Anti-angiogenesis in colorectal cancer therapy.

The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC.

M2 macrophage-derived exosomes induce angiogenesis and increase skin flap survival through HIF1AN/HIF-1α/VEGFA control.

BACKGROUND: Skin flap transplantation is a routine strategy in plastic and reconstructive surgery for skin-soft tissue defects. Recent research has shown that M2 macrophages have the potential for pro-angiogenesis during tissue healing. METHODS: In our research, we extracted the exosomes from M2 macrophages(M2-exo) and applied the exosomes in the model of skin flap transplantation. The flap survival area was measured, and the choke vessels were assessed by morphological observation. Hematoxylin and eosin (H&E) staining and Immunohistochemistry were applied to assess the neovascularization. The effect of M2-exo on the function of Human umbilical vein endothelial cells (HUVECs) was also investigated. We also administrated 2-methoxyestradiol (2-ME2, an inhibitor of HIF-1α) to explore the underlying mechanism. We tested the effects of M2-Exo on the proliferation of HUVECs through CCK8 assay and EdU staining assay. RESULTS: The survival area and number of micro-vessels in the skin flaps were increased in the M2-exo group. Besides, the dilation rate of choke vessels was also enhanced in the M2-exo group. Additionally, compared with the control group, M2-exo could accelerate the proliferation, migration and tube formation of HUVECs in vitro. Furthermore, the expression of the pro-angiogenesis factors, HIF-1α and VEGFA, were overexpressed with the treatment of the M2-exo. The expression of HIF1AN protein level was decreased in the M2-exo group. Finally, treatment with HIF-1α inhibitor reverses the pro-survival effect of M2-exo on skin flaps by interfering with the HIF1AN/HIF-1α/VEGFA signaling pathway. CONCLUSION: This study showed that M2-exosomes promote skin flap survival by enhancing angiogenesis, with HIF1AN/HIF-1α/VEGFA playing a crucial role in this process.

Construction and Validation of a Reliable Disulfidptosis-Related LncRNAs Signature of the Subtype, Prognostic, and Immune Landscape in Colon Cancer.

Disulfidptosis, a novel form of regulated cell death (RCD) associated with metabolism, represents a promising intervention target in cancer therapy. While abnormal lncRNA expression is associated with colon cancer development, the prognostic potential and biological characteristics of disulfidptosis-related lncRNAs (DRLs) remain unclear. Consequently, the research aimed to discover a novel indication of DRLs with significant prognostic implications, and to investigate their possible molecular role in the advancement of colon cancer. Here, we acquired RNA-seq data, pertinent clinical data, and genomic mutations of colon adenocarcinoma (COAD) from the TCGA database, and then DRLs were determined through Pearson correlation analysis. A total of 434 COAD patients were divided in to three subgroups through clustering analysis based on DRLs. By utilizing univariate Cox regression, the least absolute shrinkage and selection operator (LASSO) algorithm, and multivariate Cox regression analysis, we ultimately created a prognostic model consisting of four DRLs (AC007728.3, AP003555.1, ATP2B1.AS1, and NSMCE1.DT), and an external database was used to validate the prognostic features of the risk model. According to the Kaplan-Meier curve analysis, patients in the low-risk group exhibited a considerably superior survival time in comparison to those in the high-risk group. Enrichment analysis revealed a significant association between metabolic processes and the genes that were differentially expressed in the high- and low-risk groups. Additionally, significant differences in the tumor immune microenvironment landscape were observed, specifically pertaining to immune cells, function, and checkpoints. High-risk patients exhibited a low likelihood of immune evasion, as indicated by the Tumor Immune Dysfunction and Exclusion (TIDE) analysis. Patients who exhibit both a high risk and high Tumor Mutational Burden (TMB) experience the least amount of time for survival, whereas those belonging to the low-risk and low-TMB category demonstrate the most favorable prognosis. In addition, the risk groups determined by the 4-DRLs signature displayed distinct drug sensitivities. Finally, we confirmed the levels of expression for four DRLs through rt-qPCR in both tissue samples from colon cancer patients and cell lines. Taken together, the first 4-DRLs-based signature we proposed may serve for a hopeful instrument for forecasting the prognosis, immune landscape, and therapeutic responses in colon cancer patients, thereby facilitating optimal clinical decision-making.

Mechanosensitive channel MscL induces non-apoptotic cell death and its suppression of tumor growth by ultrasound.

Mechanosensitive channel of large conductance (MscL) is the most thoroughly studied mechanosensitive channel in prokaryotes. Owing to its small molecular weight, clear mechanical gating mechanism, and nanopore forming ability upon opening, accumulating studies are implemented in regulating cell function by activating mechanosensitive channel of large conductance in mammalian cells. This study aimed to investigate the potentials of mechanosensitive channel of large conductance as a nanomedicine and a mechano-inducer in non-small cell lung cancer (NSCLC) A549 cells from the view of molecular pathways and acoustics. The stable cytoplasmic vacuolization model about NSCLC A549 cells was established via the targeted expression of modified mechanosensitive channel of large conductance channels in different subcellular organelles. Subsequent morphological changes in cellular component and expression levels of cell death markers are analyzed by confocal imaging and western blots. The permeability of mitochondrial inner membrane (MIM) exhibited a vital role in cytoplasmic vacuolization formation. Furthermore, mechanosensitive channel of large conductance channel can be activated by low intensity focused ultrasound (LIFU) in A549 cells, and the suppression of A549 tumors in vivo was achieved by LIFU with sound pressure as low as 0.053 MPa. These findings provide insights into the mechanisms underlying non-apoptotic cell death, and validate the nanochannel-based non-invasive ultrasonic strategy for cancer therapy.

Low strength wastewater anammox start-up and stable operation by inoculating sponge-iron sludge: Cooperation of biological iron and iron bacteria.

The application of anaerobic ammonium oxidation (Anammox) technology in low-strength wastewater treatment still faces difficult in-situ start-ups and unstable operations. Sponge-iron sludge (R1) was used as a novel inoculum to provide a promising solution. Conventional activated sludge (R0) was used as the control. However, little is known about the feasibility and performance during the start-up and operation of Anammox combined with biological iron and iron bacteria in an iron sludge system. Anammox was successfully started both in R1 (87 days) and R0 (89 days) with a low-strength influent (with a nitrogen loading rate (NLR) of 43.64 ± 0.41 g N/(m3⋅d)). During long-term operation, the R0 nevertheless produced higher nitrates (9.7 ± 0.1 mg/L) than expected. In contrast, R1 presented no excess nitrate production (2.1 ± 0.06 mg/L). The total inorganic nitrogen (TIN) removal efficiency increased from 78.2 ± 7.1% in R0 to 86.1 ± 4.3% in R1. The iron sludge in R1 was divided equally into three parts and three different nitrogen-feeding methods were used over the 34 days of operation, as follows: first using a mixture of ammonium (27.15 ± 1.0 mg/L) and nitrite (32.7 ± 1.7 mg/L), then only ammonium (27.15 ± 1.0 mg/L) and lastly only nitrite (32.7 ± 1.7 mg/L) as the influent. R1 was a coupled system composed of Anammox, Feammox, and NOx--dependent Fe(II) oxidation (NDFO). The contribution of Feammox and NDFO to TIN removal was 27.1 ± 1.2% and 31.9 ± 0.7%. However, Anammox was the primary nitrogen transformation pathway. X-ray diffraction (XRD) analysis shows that iron hydroxide (Fe(OH)3) and iron oxide hydroxide (FeOOH) were generated in R1. The produced Fe(OH)3 and FeOOH were capable of participating in Feammox and formed a Fe(II)/Fe(III) cycle which further removed nitrogen. Therefore, a highly stable and impressive nitrogen removal performance was demonstrated in the iron sludge Anammox system under the cooperation of biological iron and iron bacteria. The study considered the enrichment of norank_c_OM190, Desulfuromonas, and Thiobacillus and their contribution to the Anammox, Feammox, and NDFO processes, respectively. This study provides a new perspective for the start-up and stable operation of low-strength wastewater Anammox engineering applications.

Gut microbiota composition influences outcomes of skeletal muscle nutritional intervention via blended protein supplementation in posttransplant patients with hematological malignancies.

BACKGROUND: Skeletal muscle atrophy is an important and independent predictor of survival after hematopoietic stem cell transplantation (HSCT). Our previous study found that soy-whey blended protein (SWP) can improve muscle mass in acute leukemia patients. OBJECTIVE: We aimed to explore potential factors that influence muscle outcomes after nutritional intervention. METHODS: In this case-control study, 13 patients who received HSCT and failed to improve muscle function within half a year were included. After two months of SWP intervention, the subjects were divided into two groups (MSI: muscle status improved; MNI: muscle status not improved). 16S rDNA sequencing, principal coordinate analysis (PCoA) and the PICRUSt algorithm were used to analyze the composition, structure and function of the intestinal microbiota between the groups. This study was registered in the Chinese Clinical Trial Registry (ChiCTR 1800017765). RESULTS: SWP significantly improved muscle status (muscle area: from 330.4 mm2 to 384.8 mm2, p = 0.02; muscle strength: from 19.2 kg to 21.3 kg, p = 0.04). However, there were a small number of subjects whose muscle status was not effectively improved. After SWP intervention, the diversity (Shannon: from 1.7 to 3.8, p = 0.01; Simpson: from 0.6 to 0.8, p = 0.015) of the intestinal microbiota in the MSI group increased significantly, whereas that in the MNI group did not. Principal component analysis (PCA) revealed separate groupings of the microbiota of the Baseline-MSI and Endpoint-MSI time points in the MSI group. Opposite patterns of microbial abundance change were found between the MSI group (75% of changed genera were increased) and the MNI group (80% of changed genera were decreased). Three bacterial taxa (negative correlation: Streptococcus; positive correlations: Ruminococcus and Veillonella) were significantly related to muscle improvement outcomes. Both pentose phosphate (p = 0.048) and amino acid biosynthesis (p = 0.039), which are related to muscle metabolism, were found to be significantly changed in the MSI group through PICRUSt algorithm prediction. CONCLUSIONS: Our results suggest that the intestinal microbiota plays important roles in the regulation of muscle metabolism.

Association of body mass index and smoking on outcome of Chinese patients with colorectal cancer.

BACKGROUND: The impact of body mass index (BMI) on the prognosis of patients with colorectal cancer remains largely unknown, particularly in Asian populations. Therefore, the aim of this study was to examine the influence of BMI on clinicopathological characteristics and mortality of Chinese colorectal cancer patients. METHODS: The study cohort consisted of 525 patients who were diagnosed with colorectal cancer and underwent radical surgery at the second hospital of Harbin Medical University between June 2004 and August 2011. Study participants were divided into two BMI categories: normal weight (BMI <23 kg/m²) and overweight (BMI ≥23 kg/m²). RESULTS: Of 525 patients, 208 patients (39.6%) were included in the normal-weight group and 317 patients were included in the overweight group. During the mean follow-up period of 48.8 months, 89 patients had disease recurrence and 131 deaths occurred. High BMI was significantly correlated with younger age, presence of diabetes, alcohol consumption, distal colon tumors, amount of lymph node harvested and pathological stage. No statistically significant correlation was found between high BMI and progression-free survival (PFS) or overall survival (OS) when the total group of patients was considered (P = 0.077 and P = 0.701, respectively). Cigarette-smoking patients had significantly shorter OS than patients who had never smoked (hazard ratio = 1.613, 95% confidence interval = 1.133 to 2.296; P = 0.008), and this difference in OS remained significant in multivariate analysis. Cigarette-smoking patients did not have significantly different PFS compared with patients who had never smoked. CONCLUSION: There was no significant correlation between obesity and outcomes of patients with colorectal cancer. In addition, our findings support the claims that cigarette smoking may be partially responsible for the divergent mortality of patients with colorectal cancer.