Bioactivities and Synergistic Effect of Elsholtzia ciliata Essential Oil and Its Main Components against Lasioderma serricorne.

Investigations have shown that storage bugs seriously harm grains during storage. In the interim, essential oils (EOs) have been proven to be a good botanical pesticide. The anti-Lasioderma serricorne properties of Elsholtzia ciliata essential oil, which was obtained by steam distillation, were evaluated using DL-limonene, carvone, and their two optical isomer components using contact, repelling, and fumigation techniques. Simultaneously, the fumigation, contact, and repellent activities of carvone and its two optical isomers mixed with DL-limonene against L. serruricorne were evaluated. The results showed that E. ciliata, its main components (R-carvone, DL-limonene), and S-carvone exhibited both fumigations (LC50 = 14.47, 4.42, 20.9 and 3.78 mg/L) and contact (LD50 = 7.31, 4.03, 28.62 and 5.63 µg/adult) activity against L.serricorne. A binary mixture (1:1) of R-carvone and DL-limonene displayed an obvious synergistic effect. A binary mixture (1:1) of carvone and its two optical isomers exhibited an obvious synergistic effect, too. Furthermore, the repellent activity of the EO, carvone, and its two optical isomers, DL-limonene, and a combination of them varied. To stop insect damage during storage, E. ciliata and its components can be utilized as bio-insecticides.

Angiotensin II type-2 receptor signaling facilitates liver injury repair and regeneration via inactivation of Hippo pathway.

The angiotensin II type 2 receptor (AT2R) is a well-established component of the renin-angiotensin system and is known to counteract classical activation of this system and protect against organ damage. Pharmacological activation of the AT2R has significant therapeutic benefits, including vasodilation, natriuresis, anti-inflammatory activity, and improved insulin sensitivity. However, the precise biological functions of the AT2R in maintaining homeostasis in liver tissue remain largely unexplored. In this study, we found that the AT2R facilitates liver repair and regeneration following acute injury by deactivating Hippo signaling and that interleukin-6 transcriptionally upregulates expression of the AT2R in hepatocytes through STAT3 acting as a transcription activator binding to promoter regions of the AT2R. Subsequently, elevated AT2R levels activate downstream signaling via heterotrimeric G protein Gα12/13-coupled signals to induce Yap activity, thereby contributing to repair and regeneration processes in the liver. Conversely, a deficiency in the AT2R attenuates regeneration of the liver while increasing susceptibility to acetaminophen-induced liver injury. Administration of an AT2R agonist significantly enhances the repair and regeneration capacity of injured liver tissue. Our findings suggest that the AT2R acts as an upstream regulator in the Hippo pathway and is a potential target in the treatment of liver damage.

Bidirectional two-sample Mendelian randomization analysis identifies causal associations between cardiovascular diseases and frozen shoulder.

BACKGROUND: Although prior observational studies indicate an association between cardiovascular diseases (CVDs) and frozen shoulder (FS), the potential causal relationship between them remains uncertain. This study aims to explore the genetic causal relationship between CVDs and FS using Mendelian randomization (MR). METHODS: Genetic variations closely associated with FS were obtained from the FinnGen Consortium. Summary data for CVD, including atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), myocardial infarction (MI), stroke, and ischemic stroke (IS), were sourced from several large-scale genome-wide association studies (GWAS). MR analysis was performed using inverse variance weighting (IVW), MR Egger, and weighted median methods. IVW, as the primary MR analysis method, complemented by other sensitivity analyses, was utilized to validate the robustness of the results. Further reverse MR analysis was conducted to explore the presence of reverse causal relationships. RESULTS: In the forward MR analysis, genetically determined risk of stroke and IS was positively associated with FS (OR [95% CI] = 1.58 (1.23-2.03), P < 0.01; OR [95% CI] = 1.46 (1.16-1.85), P < 0.01, respectively). There was no strong evidence of an effect of genetically predicted other CVDs on FS risk. Sensitivity analyses confirmed the robustness of the results. In the reverse MR analysis, no causal relationships were observed between FS and various CVDs. CONCLUSION: The study suggests that stroke increases the risk of developing FS. However, further basic and clinical research is needed to substantiate our findings.

The biochemically defined super relaxed state of myosin-A paradox.

The biochemical SRX (super-relaxed) state of myosin has been defined as a low ATPase activity state. This state can conserve energy when the myosin is not recruited for muscle contraction. The SRX state has been correlated with a structurally defined ordered (versus disordered) state of muscle thick filaments. The two states may be linked via a common interacting head motif (IHM) where the two heads of heavy meromyosin (HMM), or myosin, fold back onto each other and form additional contacts with S2 and the thick filament. Experimental observations of the SRX, IHM, and the ordered form of thick filaments, however, do not always agree, and result in a series of unresolved paradoxes. To address these paradoxes, we have reexamined the biochemical measurements of the SRX state for porcine cardiac HMM. In our hands, the commonly employed mantATP displacement assay was unable to quantify the population of the SRX state with all data fitting very well by a single exponential. We further show that mavacamten inhibits the basal ATPases of both porcine ventricle HMM and S1 (Ki, 0.32 and 1.76 µM respectively) while dATP activates HMM cooperatively without any evidence of an SRX state. A combination of our experimental observations and theories suggests that the displacement of mantATP in purified proteins is not a reliable assay to quantify the SRX population. This means that while the structurally defined IHM and ordered thick filaments clearly exist, great care must be employed when using the mantATP displacement assay.

Erratum: MicroRNA-449a Inhibits Tumor Metastasis through AKT/ERK1/2 Inactivation by Targeting Steroid Receptor Coactivator (SRC) in Endometrial Cancer: Erratum.

[This corrects the article DOI: 10.7150/jca.27748.].

dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.

Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ∼1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.

Evaluating the role of IDO1 macrophages in immunotherapy using scRNA-seq and bulk-seq in colorectal cancer.

Background: Macrophage infiltration is crucial for colorectal cancer (CRC) immunotherapy. Detailed classification of macrophage subsets will facilitate the selection of patients suitable for immunotherapy. However, the classification of macrophages in CRC is not currently detailed. Methods: In this study, we combined single-cell RNA sequencing (scRNA-seq) and bulk-seq to analyze patients with colorectal cancer. scRNA-seq data were used to study cell-cell communication and to differentiate immune-infiltrating cells and macrophage subsets. Bulk-seq data were used to further analyze immune infiltration, clinical features, tumor mutational burden, and expression of immune checkpoint molecules in patients with CRC having different macrophage subsets. Results: Seven macrophage subpopulations were identified, among which indoleamine 2,3 dioxygenase 1 (IDO1) macrophages had the most significant difference in the degree of infiltration among normal, microsatellite-unstable, and microsatellite-stable populations. We then performed gene set variation analysis using 12 marker genes of IDO1 macrophages and divided the patients into two clusters: high-IDO1 macrophages (H-IDO1M) and low-IDO1 macrophages (L-IDO1M). H-IDO1M showed higher infiltration of immune cells, higher expression of immune checkpoints, and less advanced pathological stages than L-IDO1M (p < 0.05). Conclusions: This study elucidated that IDO1-macrophage-based molecular subtypes can predict the response to immunotherapy in patients with CRC. The results provide new insights into tumor immunity and help in clinical decisions regarding designing effective immunotherapy for these patients.

Acute toxicity of Zanthoxylum bungeanum against two stored product insects and synergistic interactions between two major compounds limonene and linalool.

In order to find and develop new botanical pesticides against storage pests, components of the essential oil (EO) from Zanthoxylum bungeanum were identified by GC-MS and their insecticidal activity against the stored product pests were studied. The EO was obtained by steam distillation. Results showed that EO was rich in limonene (23.67), linalool (21.76) and linalyl anthranilate (10.87). In contact assays, linalool exhibited strongest toxicity to red flour beetle adult (LD50 = 17.06 µg/adult) and larvae (LD50 = 16.42 µg/larvae), and linalool was the most active one against the Lasioderma serricorne (LD50 = 15.36 µg/larvae). Then limonene and linalool showed different levels of fumigant activities against the two insect species. Synergism effect existed in the proportion of contact assays against Tribolium castaneum adults, and additive was observed in the proportion of 7:1 against T. castaneum larvae. This work provides important information for the development and utilization of Z. bungeanum and suggests that the EO of Z. bungeanum has the potential to serve as bio-insecticides for controlling pest damage in stored products.

Identification of Energy Metabolism-Related Gene Signatures From scRNA-Seq Data to Predict the Prognosis of Liver Cancer Patients.

The increasingly common usage of single-cell sequencing in cancer research enables analysis of tumor development mechanisms from a wider range of perspectives. Metabolic disorders are closely associated with liver cancer development. In recent years, liver cancer has been evaluated from different perspectives and classified into different subtypes to improve targeted treatment strategies. Here, we performed an analysis of liver cancer from the perspective of energy metabolism based on single-cell sequencing data. Single-cell and bulk sequencing data of liver cancer patients were obtained from GEO and TCGA/ICGC databases, respectively. Using the Seurat R package and protocols such as consensus clustering analysis, genes associated with energy metabolism in liver cancer were identified and validated. An energy metabolism-related score (EM score) was established based on five identified genes. Finally, the sensitivity of patients in different scoring groups to different chemotherapeutic agents and immune checkpoint inhibitors was analyzed. Tumor cells from liver cancer patients were found to divide into nine clusters, with cluster 4 having the highest energy metabolism score. Based on the marker genes of this cluster and TCGA database data, the five most stable key genes (ADH4, AKR1B10, CEBPZOS, ENO1, and FOXN2) were identified as energy metabolism-related genes in liver cancer. In addition, drug sensitivity analysis showed that patients in the low EM score group were more sensitive to immune checkpoint inhibitors and chemotherapeutic agents AICAR, metformin, and methotrexate.

YAP derived circ-LECRC functions as a "brake signal" to suppress hyperactivation of oncogenic YAP signalling in colorectal cancer.

Accumulating evidence indicates that circular RNAs (circRNAs) play vital roles in tumorigenesis by modulating gene expression. However, the molecular mechanisms underlying the functions of circRNAs remain largely unknown. Here, we demonstrated that a Yes1 associated transcriptional regulator (YAP1)-derived circRNA, circ-LECRC (circRNA low expressed in CRC), was significantly downregulated in colorectal cancer (CRC). High expression of circ-LECRC positively correlated with a lower TNM stage and good prognosis in CRC patients. Circ-LECRC overexpression significantly inhibited CRC cell proliferation, migration, and invasion and promoted apoptosis (P < 0.05). Additionally, we performed xenograft and lung metastasis experiments by injecting CRC cells into nude mice to mechanistically demonstrate that circ-LECRC directly binds to miR-135b-5p and relieve the suppression of its target, Krüppel-like factor 4 (KLF4). Furthermore, we found that both circ-LECRC and KLF4 inhibited YAP1 hyperactivation, which downregulates the expression of the downstream genes of the YAP1 pathway, such as EGFR, MYC, BIRC5, and CTGF. In summary, circ-LECRC regulates KLF4 expression by functioning as a competing endogenous RNA and serves as a "brake signal" to suppress hyperactivation of oncogenic YAP signalling, leading to tumour growth inhibition in CRC.

Nucleosides and amino acids, isolated from Cordyceps sinensis, protected against cyclophosphamide-induced myelosuppression in mice.

The material basis of Cordyceps sinensis (Berk.) Sacc has not yet been well understood and natural C. sinensis resources are very rare. The present study aimed to clarify the substance basis and compare the protective effect of natural and artificially-cultivated C. sinensis against cyclophosphamide (CTX)-induced myelosuppression. Both natural and artificially-cultivated C. sinensis effectively improved CTX-induced decrease of peripheral blood counts and hemopoietic growth factors, pathological changes, and apoptosis of bone marrow. Importantly, artificially-cultivated C. sinensis showed similar capacity compared with natural C. sinensis. Uridine (1), adenosine (2), L-pyroglutamic acid (3), lysinonorleucine (4), 1,3,5-trimethoxybenzene (5), D-mannitol (6), L-pyroglutamic acid methyl ester (7), tryptophan (8), and phenylalanine (9) were isolated from bioactivity-guided fraction and identified to attenuate CTX-induced myelosuppression in mice. In conclusions, nucleosides and amino acids represented the effective chemical components in C. sinensis. Artificial cultivation can be used as an effective substitute for natural C. sinensis.

Chemical Constituents of the Essential Oil Extracted from Elsholtzia densa and Their Insecticidal Activity against Tribolium castaneum and Lasioderma serricorne.

Storage pests pose a great threat to global food security. Here, we found that the essential oil (EO) extracted from E. densa possesses obvious effects against the insects that threaten stored-products. In this work, we investigated the chemical constituents of the essential oil extracted from Elsholtzia densa, and their insecticidal (contact and fumigant) toxicity against Tribolium castaneum and Lasioderma serricorne. A total of 45 compounds were identified by GC-MS, accounting for 98.74% of the total EO. Meanwhile, 11 compounds were isolated from the EO, including limonene, ß-caryophyllene, ρ-cymene, trans-phytol, α-terpineol, linalool, acetophenone, 1,8-cineole, ρ-cymen-7-ol, 1-O-cerotoylgly-cerol, and palmitic acid. Furthermore, acetophenone, ρ-cymen-7-ol, and 1-O-cerotoylgly-cerol were isolated for the first time from Elsholtzia spp. The results of the bioassays indicated that the EO had the property of insecticidal toxicity against T. castaneum and L. serricorne. All of the compounds showed different levels of insecticidal toxicity against the two species of insects. Among them, 2-ethyl-1H-imidazole had no insecticidal toxicity against T. castaneum, but possessed fumigant and obvious contact toxicity against L. serricorne. ρ-Cymen-7-ol had beneficial insecticidal toxicity against the two species of insects, and fumigant toxicity against L. serricorne. ρ-Cymen-7-ol (LD50 = 13.30 µg/adult), 1-octen-3-ol (LD50 = 13.52 µg/adult), and 3-octanol (LD50 = 17.45 µg/adult) showed significant contact toxicity against T. castaneum. Acetophenone (LD50 = 7.07 µg/adult) and ρ-cymen-7-ol (LD50 = 8.42 µg/adult) showed strong contact toxicity against L. serricorne. ρ-Cymene (LC50 = 10.91 mg/L air) and ρ-cymen-7-ol (LC50 = 10.47 mg/L air) showed powerful fumigant toxicity to T. castaneum. Limonene (LC50 = 5.56 mg/L air), acetophenone (LC50 = 5.47 mg/L air), and 3-octanol (LC50 = 5.05 mg/L air) showed obvious fumigant toxicity against L. serricorne. In addition, the EO and its chemical compounds possessed different levels of repellent activity. This work provides some evidence of the value of exploring these materials for insecticidal activity, for human health purposes. We suggest that the EO extracted from E. densa may have the potential to be developed as an insecticidal agent against stored product insect pests.

Establishment and Validation of a Genetic Label Associated With M2 Macrophage Infiltration to Predict Survival in Patients With Colon Cancer and to Assist in Immunotherapy.

BACKGROUND: Colon cancer is a malignant tumor with high morbidity and mortality. Researchers have tried to interpret it from different perspectives and divided it into different subtypes to facilitate individualized treatment. With the rise in the use of immunotherapy, its value in the field of tumor has begun to emerge. From the perspective of immune infiltration, this study classified colon cancer according to the infiltration of M2 macrophages in patients with colon cancer and further explored the same. METHODS: Cibersort algorithm was used to analyze the level of immune cell infiltration in patients with colon cancer in The Cancer Genome Atlas (TCGA) database. Weighted gene co-expression network analysis (WGCNA), Consensus Clustering analysis, Lasso analysis, and univariate Kaplan-Meier analysis were used to screen and verify the hub genes associated with M2 macrophages. Principal component analysis (PCA) was used to establish the M2 macrophage-related score (M2I Score). The correlation between M2I Score and somatic cell variation and microsatellite instability (MSI) were analyzed. Furthermore, the correlation between M2 macrophage score and differences in immunotherapy sensitivity was also explored. RESULTS: M2 macrophage infiltration was associated with poor prognosis. Four hub genes (ANKS4B, CTSD, TIMP1, and ZNF703) were identified as the progression-related genes associated with M2 macrophages. A stable and accurate M2I Score for M2 macrophages used in colon adenocarcinoma was determined based on four hub genes. The M2I Score was positively correlated with the tumor mutation load (TMB). The M2I Score of the group with high instability of microsatellites was higher than that of the group with low instability of microsatellites and microsatellite-stable group. Combined with the Cancer Immunome Atlas database, we concluded that patients with high M2I Scores were more sensitive to programmed cell death protein 1 (PD-1) inhibitors and PD-1 inhibitors combined with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors. The low-rating group may have better efficacy without immune checkpoint inhibitors or with CTLA4 inhibitors alone. CONCLUSION: Four prognostic hub genes associated with M2 macrophages were screened to establish the M2I Score. Patients were divided into two subgroups: high M2I Score group and low M2I Score group. TMB, MSI, and sensitivity to immunotherapy were higher in the high-rated group. PD-1 inhibitors or PD-1 combined with CTLA-4 inhibitors are preferred for patients in the high-rated group who are more sensitive to immunotherapy.

Potential Impact of ALKBH5 and YTHDF1 on Tumor Immunity in Colon Adenocarcinoma.

BACKGROUND: ALKBH5 and YTHDF1 are regarded as the eraser and reader, respectively, in N6-methyladenosine (m6A) modification. Recently, immune contexture has been drawing increasing attention in terms of the progression and treatment of cancers. This study aimed to determine the relationship between ALKBH5/YTHDF1 and immunological characteristics of colon adenocarcinoma (COAD). METHODS: Expression of ALKBH5 and YTHDF1 was investigated across TCGA and GEO validated in our study. Patients with COAD were divided into two clusters using consensus clustering based on the expression of ALKBH5 and YTHDF1. We then compared their clinical characteristics and performed gene set enrichment analysis (GSEA) to identify the functional differences. Immune infiltration analyses were conducted using ESTIMATE, CIBERSORT, and ssGSEA. In addition, we evaluated the expression of the targets of immune checkpoint inhibitors (ICIs) and calculated the tumor mutation burden (TMB) of the tumor samples. Weighted gene co-expression network analysis (WGCNA) was used to identify the genes related to both ALKBH5/YTHDF1 expression and immunity. GSE39582 was utilized for external validation of immunological features between the two clusters. RESULTS: Cluster 2 had high expression of ALKBH5 and lesser so of YTHDF1, whereas Cluster 1 had just the reverse. Cluster 1 had a higher N stage and pathological stage than Cluster 2. The latter had stronger immune infiltration, higher expression of targets of ICIs, more TMB, and a larger proportion of deficiency in mismatch repair-microsatellite instability-high (dMMR-MSI-H) status than Cluster 1. Moreover, WGCNA revealed 14 genes, including PD1 and LAG3, related to both the expression of ALKBH5/YTHDF1 and immune scores. CONCLUSIONS: ALKBH5 and YTHDF1 influence immune contexture and can potentially transform cold tumors into hot tumors in patients with COAD.

Insecticidal and acetylcholine esterase inhibition activity of Rhododendron thymifolium essential oil and its main constituent against two stored product insects.

In this work, we investigated the bioactivities of the essential oil (EO) extracted from the Rhododendron thymifolium and its principal germacrone against Lasioderma serricorne and Tribolium castaneum. The EO was obtained by steam distillation. Germacrone was obtained by cryogenic crystallization. The bioactivity of EO and germacrone was tested via contact and repellent activity assays. The results showed that EO and germacrone possessed contact and repellent activities against two species of insects. EO exhibited obvious contact activity against the L. serricorn adults, larvae and T. castaneum larvae with LD50 values of 29.15 µg/adult, 42.73 µg/larva, 19.65 µg/larva respectively. Germacrone exhibited excellent contact activity against the L. serricorne adults, larvae and the T. castaneum larvae with LD50 values of 17.18 µg/adult, 20.94 µg/larva, 20.93 µg/larva respectively. And at the highest testing concentrations (78.63 and 15.73 nL/cm2), the repellent activity of EO and germacrone on two target insects was comparable to that of the positive control (DEET) after 30 h exposure. In especially, in the treatment of the 120 h after the repellent activity of EO and germacrone against T.castaneum adults and larvae were still very significant and showed the same level percentage repellency as DEET. Meanwhile, germacrone exhibited inhibition of acetylcholinesterase activity with IC50 values of 3%. The results indicated that the EO of R. thymifolium and germacrone had the potential to be developed as natural insecticides and repellents for the control of T. castaneum and L. serricorne.

Efficacy of transanal drainage tube and self-expanding metallic stent in acute left malignant colorectal obstruction.

BACKGROUND: The self-expanding metal stent (SEMS) or transanal drainage tube (TDT) methods can be used as a palliative treatment before tumor resection surgery. Studies systematically comparing the efficacy and characteristics between SEMS with TDT are limited, especially in a large-scale Chinese population. This retrospective study aimed to compare the outcomes of these treatment approaches. METHODS: This was a retrospective comparative study of patients with an acute malignant left colorectal obstruction who underwent a preoperative decompressive procedure with SEMS or TDT intervention between December 2014 and October 2017. The indicators after endoscopic treatment and tumor resection surgery between the SEMS and TDT groups were compared. RESULTS: 206 patients underwent endoscopic intervention to relieve obstruction, including 139 patients treated with SEMS and 67 patients treated with TDT. The technical success rates of the SEMS group and TDT group were 97.1% and 95.6%, respectively, and the rates of obstruction relief were 92.8% and 86.6%, respectively. TDT was more easily translocated than SEMS (P=0.02), and there was no significant difference in the incidence of other complications. However, SEMS had a lower complication rate than TDT (P=0.02), and could alleviate the obstruction faster (P<0.01). There were 72 patients and 44 patients who took resection surgery in the SEMS group and TDT group, respectively. The direct anastomosis rates were 73.6% and 63.6% (P=0.26), respectively, and only 1 case in the TDT group had anastomotic leakage. The surgery time of the SEMS group was significantly shorter than that of the TDT group (P=0.01). There was no significant difference between the 2 groups in terms of postoperative hospital stay (P=1.00) or total treatment costs for patients undergoing surgery (P=0.26). CONCLUSIONS: Both TDT and SEMS could effectively relieve acute left malignant colorectal obstruction with safe and reliable results, and they could both reduce the stomas rate compared with traditional surgery. SEMS could alleviate obstruction faster than TDT and had fewer complications.

Association between body mass index and survival outcomes for cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been increasingly applied in the treatment of several kinds of malignancies. Some clinical demographic characteristics were reported to be associated with the ICIs efficacy. The purpose of our current meta-analysis was to clearly evaluated the relationship between BMI and ICIs efficacy for cancer patients receiving immunotherapy. METHODS: A systematic search of Pubmed, EMBASE and conference proceedings was performed to investigate the influence of BMI on ICIs efficacy. Pooled analysis for overall survival (OS), progression-free survival (PFS) and immune-related adverse effects (IRAEs) were analyzed in current study. RESULTS: A total of 13 eligible studies comprising 5279 cancer patients treated with ICIs were included in the analysis. The pooled analysis showed there is positive association between high BMI and improved OS and PFS among patients with ICIs treatment (OS: HR = 0.62, 95% CI 0.55-0.71, P < 0.0001; I2 = 26.3%, P = 0.202); PFS: HR = 0.71, 95% CI 0.61-0.83, P < 0.0001; I2 = 0%, P = 0.591). There is no significant difference between the incidence of all grade IRAEs between obese, overweight patients and normal patients (Overweight vs Normal: pooled RR = 1.28, 95% CI 0.76- 2.18, P = 0.356; Obese vs Normal: pooled RR = 1.36, 95% CI 0.85- 2.17, P = 0.207). CONCLUSION: An improved OS and PFS were observed in patients with high BMI after receiving ICIs treatment compared with patients of low BMI. No significant association between BMI and incidence of IRAEs was found in cancer patients after ICIs treatment.

LINC02595 promotes tumor progression in colorectal cancer by inhibiting miR-203b-3p activity and facilitating BCL2L1 expression.

Colorectal cancer (CRC) is one of the most prevalent tumors worldwide. Recently, long noncoding RNAs (lncRNAs) have been recognized as key regulators in postgenomic biology. Numerous lncRNAs have been identified as diagnostic biomarkers and therapeutic targets. However, the molecular mechanisms underlying the role of lncRNAs in CRC progression are not fully understood. Differentially expressed lncRNAs and messenger RNAs were investigated using a microarray approach in five paired primary CRC tumor tissues and the corresponding nontumor tissues and confirmed in an additional 116 paired tissues and 21 inflammatory bowel disease tissues and 15 adjacent normal tissues by a quantitative real-time polymerase chain reaction. We also performed comprehensive transcriptome profiling analysis on Gene Expression Omnibus and The Cancer Genome Atlas datasets. We identified LINC02595 and evaluated its clinical significance as a plasma biomarker. The function of LINC02595 was evaluated using a panel of in vivo and vitro assays, including cell counting kit-8, colony formation, cell cycle, apoptosis, RNA fluorescence in situ hybridization, luciferase reporter, immunohistochemistry, and CRC xenografts. We found that LINC02595 is upregulated in tumor tissues and blood samples of patients with CRC and CRC cell lines. Functional research found that LINC02595 promotes CRC cell growth, influences the cell cycle, and reduces apoptosis in vitro and vivo. Mechanistically, LINC02595 promoted BCL2-like 1 (BCL2L1) expression through miR-203b-3p sponging. Our research demonstrated that LINC02595 is an oncogene in CRC and established the presence of a LINC02595-miR-203b-BCL2L1 axis in CRC, which might provide a new diagnostic biomarker and therapeutic targets for the treatment of this disease.

Soft tissue release combined with joint-sparing osteotomy for treatment of cavovarus foot deformity in older children: Analysis of 21 cases.

BACKGROUND: Cavovarus foot is a common form of foot deformity in children, which is clinically characterized by an abnormal increase of the longitudinal arch of the foot, and it can be simultaneously complicated with forefoot pronation and varus, rearfoot varus, Achilles tendon contracture, or cock-up toe deformity. Muscle force imbalance is the primary cause of such deformity. Many diseases can lead to muscle force imbalance, such as tethered cord syndrome, cerebral palsy, Charcot-Marie-Tooth disease, and trauma. At present, many surgical treatments are available for cavovarus foot. For older children, priority should be given to midfoot osteotomy and fusion. Since complications such as abnormal foot length, foot stiffness, and abnormal gait tend to develop postoperatively, it is important to preserve the joints and correct the deformity as much as possible. Adequate soft tissue release and muscle balance are the keys to correcting the deformity and avoiding its postoperative recurrence. AIM: To assess the efficacy of soft tissue release combined with joint-sparing osteotomy in the treatment of cavovarus foot deformity in older children. METHODS: The clinical data of 21 older children with cavovarus foot deformity (28 feet) who were treated surgically at the Ninth Department of Orthopedics of Jizhong Energy Xingtai Mining Group General Hospital from November 2014 to July 2017 were retrospectively analyzed. The patients ranged in age from 10 to 14 years old, with an average age of 12.46 ± 1.20 years. Their main clinical manifestations were deformity, pain, and gait abnormality. The patients underwent magnetic resonance imaging of the lumbar spine, electromyographic examination, weight-bearing anteroposterior and lateral X-rays of the feet, and the Coleman block test. Surgical procedures including metatarsal fascia release, Achilles tendon or medial gastrocnemius lengthening, "V"-shaped osteotomy on the dorsal side of the metatarsal base, opening medial cuneiform wedge osteotomy, closing cuboid osteotomy, anterior transfer of the posterior tibial tendon, peroneus longus-to-brevis transfer, and calcaneal sliding osteotomy to correct hindfoot varus deformity were performed. After surgery, long leg plaster casts were applied, the plaster casts were removed 6 wk later, Kirschner wires were removed, and functional exercise was initiated. The patients began weight-bearing walk 3 mo after surgery. Therapeutic effects were evaluated using the Wicart grading system, and Meary's angles and Hibbs' angles were measured based on X-ray images obtained preoperatively and at last follow-up to assess their changes. RESULTS: The patients were followed for 6 to 32 mo, with an average follow-up period of 17.68 ± 6.290 mo. Bone healing at the osteotomy site was achieved at 3 mo in all cases. According to the Wicart grading system, very good results were achieved in 18 feet, good in 7, and fair in 3, with a very good/good rate of 89.3%. At last follow-up, mean Meary's angle was 6.36° ± 1.810°, and mean Hibbs' angle was 160.21° ± 4.167°, both of which were significantly improved compared with preoperative values (24.11° ± 2.948° and 135.86° ± 5.345°, respectively; P < 0.001 for both). No complications such as infection, skin necrosis, or bone nonunion occurred. CONCLUSION: Soft tissue release combined with joint-sparing osteotomy has appreciated efficacy in the treatment of cavovarus foot deformity in older children.

Suppressive effect of microRNA-449a on the NDRG1/PTEN/AKT axis regulates endometrial cancer growth and metastasis.

Database screening indicated that microRNAs (miRNAs) are involved in pathogenesis of endometrial cancer. Among these miRNAs, miR-449a might be involved in tumorigenesis and lower expression of miR-449a was associated with poor prognosis. However, the role of miR-449a and its underlying molecular mechanism in endometrial cancer (EC) has not been investigated. In this study, our analysis found that miR-449a expression is inversely correlated with the stage of EC. Downregulation of miR-449a was correlated with tumor progression and poor prognosis in the EC patients. Results of functional analyses revealed that overexpression of miR-449a in human EC cells alleviated cell proliferation, invasion and metastasis. Conversely, loss of miR-449a in EC cancer cells facilitated all these cellular activities. Moreover, we identified N-myc downstream-regulated gene 1 (NDRG1) as a direct and functional target gene of miR-449a in EC cells, and the expression of NDRG1 in 87 EC specimens were inversely correlated with that of miR-449a. Additionally, further studies show that the down-regulation of NDRG1 expression inhibited proliferation and metastasis of EC cells through the PTEN/AKT pathway. Therefore, these results suggest that miR-449a suppresses the growth and metastasis of EC by directly targeting the NDRG1 gene and that the activation of miR-449a may represent an effective therapeutic strategy in EC.