Immunocytes interact directly with cancer cells in the tumor microenvironment: one coin with two sides and future perspectives.

The tumor microenvironment is closely linked to the initiation, promotion, and progression of solid tumors. Among its constitutions, immunologic cells emerge as critical players, facilitating immune evasion and tumor progression. Apart from their indirect impact on anti-tumor immunity, immunocytes directly influence neoplastic cells, either bolstering or impeding tumor advancement. However, current therapeutic modalities aimed at alleviating immunosuppression from regulatory cells on effector immune cell populations may not consistently yield satisfactory results in various solid tumors, such as breast carcinoma, colorectal cancer, etc. Therefore, this review outlines and summarizes the direct, dualistic effects of immunocytes such as T cells, innate lymphoid cells, B cells, eosinophils, and tumor-associated macrophages on tumor cells within the tumor microenvironment. The review also delves into the underlying mechanisms involved and presents the outcomes of clinical trials based on these direct effects, aiming to propose innovative and efficacious therapeutic strategies for addressing solid tumors.

Enhanced denitrification using high-molecular-weight poly(lactic acid) blended with lactide as an effective carbon source.

The utilization of wasted Poly(lactic acid) (PLA) as low-cost carbon sources in solid-phase denitrification is hindered by its low biodegradability, which can be attributed to its high molecular weight. This study presents a new approach by blending high-molecular-weight PLA with a small amount of ʟ-lactide (PLA/LAx) to treat nitrate-contaminated wastewater. The addition of ʟ-lactide enhanced the release of carbon from high-molecular-weight PLA. An impressive denitrification efficiency of 96.7% was achieved, accompanied by extremely low levels of accumulated NO2--N (0.1 mg/L) and NH4+-N (0.4 mg/L). The quantity of ʟ-lactide used significantly impacted the bacterial community structure. A high abundance of the phyla Bacteroidota and Chloroflexi associated with polymer degradation was observed. The most dominant denitrifier was the genus unclassified_f__Rhodocyclaceae belonged to the phylum Proteobacteria. This study demonstrates that blending PLA with just 5 wt% lactide can transform it into a highly effective solid-phase carbon source to eliminate nitrates.

Low pretreatment prognostic nutritional index predicts poor survival in breast cancer patients: A meta-analysis.

BACKGROUND: Prognostic nutritional index (PNI), as an indicator of nutritional immune status, has been shown to be associated with therapeutic effects and survival of solid tumors. However, the prognostic role of PNI before treatment in human breast cancer (BC) is still not conclusive. Hence, we performed this meta-analysis to assess the value of it in prognosis prediction for BC patients. MATERIALS AND METHODS: We searched PubMed, Embase, Web of Science and EBSCO to identify the studies evaluating the association between PNI and survival such as overall survival (OS), disease-free survival (DFS) of BC, and computed extracted data into hazard ratios (HRs) for OS, DFS and clinicopathological features with STATA 12.0. RESULTS: A total of 2322 patients with BC from 8 published studies were incorporated into this meta-analysis. We discovered that low pretreatment PNI was significantly associated with worse OS, but not with DFS in BC patients. In stratified analyses, the result showed that decreased PNI before treatment was remarkably related with lower 3-year, 5-year, 8-year and 10-year OS, but not with 1-year survival rate in BC. In addition, although reduced PNI could not impact 1-year, 3-year or 5-year DFS, it considerably deteriorated 8-year and 10-year DFS in patients. CONCLUSION: Low pretreatment PNI deteriorated OS, 8-year and 10-year DFS in BC patients, implicating that it is a valuable prognostic index and improving the nutritional immune status may offer a therapeutic strategy for these patients.

Ferric-loaded lipid nanoparticles inducing ferroptosis-like cell death for antibacterial wound healing.

Skin infection is a major health issue that usually is caused by the continuous proliferation of bacteria in wounds. With the abuse of antibiotics worldwide, the battle against skin infection is becoming more and more difficult. Therefore, the development of new ways with different antibacterial mechanisms to current antibiotics is urgently needed. Inspired by the powerful inhibition of ferroptosis used in cancer therapy, here in our study, ferric-loaded lipid nanoparticles (Fe-LNPs) with unform size (∼130 nm) and surface charge (∼12 mV) were constructed and found to effectively inhibit the growth of both Gram positive (Staphylococcus aureus, S. aureus) and negative (Escherichia coli, E. coli) strains, possibly due to induction of ferroptosis-like cell death mechanisms. Most importantly, Fe-LNPs can also effectively inhibit the proliferation of S. aureus in a skin infection model and promote the healing of wounds. The Fe-LNPs can be applied as a powerful antibacterial formulation for future application in clinic.

Hydrophobic Biodegradable Hyperbranched Copolymers with Excellent Marine Diatom Resistance.

As the utilization of degradable polymer coatings increased, the accompanying trade-off between good degradability and high-efficiency antidiatom adhesion due to their hydrophobic nature remains unresolved. The study presents a new hydrophobic surface-fragmenting coating consisting of degradable hyperbranched polymers (hereafter denoted as h-LLAx) synthesized by reversible complexation-mediated copolymerization with isobornyl acrylate (IBOA) and divinyl-functional oligomeric poly(l-lactide) (OLLA-V2), both derived from biomass, that exhibited superior resistance (∼0 cell mm-2) to marine diatom Navicula incerta (N. incerta) attachment with higher OLLA content. The combined impact of the microscale hollow semisphere micelles that self-assembled degradable hyperbranched copolymers and hydrolysis-driven self-renewable surfaces following immersion in seawater may account for the remarkable resistance of h-LLAx coatings against N. incerta. Detailed investigations were conducted across multiple perspectives, from hydrolytic degradation to broad-spectrum antibacterial attachment to ecotoxicity assessment. The excellent features of high resistance to marine diatoms and bacterial attachment, degradability, and environmental friendliness make the as-prepared h-LLAx coatings widely sought after for antifouling coating applications.

Elevated baseline circulating platelet-to-lymphocyte ratio and survival in initial stage â £ gastric cancer patients: A meta-analysis.

BACKGROUND: Systemic inflammatory response (SIR) plays important roles in initiation, promotion and progression of tumor. However, the prognostic role of baseline circulating platelet-to-lymphocyte ratio (PLR) (known as a marker of SIR) in human initial stage Ⅳ gastric cancer (GC) remains controversial. Hence, we performed this meta-analysis to assess the value of it in prognosis prediction for these patients. MATERIALS AND METHODS: We searched PubMed, Embase and EBSCO to identify the studies and computed extracted data with STATA 12.0. RESULTS: A total of 3025 patients with initial stage Ⅳ GC from 13 published studies were incorporated into this meta-analysis. We found that elevated baseline circulating PLR was significantly associated with decreased overall survival (OS), but not with progression-free survival (PFS) in stage Ⅳ GC patients. However, in stratified analyses, high PLR was only associated with worse 1-year and 2-year OS, but not with 3-year or 4-year OS; In addition, it was considerably related with reduced 6-month PFS, but not with 1-year or 2-year PFS. Moreover, high PLR markedly correlated with peritoneal metastasis of GC. CONCLUSION: Elevated baseline circulating PLR decreased 1-year OS and 6-month PFS in initial stage Ⅳ GC patients, implicating that it is a valuable prognostic index for these patients and modifying the inflammatory responses may have a potential for effective treatment.

LAG-3+ tumor-infiltrating lymphocytes ameliorates overall survival in triple-negative breast cancer patients.

Purpose: Immune checkpoint molecule lymphocyte-activating gene-3 (LAG-3), which is expressed on active lymphocytes, has proven to be associated with immunosuppression and cancer progression in a variety of solid tumors. However, the role of LAG-3+ lymphocytes in human breast cancer (BC) is still not conclusive. We therefore performed a meta-analysis to clarify the role of these cells in prognosis prediction for BC. Methods: We searched PubMed, Embase, and EBSCO to identify the studies evaluating the association of LAG-3+ lymphocyte infiltration and overall survival (OS) and/or disease-free survival (DFS) in BC patients, then combined extracted data with STATA 12.0. Results: Eight published studies involving 5,859 BC patients were incorporated into this meta-analysis. We noted that a high number of LAG-3+ tumor-infiltrating lymphocytes were not appreciably associated with OS and DFS in BC patients. Strikingly, in stratified analyses based on the molecular type of BC, LAG-3+ lymphocyte infiltration was remarkably associated with better OS rather than DFS in triple-negative breast cancer (TNBC), whereas it significantly influenced neither OS nor DFS in Her2-positive BC. However, an increased density of these lymphocytes indicated a trend for better OS in Her2-positive BC. In addition, we found that LAG-3+ lymphocyte infiltration was also remarkably associated with prolonged OS in Her2-positive BC patients when they were measured by immunohistochemistry (IHC). In addition, an elevated number of these lymphocytes did not correlate with pathological complete response rate or clinicopathological features including lymph node metastasis. Conclusion: The infiltration of LAG-3+ lymphocytes ameliorates OS in TNBC and Her2-positive BC, implicating that it is a valuable prognostic biomarker, and applications of anti-LAG-3 antagonists may possibly be not a promising therapeutic strategy for human BC especially for TNBC.

PDGFR-ß+ fibroblasts deteriorate survival in human solid tumors: a meta-analysis.

Fibroblasts are a highly heterogeneous population in tumor microenvironment. PDGFR-ß+ fibroblasts, a subpopulation of activated fibroblasts, have proven to correlate with cancer progression through multiple of mechanisms including inducing angiogenesis and immune evasion. However, the prognostic role of these cells in solid tumors is still not conclusive. Herein, we carried out a meta-analysis including 24 published studies with 6752 patients searched from PubMed, Embase and EBSCO to better comprehend the value of such subpopulation in prognosis prediction for solid tumors. We noted that elevated density of intratumoral PDGFR-ß+ fibroblasts was remarkably associated with worse overall survival (OS) and disease-free survival (DFS) of patients. In subgroup analyses, the data showed that PDGFR-ß+ fibroblast infiltration considerably decreased OS in non-small cell lung cancer (NSCLC), breast and pancreatic cancer, and reduced DFS in breast cancer. In addition, increased number of PDGFR-ß+ fibroblasts appreciably correlated with advanced TNM stage of patients. In conclusion, PDGFR-ß+ fibroblast infiltration deteriorates survival in human solid tumors especially in NSCLC, breast and pancreatic cancer. Hence, they may offer a practicable prognostic biomarker and a potential therapeutic strategy for these patients.

Erratum: High expression of NSUN5 promotes cell proliferation via cell cycle regulation in colorectal cancer.

[This corrects the article on p. 3858 in vol. 12, PMID: 32774740.].

An IL6-Adenosine Positive Feedback Loop between CD73+ γδTregs and CAFs Promotes Tumor Progression in Human Breast Cancer.

The tumor microenvironment induces immunosuppression via recruiting and expanding suppressive immune cells such as regulatory T cells (Treg) to promote cancer progression. In this study, we documented that tumor-infiltrating CD73+ γδTregs were the predominant Tregs in human breast cancer and exerted more potent immunosuppressive activity than CD4+ or CD8+ Tregs. We further demonstrated that cancer-associated fibroblast (CAF)-derived IL6, rather than TGFß1, induced CD73+ γδTreg differentiation from paired normal breast tissues via the IL6/STAT3 pathway to produce more adenosine and become potent immunosuppressive T cells. CD73+ γδTregs could in turn promote IL6 secretion by CAFs through adenosine/A2BR/p38MAPK signaling, thereby forming an IL6-adenosine positive feedback loop. CD73+ γδTreg infiltration also impaired the tumoricidal functions of CD8+ T cells and significantly correlated with worse prognosis of patients. The data indicate that the IL6-adenosine loop between CD73+ γδTregs and CAFs is important to promote immunosuppression and tumor progression in human breast cancer, which may be critical for tumor immunotherapy.

High expression of NSUN5 promotes cell proliferation via cell cycle regulation in colorectal cancer.

NSUN5, a gene encodes a cytosine-5 RNA methyltransferase, is rarely mentioned in cancers. Our study is the first one to evaluate the role of NSUN5 in the progression of colorectal cancer. Data from TCGA was used to show the different expression of NSUN5 between CRC tumor tissues and adjacent normal ones. The NSUN5 expression in the tissue microarray was detected by immunohistochemistry (IHC). qRT-PCR was conducted for NSUN5 expression examination in CRC cell lines. Cell proliferation was analyzed by the Celigo machine. GESA and correlation analysis were performed to reveal the possible underlying mechanism. The effects of NSUN5 expression on CRC cell behavior in vitro were analyzed by flow cytometry and ß-galactosidase staining. The expression of cell-cycle related proteins were evaluated by western blot. Subcutaneously implanted tumor model was carried out for animal experiment. NSUN5 expression was up-regulated in CRC tumor tissues and cells, and associated with advanced tumor stages (III, IV). NSUN5 could promote cell proliferation, trigger cell cycle arrest in vitro and boost tumor growth in vivo. In addition, knockdown of NSUN5 could lead to a higher expression of Rb and a lower expression of CDK4, CDK6, p-Rb and CCNE1, but made no difference on P21, Bcl-2, caspase3 and C-Caspase3 of CRC cells. Taken together, we identify NSUN5 as a promoter in CRC development via cell cycle regulation.

Cellular immunotherapy plus chemotherapy ameliorates survival in gastric cancer patients: a meta-analysis.

The efficacy of cellular immunotherapy plus chemotherapy in treatment of gastric cancer (GC) remains inconsistent even controversial. Hence, we performed a meta-analysis to better comprehend the clinical value of cellular immunotherapy plus chemotherapy for GC patients. We searched PubMed, Embase and EBSCO databases to identify the studies evaluating the association of cellular immunotherapy plus chemotherapy and overall survival (OS) and/or disease-free survival (DFS) in patients with GC, and then combined relevant data into hazard ratios (HRs) for OS, DFS and clinicopathological features such as TNM stage, etc. with STATA 12.0. Eleven studies with 1244 patients were included in this meta-analysis. We found that cellular immunotherapy plus chemotherapy remarkably improved overall survival (OS) and diseases-free survival (DFS) as compared to the chemotherapy for GC patients. In subgroup analyses, pooled data showed that the combined therapy was significantly associated with better 3-year and 5-year survival rate, but not with 1-year survival rate of patients; the application of cellular immunotherapy based on either CIK or DC-CIK cells could enhance survival as well as NK, γδT and CIK cells-based immunotherapy. More importantly, the addition of cellular immunotherapy considerably improved OS and DFS only in patients with stage III rather than stage II. In addition, we also discovered that the combined therapy did not cause intolerable side effects to patients. Cellular immunotherapy plus chemotherapy ameliorates survival in GC, especially in patients with stage III, implicating that it is a valuable therapeutic strategy for these patients.

Tumor-associated tissue eosinophilia predicts favorable clinical outcome in solid tumors: a meta-analysis.

BACKGROUND: Activated eosinophils have been deemed to affect carcinogenesis and tumor progression via various mechanisms in tumor microenvironment. However, the prognostic role of tumor-associated tissue eosinophilia (TATE) in human cancers remains controversial. Therefore, we conducted this meta-analysis to better comprehend the association between TATE and clinical outcomes of patients. METHODS: We searched PubMed, Embase and EBSCO to determine the researches assessing the association between TATE and overall survival (OS) and/or disease-free survival (DFS) in patients with cancer, then combined relevant data into hazard ratios (HRs) or odds ratio (OR) for OS, DFS and clinicopathological features including lymph node metastasis etc. with STATA 12.0. RESULTS: Twenty six researches with 6384 patients were included in this meta-analysis. We found that the presence of TATE was significantly associated with improved OS, but not with DFS in all types of cancers. In stratified analyses based on cancer types, pooled results manifested that the infiltration of eosinophils was remarkably associated with better OS in esophageal carcinoma and colorectal cancer. In addition, TATE significantly inversely correlated with lymph node metastasis, tumor stage and lymphatic invasion of cancer. CONCLUSION: TATE promotes survival in cancer patients, suggesting that it is a valuable prognostic biomarker and clinical application of biological response modifiers or agonists promoting TATE may be the novel therapeutic strategy for patients.

The prognostic role of preoperative circulating neutrophil-lymphocyte ratio in primary bladder cancer patients undergoing radical cystectomy: a meta-analysis.

BACKGROUND: Systemic inflammatory response (SIR) plays important roles in initiation, promotion and progression of tumor. However, the prognostic role of preoperative circulating neutrophil-lymphocyte ratio (NLR) (known as a marker of SIR) in human primary bladder cancer (BC) undergoing radical cystectomy (RC) remains controversial. Hence, we performed this meta-analysis to better understand the role of preoperative circulating NLR in prognosis prediction for primary BC patients undergoing RC. METHODS: We searched PubMed, Embase and EBSCO to identify the studies and computed extracted data with STATA 12.0. RESULTS: A total of 11,945 patients with BC from 18 published studies were incorporated into this meta-analysis. We found that elevated NLR was significantly associated with decreased 3-year and 5-year overall survival (OS), 1-year, 3-year and 5-year recurrence-free survival (RFS), but not with 1-year or 10-year OS, or 10-year RFS in primary BC patients who underwent RC. The results also showed that neoadjuvant chemotherapy (NAC) had a significant impact on the negative prognostic effect of NLR. In addition, high NLR significantly correlated with unfavorable clinicopathological features of BC. CONCLUSION: Elevated preoperative circulating NLR leads to an unfavorable outcome in primary BC undergoing RC, especially in patients without NAC, implicating that it might be a valuable prognostic index for these patients.

Activated Tumor-infiltrating Fibroblasts Predict Worse Prognosis in Breast Cancer Patients.

Purpose: Activated tumor-infiltrating fibroblasts were significantly associated with survival of cancer patients. However, they are heterogeneous population, and the prognostic role of these cells in human breast cancer still remains controversial. Herein, we performed the meta-analysis to better understand the role of these cells in prognosis prediction for breast cancer patients. Methods: We searched PubMed and EBSCO to identify the studies evaluating the association of intratumoral activated fibroblast density detected by immunohistochemical (IHC) method and overall survival (OS) and/or disease-free survival (DFS) in breast cancer patients, then computed extracted data into hazard ratios (HRs) for OS, DFS and clinicopathological features such as lymph node metastasis, TNM stage with STATA 12.0. Results: A total of 3680 patients with breast cancer from 15 published studies were incorporated into this meta-analysis. We found that the infiltration of activated fibroblasts significantly decreased overall survival (OS) and disease-free survival (DFS) in patients. In stratified analyses, high density of FSP-1+ or podoplanin+ fibroblasts was significantly associated with worse OS; while α-SMA+ or podoplanin+ fibroblast infiltration was associated with worse DFS in breast cancer. In addition, elevated number of activated tumor-infiltrating fibroblasts significantly correlated with lymph node metastasis and poor tumor differentiation of patients. Conclusion: The infiltration of activated fibroblasts, especially the FSP-1+ or podoplanin+ fibroblasts leads to worse clinical outcome in breast cancer patients, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment.

Tumor-Infiltrating Podoplanin+ Fibroblasts Predict Worse Outcome in Solid Tumors.

BACKGROUND/AIMS: Tumor-infiltrating fibroblasts are a heterogeneous population, and different subpopulations play differential roles in tumor microenvironment. However, the prognostic role of podoplanin+ fibroblasts in human solid tumors still remains controversial. Therefore, we performed the meta-analysis to better understand the role of this subpopulation in prognosis prediction for patients with solid tumor. METHODS: We searched PubMed and EBSCO to identify the studies evaluating the association of intratumoral podoplanin+ fibroblast density detected by immunohistochemical method and overall survival (OS) and/or disease-free survival (DFS) in patients with solid tumor, then computed extracted data into hazard ratios for OS, DFS and clinicopathological features with STATA 12.0. RESULTS: A total of 4883 patients from 29 published studies were incorporated into this meta-analysis. We found that podoplanin+ fibroblast infiltration significantly decreased OS and DFS in all types of solid tumors. In stratified analyses, podoplanin+ fibroblast infiltration was significantly associated with worse OS in cholangiocarcinoma, breast, lung and pancreatic cancer. And these cells were inversely associated with DFS in breast, lung and pancreatic cancer. In addition, high density of these cells significantly correlated with unfavorable clinicopathological features such as lymph node metastasis, TNM stage, lymphatic and vascular invasion of solid tumor. CONCLUSION: Podoplanin+ fibroblast infiltration leads to worse clinical outcome in solid tumors, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment.

Nanoscale Assembly of Copper Bearing-Sleeve via Cold-Welding: A Molecular Dynamics Study.

A bearing is an important component in contemporary machinery and equipment, whose main function is to support the mechanical rotator, reduce the friction coefficient during its movement, and guarantee the turning accuracy. However, assembly of a nanoscale bearing and sleeve is a challenging process for micro-nano mechanical manufacturers. Hence, we show the cold-welding mechanism of a copper nanobearing-nanosleeve via molecular dynamic simulations. We demonstrate that it is feasible to assemble a bearing and sleeve at the nanoscale to form a stable mechanism. The effect of temperature in the range of 150 to 750 K is investigated. As the temperature rises, the mechanical strength and the weld stress of the welded structures markedly decrease, accompanied by the observation of increasing disorder magnitude. This comparison study is believed to facilitate future mechanical processing and structural nano-assembly of metallic elements for better mechanical performance.

Podoplanin-positive cancer-associated fibroblasts predict poor prognosis in lung cancer patients.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are a heterogeneous population, and different subpopulations play differential roles in tumor microenvironment. However, the prognostic role of podoplanin-positive CAFs in human lung cancer still remains controversial. METHODS: Herein, we performed a meta-analysis including 12 published studies with 1,802 patients identified from PubMed and EBSCO to assess the prognostic impact of podoplanin-positive CAFs in lung cancer patients. RESULTS: We found that podoplanin+ fibroblast infiltration significantly decreased overall survival (OS), disease-free survival (DFS), and progression-free survival in patients. In stratified analyses, podoplanin+ fibroblast infiltration was significantly associated with worse OS and DFS in both squamous cell carcinoma and adenocarcinoma of lung. In addition, high density of podoplanin-positive CAFs significantly correlated with unfavorable clinicopathological features such as lymph node metastasis, and lymphatic, vascular, and pleural invasion of patients. CONCLUSION: Podoplanin+ fibroblast infiltration leads to worse clinical outcome in lung cancer patients, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment.

Molecular dynamics study on cold-welding of 3D nanoporous composite structures.

Nanoporous metals are a class of novel nanomaterials with potential applications in many fields. Herein, we demonstrate the cold-welding mechanism of nanoporous metals with various combinations using molecular dynamics simulations. This study shows that it is possible to cold-weld two nanoporous metals to form a novel composite material. The influence of temperature, in the range of 300-900 K, on the mechanical properties of the resultant composite material was investigated. With an increase in temperature, the weld stress and the mechanical strength of the nanoporous structures significantly decreased as an increase in disorder magnitude was observed. These results could lead to bottom-up nanofabrication and nanoassembly of combined nanoporous metals for high mechanical performance.

Prognostic role of tumor-infiltrating CD57-positive lymphocytes in solid tumors: a meta-analysis.

The prognostic role of tumor-infiltrating CD57-positive lymphocytes (CD57+ lymphocytes) in human solid tumors remains controversial. Herein, we conducted a meta-analysis including 26 published studies with 7656 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating CD57+ lymphocytes in human solid tumors. We found that CD57+ lymphocyte infiltration significantly improved overall survival (OS) including 1 - year, 3 - year and 5 - year survival, and disease - free survival (DFS) in all types of solid tumors. In stratified analyses, CD57+ lymphocyte infiltration was significantly associated with better OS in hepatocellular, esophageal, head and neck carcinoma, non-small cell lung cancer, 5 - year survival in colorectal cancer, and 3 - year and 5 - year survival in gastric cancer, but not with 1 - year survival in gastric cancer, or 1 - year or 3 - year survival in colorectal cancer. In addition, high density of intratumoral CD57+ lymphocytes was significantly inversely correlated with lymph node metastasis and TNM stage of solid tumor. In conclusion, CD57+ lymphocyte infiltration leads to a favorable clinical outcome in solid tumors, implicating that it is a useful biomarker for prognosis and adoptive immunotherapy based on these cells may be a promising choice for treatment.