a multiple object tracking (MOT) task, which is a well-established paradigm for the assessment of visual attention. Visual tracking accuracy was affected by the sport type (p

Abstract Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.

Maternal stress has been associated with poor birth outcomes, including preterm birth, infant mortality, and low birth weight. Bone development disorders in the embryo as a result of maternal stress are believed to be mediated through oxidative stress damage. Various species of free radicals, such as alkoxyl radicals, can be formed through endogenous redox response or exogenous stimuli in the womb and transmitted to embryos. Yet, whether these free radicals lead to abnormal fetal bone development is unclear. Here, we demonstrate prenatal bone growth retardation and ferroptosis-related signals of chondrocytes were induced by classic alkoxyl radical generators. We also show that alkoxyl radicals lead to significant accumulation of oxidized phospholipids in chondrocytes, through the iron-mediated Fenton reaction in embryos. We further demonstrate a role for the lipid peroxidation end product, 4-HNE, which forms adducts with the pivotal chondrogenesis transcription factor SOX9, leading to its degradation, therefore dampening chondrogenesis. Our data define a critical role for phospholipid peroxidation in alkoxyl radicals-evoked abnormal chondrogenesis, and pinpoint it being a precise target for treating oxidative stress-related bone development disorders.

BackgroundAs a recognized highly immunogenic tumor, immune checkpoint blockades (ICB) have been widely used as a systemic treatment option for melanoma. However, only about half of treated patients could benefit from it in Caucasians, and only about 15% in Chinese melanoma patients. Robust predictive biomarkers are needed. HHLA2, a new-found member of B7 family, is generally expressed in kinds of tumors, such as melanoma. This study focuses on illustrating the prognostic value of HHLA2 in melanoma immunotherapy and its association with tumor-infiltrating lymphocytes.MethodsHHLA2 expression in pan-cancer and the association with prognosis and immune microenvironment were identified by analyzing gene expression profiles from TCGA database with selected bioinformatics tools and methods. Tumor tissues from 81 cases with advanced and unresectable melanoma were collected for detecting HHLA2 and CD8 levels by immunohistochemistry.ResultsHHLA2 was found to be ubiquitously expressed in pan-cancer with high level and correlate with the prognosis of patients. Further comprehensive analysis from TCGA database demonstrated that the highly expressed HHLA2 was remarkably correlated with better prognosis, high infiltration status of various immune-active cells and immune activated pathways in skin cutaneous melanoma (SKCM). Moreover, immunohistochemistry (IHC) analyses of FFPE tissue from melanoma patients revealed that HHLA2 high expression was strongly related to improved response to ICB and indicated a longer progression-free survival (PFS) and overall survival (OS). Besides, HHLA2 expression was found to have a positive association with the density of CD8+ TILs.ConclusionOur findings revealed that high expression of HHLA2 has important values in predicting the response to ICB and indicating improved PFS and OS in patients with advanced and unresectable melanoma, suggesting that HHLA2 may serve as a costimulatory ligand in melanoma, which renders it as an ideal biomarker for immunotherapy.

B7H3 is a transmembrane B7 family checkpoint molecule present on many cancer cells. Here the authors show that FUT8 mediates fucosylation of B7H3 to limit the immune response to triple-negative breast cancer as a potentially targeted mechanism of non-responsiveness to current checkpoint therapies.

Abstract Background Super-enhancers (SEs) play a crucial role in cancer, which is often associate with activated oncogenes. However, little is known about how SEs facilitate tumour suppression. Individuals with Down syndrome exhibit a remarkably reduced incidence of breast cancer (BC), moving the search for tumor suppressor genes on human chromosome 21 (HSA21). In this study, we aim to identify and explore potential mechanisms by which SEs are established for tumor suppressor RCAN1.4 on HSA21 in BC. Methods In silico analysis and immunohistochemical staining were used to assess the expression and clinical relevance of RCAN1.4 and RUNX3 in BC. Function experiments were performed to evaluate the effects of RCAN1.4 on the malignancy of breast carcinoma in vitro and in vivo. ChIP-seq data analysis, ChIP-qPCR, double-CRISPR genome editing, and luciferase reporter assay were utilized to confirm RUNX3 was involved in regulating RCAN1.4-associated SE in BC. The clinical value of co-expression of RCAN1.4 and RUNX3 was evaluated in BC patients. Results Here, we characterized RCAN1.4 as a potential tumour suppressor in BC. RCAN1.4 loss promoted tumour metastasis to bone and brain, and its overexpression inhibited tumour growth by blocking the calcineurin-NFATc1 pathway. Unexpectedly, we found RCAN1.4 expression was driven by a ~ 23 kb-long SE. RCAN1.4-SEdistal was sensitive to BRD4 inhibition, and its deletion decreased RCAN1.4 expression by over 90% and induced the malignant phenotype of BC cells. We also discovered that the binding sites in the SE region of RCAN1.4 were enriched for consensus sequences of transcription factor RUNX3. Knockdown of RUNX3 repressed the luciferase activity and also decreased H3K27ac enrichment binding at the SE region of RCAN1.4. Furthermore, abnormal SE-driven RCAN1.4 expression mediated by RUNX3 loss could be physiologically significant and clinically relevant in BC patients. Notably, we established a prognostic model based on RCAN1.4 and RUNX3 co-expression that effectively predicted the overall survival in BC patients. Conclusions These findings reveal an important role of SEs in facilitating tumour suppression in BC. Considering that the combination of low RCAN1.4 and low RUNX3 expression has worse prognosis, RUNX3-RCAN1.4 axis maybe a novel prognostic biomarker and therapeutic target for BC patients.

T cell mediated therapies have proven largely unsuccessful in triple-negative breast cancer (TNBC). Here, the authors show that autophagy is reduced in TNBC, which results in an increase in Tenascin C and reduced activation of tumour infiltrating lymphocytes.

Abstract Background Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target. Methods We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo. Results LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N6-methyladenosine (m6A) ‘reader’. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models. Conclusion LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

Abstract Background Chlamydia trachomatis (CT) infection is one of the most pervasive sexually transmitted infections and has high prevalence in urogenital and extra-urogenital sites among men who have sex with men (MSM). This study investigated anatomical site-specific prevalence and genotypes of CT among MSM recruited from three geographic areas in China. Methods We collected urine specimens and anorectal, pharyngeal swab specimens from 379 MSM. CT infection was identified using polymerase chain reaction and CT genotyping was determined by sequences of the ompA gene. Results The results indicated that the overall prevalence of CT infection was 18.2% (95% confidence intervals [CIs], 13.9–22.5%) and significantly different between the cities (p = 0.048). The infection was most common at the anorectal site (15.6, 95%CIs 11.6–19.5%) followed by urethral (3.2, 95%CIs 1.4–5.0%) and oropharyngeal sites (1.6, 95%CIs 0.3–2.9%). Genotypes D and G were the most common CT strains in this population but genotype D was significantly predominated in Nanjing while genotype G was in Wuhan. No genotype related to lymphogranuloma venereum was found. CT infection was significantly related to the infection of Neisseria gonorrhoeae (adjusted odds ratio [aOR] 14.27, 95%CIs 6.02–33.83, p

Obsessive Compulsive Drinking Scale (OCDS) was established and introduced to measure the craving for alcohol and the severity of alcohol dependence. However, the Chinese version of OCDS is still unavailable and has not been validated in the Chinese population. We tended to translate and validate the OCDS in Chinese. We translated original OCDS into Chinese through bi-direction translations and tested the reliability and validity. We found that Chinese OCDS had high internal consistency and good test-retest reliability. The Chinese OCDS also presented good internal structure to reflect the severity of alcohol dependence. The Chinese OCDS could be used in clinical studies and research among the Chinese population.

Background: Traditional laparoscopic No.12a lymph node dissection in radical gastrectomy for gastric cancer may damage the peripheral blood vessels, and is not conducive to the full exposure of the portal vein and the root ligation of the left gastric vein. We recommend a new surgical procedure, the portal vein approach, to avoid these problems. Methods: 25 patients with advanced gastric cancer underwent radical laparoscopic gastrectomy and No.12a lymph node were dissected by portal vein approach, including 7 cases with total gastrectomy, 18 cases with distal gastric resection, 14 males and 11 females. Operative time, intraoperative blood loss, time to first flatus, postoperative hospital stay, number of total lymph node dissection and No.12a lymph node dissection, No.12a lymph node metastasis rate and postoperative complications were statistically observed. Results: All the patients were operated successfully and No.12a lymph node were cleaned by portal vein approach. A total of 683 lymph nodes were dissected, with the average number of lymph nodes dissection and positive lymph nodes were (27.3 ± 12.7) and (3.8 ± 5.6) respectively. The average number of No.12a lymph node dissection was (2.4 ± 1.95) and the metastasis rate of No.12a lymph node was 16% (4/25). The average operation time of radical laparoscopic distal and total gastrectomy were (239.2 ± 51.4) min and (295.1 ± 27.7) min respectively. The mean intraoperative blood loss was (134.0 ± 65.7) ml, and postoperative first anal exhaust time was (2.24 ± 0.86) d. The mean time to fluid intake was (4.2 ± 1.7) d, and postoperative hospitalization time was (9.6 ± 5.0) d. Without portal vein injure, anastomotic leakage, gastrointestinal bleeding, intestinal obstruction and other complications were observed in all patient. Conclusion: Our results show that the laparoscopic No.12a lymph node dissection by portal vein approach for gastric cancer is safe, feasible and has certain clinical application value.

Alcohol use disorder (AUD) is a ubiquitous substance use disorder in the world, of which neural mechanisms remain unclear. Alcohol consumption induces neuro-adaptations in the dopaminergic system originating from the ventral tegmental area (VTA), an important brain region for the reward function in AUD. Endogenous brain-derived neurotrophic factor (BDNF)-TrkB implicated in the development of neuroplasticity, including long-term potentiation of GABAergic synapses (LTPGABA). We previously found that ethanol blocks LTPGABA in the VTA, either in vivo or in vitro. 7,8-dihydroflavone (7,8-DHF), a BDNF-mimicking small compound, was recently found to penetrate the blood–brain barrier to mimic the biological role of BDNF-TrkB. In this study, we demonstrate that repeated ethanol consumption (including intermittent and continuous ethanol exposure) results in low expression of BDNF in rat VTA. The amount of ethanol intake enhances significantly in rats with intermittent ethanol exposure after 72 h abstinence. Withdrawal signs emerge in rats with continuous ethanol exposure within 3 days after abstinence. Using behavioral tests, intraperitoneal injection of 7,8-DHF can reduce excessive ethanol consumption and preference as well as withdrawal signs in rats with repeated ethanol exposure. Interestingly, microinjection of K252a, an antagonist of TrkB, into the VTA blocks the effects of 7,8-DHF on ethanol-related behaviors. Furthermore, direct microinjection of BDNF into the VTA mimics the effect of 7,8-DHF on ethanol related behaviors. Taken together, 7,8-DHF attenuates alcohol-related behaviors in rats undergoing alcohol consumption via TrkB in the VTA. Our findings suggest BDNF-TrkB in VTA is a part of regulating signals for opposing neural adaptations in AUD, and 7,8-DHF may serve as a potential candidate for treating alcoholism.

We aimed to profile the metabolism of soybean roots that were infected with soybean cyst nematodes and treated with Bacillus simplex to identify metabolic differences that may explain nematode resistance. Compared with control soybean roots, B. simplex-treated soybean roots contained lower levels of glucose, fructose, sucrose, and trehalose, which reduced the nematodes' food source. Furthermore, treatment with B. simplex led to higher levels of melibiose, gluconic acid, lactic acid, phytosphingosine, and noradrenaline in soybean roots, which promoted nematocidal activity. The levels of oxoproline, maltose, and galactose were lowered after B. simplex treatment, which improved disease resistance. Collectively, this study provides insight into the metabolic alterations induced by B. simplex treatment, which affects the interactions with soybean cyst nematodes.

Objective Because of the complicated blood supply and vascular structure of the pancreas, blood vessel reconstruction and reshaping are generally required during pancreas transplantation. We modified the vascular preparation procedure for the donor pancreas (i.e., no vascular reconstruction was performed) based on experiences in our department and in other domestic and international transplantation centers. Methods Twelve donor pancreas preparations without vascular reconstruction were performed. The patch (Carrel patch), celiac trunk, and superior mesenteric artery were preserved as arterial inflow channels for the donor pancreas. The common hepatic artery and the gastroduodenal artery were transected at a site 0.5 cm away from the bifurcation. The bifurcated portion was preserved for the donor liver. The stumps of the gastroduodenal artery and common hepatic artery were then ligated. The portal vein was transected in the middle of the hepatoduodenal ligament during separation of the liver and pancreas. The partial portal vein preserved with the pancreas was used as the outflow channel of the donor pancreas. Results The transplanted pancreas functioned well in the recipients, and no vascular complications were reported. Conclusion The overall efficacy of pancreas transplantation without vascular reconstruction has been improved.

Neuroblastoma cell differentiation is regulated by Id proteins. Here, the authors show that CaMKII-mediated phosphorylation of Beclin 1 can activate K63-linked ubiquitination and autophagic degradation of Id proteins uncovering a role for autophagy in cell differentiation.

By the method of 1H NMR prescreening and tracing the diagnostic signals, 6-methylpyridinone derivatives, (8R,9S)-dihydroisoflavipucine (1), (8S,9S)-dihydroisoflavipucine (2), 3-(1-hydroxy-4-methyl-2-oxopentylidene)-6-methylpyridine-2,4(1H,3H)-dione (3), 4-hydroxy-3-(2-hydroxy-4-methylpentanoyl)-6-methylpyridin-2(1H)-one (4), 4-hydroxy-3-[(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)methyl]-6-methylpyridin-2(1H)-one (5) and a known 6-methylpyranone derivative 3,3′-methylenebis(4-hydroxy-6-methyl-2H-pyran-2-one) (6) were isolated from the marine fungus Leptosphaerulina sp., which was collected from the starfish Acanthaster planci from the South China Sea. Compounds 2 and 3 are new compounds. Their structures were elucidated on the basis of MS, 1D and 2D NMR, and X-ray single crystal diffraction data. The absolute configurations of compounds 1 and 2 were determined by analysis on the experimental circular-dichroism spectra.

Immune checkpoint blockade of programmed cell death protein 1 (PD-1) had an impressive long-lasting effect in a portion of advanced-stage melanoma patients, however, this therapy failed to induce responses in several patients; how to increase the objective response rate is very important. Cellular FLICE-inhibitory protein (c-FLIP) could inhibit apoptosis directly at the death-inducing signaling complex of death receptors and is also considered to be the main cause of immune escape. The overexpression of c-FLIPL occurs frequently in melanoma and its expression is associated with the prognosis. We found that the level of c-FLIPL expression was associated with the PD-1 blockade response rate in melanoma patients. Thus, we performed this research to investigate how c-FLIPL regulates immunotherapy in melanoma. We demonstrate that down regulation of c-FLIPL enhances the PD-1 blockade efficacy in B16 melanoma tumor model. Down regulation of c-FLIPL could increase the tumor apoptosis and enhance the antitumor response of T cells in the lymphocyte tumor cells co-culture system. Moreover, knockdown of c-FLIPL could decrease the expression of PD-L1 and recruit more effector T cells in the tumor microenvironment. Our results may provide a new combined therapeutic target for further improving the efficacy of PD-1 blockade in melanoma.

Three new compounds, monarubins A−C (1, 6 and 13), together with ten known compounds, including four alkaloids (2−5), two isocoumarins (7 and 8) and four polyketides (9−12), were isolated from marine shellfish-associated fungus Monascus ruber BB5. The structures were determined on the basis of the 1D and 2D NMR, MS, UV and IR data. The absolute configurations of compounds 3, 6 and 13 were determined by ECD calculations. The NMR data of compounds deoxyhydroxyaspergillic acid (3) and 2-hydroxy-6-(1-hydroxy-1-methylpropyl)-3-sec-buthylpyrazine (4) were first reported. All of the isolated compounds were evaluated for their cytotoxic activities against human nasopharyngeal carcinoma cell lines CNE1, CNE2, SUNE1 and HONE1 and hepatocellular carcinoma cell lines QGY7701 and HepG2. Monarubin B (6) displayed potent cytotoxicities against the cancer cell lines HepG2 and QGY7701 with IC50 values of 1.72 and 0.71 μΜ, respectively; lunatinin (7) showed moderate cytotoxic activities against the cancer cell lines HepG2, QGY7701 and SUNE1 with the IC50 values of 9.60, 7.12 and 28.12 μΜ, respectively.

Aims: To explore the expression of miR-24-3p in human arteries with arteriosclerosis obliterans (ASO) as well as the role of miR-24-3p in the pathogenesis of ASO. Methods: We used quantitative real-time PCR (qRT-PCR) and in situ hybridization to monitor miR-24-3p expression in human arteries. To investigate the effect of miR-24-3p on human arterial smooth muscle cells (HASMCs), we applied cell counting and EdU assays to monitor proliferation and transwell and wound healing assays to investigate migration and flow cytometry to investigate apoptosis. Furthermore, we applied 3'-untranslated region (3'-UTR) luciferase assays to investigate the role of miR-24-3p in targeting platelet-derived growth factor receptor B (PDGFRB) and c-Myc. Results: MiR-24-3p was mainly located in the media of arteries and was downregulated in ASO arteries compared with normal arteries. Platelet-derived growth factor BB (PDGF-BB) treatment reduced the expression of miR-24-3p in primary cultured HASMCs. MiR-24-3p mimic oligos inhibited the proliferation and migration, and promotes apoptosis of HASMCs. Our 3'-UTR luciferase assays confirmed that PDGFRB and c-Myc were targets of miR-24-3p. Conclusion: The results suggest that miR-24-3p regulates the proliferation and migration of HASMCs by targeting PDGFRB and c-Myc. The PDGF/miR-24-3p/PDGFRB and PDGF/miR-24-3p/c-Myc pathways may play critical roles in the pathogenesis of ASO. These findings highlight the potential for new therapeutic targets for ASO.

Bioassay-guided fractionation of an ethanol extract of the pericarps of Garcinia mangostana led to the isolation of two new prenylated xanthones, named 1,3,7-trihydroxy-2-(3-methyl-2-butenyl)-8-(3-hydroxy-3-methylbutyl)-xanthone (1) and 1,3,8-trihydroxy-2-(3-methyl-2-butenyl)-4-(3-hydroxy-3-methylbutanoyl)-xanthone (2), together with the five known compounds garcinones C (3) and D (4), gartanin (5), xanthone I (6), and γ-mangostin (7). Their structures were elucidated primarily based on MS and NMR data. Compounds 1–7 showed significant cytotoxic activities against various human cancer cell lines.

Chondrostereum sp., a marine fungus isolated from a soft coral Sarcophyton tortuosum, can yield hirsutane framework sesquiterpenoids. However, the metabolites profiles vary dramatically with the composition change of the culture media. This fungus was cultured in a liquid medium containing glycerol as the carbon source, and two new metabolites, chondrosterins I and J (1 and 2), were obtained. Their structures were elucidated primarily based on MS, NMR and X-ray single-crystal diffraction data. By comparison with the known hirsutane sesquiterpenoids, chondrosterins I and J have unique structural features, including a methyl was migrated from C-2 to C-6, and the methyl at C-3 was carboxylated. Compound 2 exhibited potent cytotoxic activities against the cancer cell lines CNE-1 and CNE-2 with the IC50 values of 1.32 and 0.56 μM.

The composition of the culture medium has great influence on the metabolite production of the marine fungus Pseudallescheria boydii F44-1. By adding amino acids to GPY culture medium, two new bisindole alkaloids, pseudboindoles A and B (1 and 2), together with 11 known indole alkaloids were isolated from the culture broth. Their structures were elucidated by comprehensive analysis of the NMR, MS, IR, and UV spectra. The 3,3′-cyclohexylidenebis(1H-indole) (3) showed cytotoxic activity against various cancer cell lines.

The marine fungus Chondrostereum sp. was collected from a soft coral of the species Sarcophyton tortuosum from the South China Sea. Three new compounds, chondrosterins F–H (1, 4 and 5), together with three known compounds, incarnal (2), arthrosporone (3), and (2E)-decene-4,6,8-triyn-1-ol (6), were isolated. Their structures were elucidated primarily based on NMR and MS data. Incarnal (2) exhibited potent cytotoxic activity against various cancer cell lines.

Hirsutanol A is a novel sesquiterpene compound purified from the marine fungus Chondrostereum sp in the coral Sarcophyton tortuosum. Our previous studies had demonstrated that hirsutanol A exerted potent cytotoxic effect in many kinds of cancer cell lines. Here, the anticancer molecular mechanisms of hirsutanol A were investigated in breast cancer MCF-7 cells. The results showed that hirsutanol A could inhibit cell proliferation, elevate reactive oxygen species (ROS) level, and induce apoptosis and autophagy. Co-treatment with the potent antioxidant agent N-acetyl-l-cysteine could effectively reverse the effect of enhanced ROS production, which in turn, reduces growth inhibition, apoptosis, and autophagy mediated by hirsutanol A. In addition, blocking autophagy by bafilomycin A1 or Atg7-siRNA could synergistically enhance the antiproliferative effect and apoptosis induced by hirsutanol A. These data suggested that hirsutanol A could induce apoptosis and autophagy via accumulation of ROS and co-treatment with an autophagy inhibitor could sensitize MCF-7 cells to hirsutanol A. Keywords:: hirsutanol A, apoptosis, autophagy, reactive oxygen species (ROS), breast cancer

Phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells and thus has been considered as a promising drug target. To ascertain a therapeutical approach of nasopharyngeal carcinoma (NPC), we hypothesized NVP-BEZ235, a novel and potent imidazo[4,5-c] quinolone derivative, that dually inhibits both PI3K and mTOR kinases activities, had antitumor activity in NPC. Expectedly, we found that NVP-BEZ235 selectively inhibited proliferation of NPC cells rather than normal nasopharyngeal cells using MTT assay. In NPC cell lines, with the extended exposure, NVP-BEZ235 selectively inhibited proliferation of NPC cells harboring PIK3CA mutation, compared to cells with wild-type PIK3CA. Furthermore, exposure of NPC cells to NVP-BEZ235 resulted in G1 growth arrest by Propidium iodide uptake assay, reduction of cyclin D1and CDK4, and increased levels of P27 and P21 by Western blotting, but negligible apoptosis. Moreover, we found that cisplatin (CDDP) activated PI3K/AKT and mTORC1 pathways and NVP-BEZ235 alleviated the activation by CDDP through dually targeting PI3K and mTOR kinases. Also, NVP-BEZ235 combining with CDDP synergistically inhibited proliferation and induced apoptosis in NPC cells. In CNE2 and HONE1 nude mice xenograft models, orally NVP-BEZ235 efficiently attenuated tumor growth with no obvious toxicity. In combination with NVP-BEZ235 and CDDP, there was dramatic synergy in shrinking tumor volumes and inducing apoptosis through increasing Noxa, Bax and decreasing Mcl-1, Bcl-2. Based on the above results, NVP-BEZ235, which has entered phase I/II clinical trials in patients with advanced solid tumors, has a potential as a monotherapy or in combination with CDDP for NPC treatment.

It has been suggested that autophagy-related Beclin 1 plays a critical role in the regulation of tumor development and/or progression, but its prognostic significance and relationship with Bcl-xL expression in ovarian carcinoma are unclear.In the present study, the methods of Western blotting and immunohistochemistry (IHC) were utilized to investigate the expression status of Beclin 1 and Bcl-xL in fresh ovarian tissues and paraffin-embedded epithelial ovarian tumor tissues. Decreased expression of Beclin 1 was examined by IHC in 8.3% of normal ovaries, in 15.4% of cystadenomas, in 20.0% of borderline tumors, and in 55.6% of ovarian carcinomas, respectively. In ovarian carcinomas, decreased expression of Beclin 1 was correlated closely with ascending histological grade, later pT/pN/pM status and/or advanced clinical stage (P

By the method of 1H NMR prescreening and tracing the diagnostic proton signals of the methyl groups, three additional new triquinane-type sesquiterpenoids—chondrosterins K–M (1–3) and the known sesquiterpenoid anhydroarthrosporone (4)—were isolated from the marine fungus Chondrostereum sp. Their structures were elucidated on the basis of MS, 1D, and 2D NMR data. Chondrosterin K is a rare hirsutane sesquiterpenoid, in which a methyl group was migrated from C-2 to C-6 and has a double bond between C-2 and C-3. Compounds 1–3 showed significant cytotoxicities against various cancer cell lines in vitro.

BACKGROUND: To determine the prevalence and risk factors associated with idiopathic epiretinal membranes (iERM) in a Chinese population aged 60 years or older in Beixinjing Blocks, Shanghai. METHODS: This population-based study consisted of 3727 participants (89.7% of the eligible). It was performed to describe the prevalence of iERM and possible demographic, systemic, and ocular factors associated with iERM. Each participant underwent a standardized interview and comprehensive ophthalmic examination. iERM was identified and graded from retinal photographs. Then, a case-control study comparing the participants with vs. without iERM was performed to further study the associations between iERM and blood biochemical test results (including fasting plasma glucose, serum creatinine, total cholesterol, and triglyceride), ocular biological parameters (including the axial length, corneal curvature, refractive diopter, intraocular press, and anterior chamber depth), and the data of optical coherence tomography. RESULTS: The prevalence of iERM was 1.02%. iERM was significantly associated with diabetes (OR: 2.457; 95% CI: 1.137, 5.309) and a higher level of education (OR: 1.48; 95% CI: 1.123, 1.952). Blood biochemical test results and ocular biological parameters showed no significant differences between the iERM and control groups, whereas the incidence of posterior vitreous detachment in the iERM group was much higher than in the control group (26.5% vs. 8.8%), but this difference was not statistically significant. Moreover, the eyes with iERM had poorer visual acuity than the eyes without iERM (P

BACKGROUND: A number of published randomized controlled trials have been conducted to evaluate visual performance of blue light-filtering intraocular lenses (IOL) and UV light-filtering intraocular lenses (IOL) after cataract phacoemulsification surgery. However, results have not always been consistent. Therefore, we carried out a meta-analysis to compare the effectiveness of blue light-filtering IOLs versus UV light-filtering IOLs in cataract surgery. METHODS AND FINDINGS: Comprehensive searches of PubMed, Embase, Cochrane Library and the Chinese BioMedical literature databases were performed using web-based search engines. Fifteen trials (1690 eyes) were included for systematic review, and 11 of 15 studies were included in this meta-analysis. The results showed that there were no significant differences in postoperative mean best corrected visual acuity, contrast sensitivity, overall color vision, or in the blue light spectrum under photopic light conditions between blue light-filtering IOLs and UV light-filtering IOLs [WMD = -0.01, 95%CI (-0.03, 0.01), P = 0.46; WMD = 0.07, 95%CI (-0.04, 0.19), P = 0.20; SMD = 0.14, 95%CI (-0.33, 0.60), P = 0.566; SMD = 0.20, 95%CI (-0.04, 0.43), P = 0.099]. However, color vision with blue light-filtering IOLs was significantly reduced in the blue light spectrum under mesopic light conditions [SMD = 0.74, 95%CI (0.29, 1.18), P = 0.001]. CONCLUSION: This meta-analysis demonstrates that postoperative visual performance with blue light-filtering IOLs is approximately equal to that of UV light-filtering IOLs after cataract surgery, but color vision with blue light-filtering IOLs demonstrated some compromise in the blue light spectrum under mesopic light conditions.

BACKGROUND: Topotecan produces DNA damage that induces autophagy in cancer cells. In this study, sensitising topotecan to colon cancer cells with different P53 status via modulation of autophagy was examined. METHODOLOGY/PRINCIPAL FINDINGS: The DNA damage induced by topotecan treatment resulted in cytoprotective autophagy in colon cancer cells with wild-type p53. However, in cells with mutant p53 or p53 knockout, treatment with topotecan induced autophagy-associated cell death. In wild-type p53 colon cancer cells, topotecan treatment activated p53, upregulated the expression of sestrin 2, induced the phosphorylation of the AMPKα subunit at Thr172, and inhibited the mTORC1 pathway. Furthermore, the inhibition of autophagy enhanced the anti-tumour effect of topotecan treatment in wild-type p53 colon cancer cells but alleviated the anti-tumour effect of topotecan treatment in p53 knockout cells in vivo. CONCLUSIONS/SIGNIFICANCE: These results imply that the wild-type p53-dependent induction of cytoprotective autophagy is one of the cellular responses that determines the cellular sensitivity to the DNA-damaging drug topotecan. Therefore, our study provides a potential therapeutic strategy that utilises a combination of DNA-damaging agents and autophagy inhibitors for the treatment of colon cancer with wild-type p53.

BACKGROUND: Autophagy is an evolutionarily conserved protein degradation pathway. A defect in autophagy may contribute to tumorigenesis. Autophagy inducers could have a potential function in tumor prevention and treatment. METHODOLOGY/PRINCIPAL FINDINGS: Our results showed that Rhabdastrellic acid-A, an isomalabaricane triterpenoid isolated from the sponge Rhabdastrella globostellata, inhibited proliferation of human cancer cell lines Hep3B and A549 and induced caspase-independent cell death in both the cell lines. Further investigation showed that Rhabdastrellic acid-A induced autophagy of cancer cells determined by YFP-LC3 punctation and increased LC3-II. The pretreatment with autophagy inhibitor 3-MA inhibited Rhabdastrellic acid-A-induced cell death. Knockdown of autophagy-related gene Atg5 inhibited Rhabdastrellic acid-A-induced cell death in A549 cells. Also, phospho-Akt and its downstream targets significantly decreased after treatment with Rhabdastrellic acid-A in both cancer cell lines. Transfection of constitutive active Akt plasmid abrogated autophagy and cell death induced by Rhabdastrellic acid-A. CONCLUSIONS/SIGNIFICANCE: These results suggest that Rhabdastrellic acid-A could induce autophagy-associated cell death through blocking Akt pathway in cancer cells. It also provides the evidence that Rhabdastrellic acid-A deserves further investigation as a potential anticancer or cancer preventive agent.

The scientific community has witnessed extensive developments and applications of organoboron compounds as synthetic elements and metal-free catalysts for the construction of small molecules, macromolecules, and functional materials over the last two decades. This review highlights the achievements of organoboron-mediated polymerizations in the past several decades alongside the mechanisms underlying these transformations from the standpoint of the polymerization mode. Emphasis is placed on free radical polymerization, Lewis pair polymerization, ionic (cationic and anionic) polymerization, and polyhomologation. Herein, alkylborane/O2 initiating systems mediate the radical polymerization under ambient conditions in a controlled/living manner by careful optimization of the alkylborane structure or additives; when combined with Lewis bases, the selected organoboron compounds can mediate the Lewis pair polymerization of polar monomers; the bicomponent organoboron-based Lewis pairs and bifunctional organoboron-onium catalysts catalyze ring opening (co)polymerization of cyclic monomers (with heteroallenes, such as epoxides, CO2, CO, COS, CS2, episulfides, anhydrides, and isocyanates) with well-defined structures and high reactivities; and organoboranes initiate the polyhomologation of sulfur ylides and arsonium ylides providing functional polyethylene with different topologies. The topological structures of the produced polymers via these organoboronmediated polymerizations are also presented in this review mainly including linear polymers, block copolymers, cyclic polymers, and graft polymers. We hope the summary and understanding of how organoboron compounds mediate polymerizations can inspire chemists to apply these principles in the design of more advanced organoboron compounds, which may be beneficial for the polymer chemistry community and organometallics/organocatalysis community. [ABSTRACT FROM AUTHOR]