Cancer-related Inflammation Research Articles

Changes in Skeletal Muscle Mass in the First 3 Months Following Gastrointestinal Cancer Surgery: A Prospective Study.

Surgical resection is the primary treatment for gastrointestinal (GI) cancers, but postoperative skeletal muscle loss (SML) is common and linked to poor prognosis. This study aims to identify patterns of muscle change, examine its association with quality of life (QoL), and explore predictors of SML in the first 3 months. A prospective cohort study was conducted on patients newly diagnosed with GI cancer and undergoing surgery in China between September 2021 and May 2022. Skeletal muscle mass (SMM) and QoL were assessed at admission, 7 days, 1 month, and 3 months post-surgery. Demographic, clinical data, and biomarkers were collected. Missing data were imputed using multiple imputation. Data were analyzed using growth mixture modelling, bivariate analyses, and logistic regression. A total of 483 patients completed baseline assessment. Of the 242 patients with complete muscle assessments, 92% experienced SML. Three distinct patterns of muscle change were identified: 57% had normal preoperative SMM with mild postoperative SML, 16% had low preoperative SMM with moderate SML, and 27% had normal preoperative mass but severe postoperative SML. Moderate/severe SML was associated with more postoperative complications, poorer health, and higher symptom burden. Independent predictors included advanced age, preoperative sarcopenia, advanced cancer stage, and low prognostic nutrition index (PNI ≤ 45). The results did not change when using imputed values. Although SML is prevalent, patterns of muscle change are heterogeneous among patients. Advanced age, preoperative sarcopenia, advanced cancer stage, and cancer-related inflammation are predictors for moderate/severe SML, highlighting the need for early detection and management.

Ashwagandha (Withania somnifera) in Cancer Therapy: Anticancer Activities and Their Mechanisms

Cancers are characterized by rapid development of abnormal cells that multiply uncontrollably, leading to invasive tumors. By 2040, new cancer cases worldwide are expected to reach 30.2 million. In response, research focuses on the anti-cancer properties of ashwagandha (Withania somnifera), used in traditional Indian medicine. Ashwagandha exhibits anti-inflammatory effects by modulating pathways like NF-kB, Nrf2/HO-1, JAK-STAT, MAPK, and NLRP3, reducing cancer-related inflammation. It also has strong antioxidant properties due to compounds like withanolides, increasing antioxidant enzyme activity and reducing oxidative stress, potentially lowering cancer risk. Ashwagandha extract shows cytotoxic effects against cancer cells, inducing apoptosis and arresting cells in the resting phase, leading to DNA damage in cancer cells. It inhibits angiogenesis, the process of forming new blood vessels that supply tumors, through mechanisms such as VEGF inhibition and reduced macrophage infiltration. Additionally, ashwagandha modulates T lymphocytes and cytokine production, enhancing the immune response against cancer, and stimulates NK cell activity, crucial for controlling tumor growth and development. Supplementation with ashwagandha reduces cortisol levels and improves cognitive functions and quality of life in people experiencing stress, potentially lowering cancer risk. Research suggests ashwagandha may be a valuable addition to anti-cancer therapy, acting on various levels of cancer pathogenesis. However, further clinical studies are needed to fully understand its mechanisms of action and to evaluate its efficacy and safety in cancer treatment.

NLRP12/C1qA positive feedback in tumor-associated macrophages regulates immunosuppression through LILRB4/NF-κB pathway in lung adenocarcinoma

The anti-tumor immune response is greatly hindered by the protumor polarization of tumor-associated macrophages (TAMs). Cancer-related inflammation plays a central role in TAMs protumor polarization. Our study explored the unique positive feedback loop between inflammasome and complement in TAMs. The present study identified NOD-like receptors family pyrin domain containing 12 (NLRP12) formed positive feedback with C1qA and drove TAMs protumor polarization via the LILRB4/NF-κB pathway. In addition, NLRP12 was predominantly expressed in TAMs and was associated with poorer prognosis in lung adenocarcinoma (LUAD) patients. Knocking down LILRB4 inhibited TAMs protumor polarization. NLRP12-overexpressing TAMs promoted tumor cells’ malignant progression and inhibited T cells’ proliferation and cytotoxic function. Lastly, NLRP12 knockout (NLRP12−/−) reversed macrophage polarization, enhanced T-cell anti-tumor immunity, and suppressed tumor growth. Our findings highlighted the essential role of NLRP12/C1qA positive feedback loop and the LILRB4/NF-κB pathway in promoting TAMs protumor polarization. Inhibition of NLRP12 suppressed tumor development and promoted immune response. NLRP12 may be a promising target for LUAD immunotherapy.

Exploring the Structure-Activity Relationship of COX Inhibitors with Anticancer Effects: A Comprehensive Review.

Cancer is a multifaceted disease with high mortality rates, and current treatments face challenges such as chemoresistance and tumor adaptation. Since Virchow reported the first case of cancer-related chronic inflammation, numerous clinical and epidemiological studies have indicated that around 15-20% of malignant tumors are caused by inflammation. Cyclooxygenase-2 (COX-2), which is the key enzyme in inflammation, has been implicated in tumorigenesis through various mechanisms, including promoting angiogenesis, inhibiting apoptosis, and enhancing the invasiveness of cancer cells. Moreover, COX inhibitors have demonstrated a substantial reduction in death rates associated with esophageal and colon cancer. In this context, targeting COX-2 is an effective strategy for cancer prevention and treatment. This review focuses on the analysis of studies conducted between 2014 and 2024, which evaluate the structure-activity relationship of molecules intended to exhibit cytotoxic activity through COX inhibition. The studies followed both classical and non-classical COX-2 selective drug design strategies. While some focused on the classical approach, utilizing diaryl heterocyclic structures, others explored non-classical designs with a cyclic central scaffold and a linear core. Additionally, several manuscripts employed well-known COX inhibitors, including licofelone, indomethacin, naproxen, tolfenamate, celecoxib, flumizole, and ketoprofen, as starting points for further derivatization and optimization. Cytotoxic activity was evaluated using various cell lines, including MCF- 7, HCT-116, and A549, through assays such as MTT, CellTiter, and MTS. Additionally, studies examined the relationship between COX-2 inhibition and key cancer pathways, including apoptosis and the involvement of enzymes like HDAC, EGFR, and topoisomerase. The majority of studies reported promising cytotoxic activity in COX-2 selective inhibitors. Compounds synthesized with diphenyl heterocyclic scaffolds exhibited enhanced COX-2 selectivity and anticancer efficacy. In particular, derivatives in studies 9, 16, and 24 demonstrated significant activity comparable to standard drugs like celecoxib and doxorubicin. However, only a few studies indicated a weak correlation between COX-2 inhibition and cytotoxicity, suggesting the need for further investigation into other cancer-related mechanisms. This review highlights the potential of COX-2 selective inhibitors in anticancer drug development. The findings support the development of selective COX-2 inhibitors with diverse chemical structures as a promising strategy for cancer therapy.

Unwrapping the immunological alterations in testicular germ cell tumors: From immune homeostasis to malignancy and emerging immunotherapies.

Testicular germ cell tumors (TGCTs), derived from primordial germ cells, are rare malignancies with high curative potential. However, the emergence of new evidence indicating that 15% of patients experience tumor progression, leading to death, underscores the need for innovative therapeutics. This review aimed to explore the immune status in maintaining testicular health and the immune-related aspects of malignancy. Furthermore, it presents an overview of current data on the use of immunotherapy for TGCT patients. Recent advances in immunology have opened a promising avenue for studying diseases and highlighted its role in treating diseases. While the immunopathological facets of TGCTs are not fully understood, investigations suggest a complex interplay among testis-resident immune cells, testis-specific cells (i.e., Sertoli cells (SCs) and Leydig cells (LCs)), and immune-regulating mediators (e.g., sex hormones) in the normal testicle that foster the testicular immune privilege (TIP). Although TIP plays a crucial role in sperm production, it also makes testis vulnerable to tumor development. In the context of cancer-related inflammation, disruption of TIP leads to an imbalanced immune response, resulting in chronic inflammation that can contribute to testicular tissue dysfunction or loss, potentially aiding in cancer invasion and progression. Comparing the immune profiles of normal and malignant testes is valuable and may provide insights into different aspects of testicular immunity and immune-based treatment approaches. For patients resistant to chemotherapy and with a poor prognosis, immunotherapy has shown promising results. However, its effectiveness in treating resistant TGCTs or preventing tumor recurrence is still uncertain.

Pericytes: jack-of-all-trades in cancer-related inflammation.

Pericytes, recognized as mural cells, have long been described as components involved in blood vessel formation, playing a mere supporting role for endothelial cells (ECs). Emerging evidence strongly suggests their multifaceted roles in tissues and organs. Indeed, pericytes exhibit a remarkable ability to anticipate endothelial cell behavior and adapt their functions based on the specific cells they interact with. Pericytes can be activated by pro-inflammatory stimuli and crosstalk with immune cells, actively participating in their transmigration into blood vessels. Moreover, they can influence the immune response, often sustaining an immunosuppressive phenotype in most of the cancer types studied. In this review, we concentrate on the intricate crosstalk between pericytes and immune cells in cancer, highlighting the primary evidence regarding pericyte involvement in primary tumor mass dynamics, their contributions to tumor reprogramming for invasion and migration of malignant cells, and their role in the formation of pre-metastatic niches. Finally, we explored recent and emerging pharmacological approaches aimed at vascular normalization, including novel strategies to enhance the efficacy of immunotherapy through combined use with anti-angiogenic drugs.

Correlation between PLR and NLR with Tumor Size in Breast Cancer Patients

Breast cancer is the most common malignancy in females globally and one of the main causes of cancer death. There are several markers of cancer-related inflammation to help predict the relationship between pathologic characteristics of breast cancer. The research objective was to analyze the correlation between PLR and NLR with associated tumor size in breast cancer. This was a retrospective study with a cross-sectional design. This study used secondary data from the medical records of breast cancer patients who met the inclusion criteria at Siti Khodijah Hospital, Sidoarjo from January 2021 to March 2023. The sample size was 54 subjects, patients with breast cancer confirmed by pathology anatomy. The exclusion criteria were patients with infection, autoimmune disease, and hematology disorder. All the subjects were female. The mean age at the time of breast cancer diagnosis was 50.18±10.23 years, range of 27-80 years old. Most of the patients were over 50 years as much as 28 (51.85 %), while there were 26 (48.14%) > 50 years. The PLR range was 15.45-600.0, the NLR range was 0.58-9.98, tumor size range was 0.5-10.0 cm. Correlation between PLR and NLR with tumor size in breast cancer (p=0.351 and p=0.339). Correlation analysis showed that PLR and NLR had no significant correlation with tumor size ( r= -0.129, p=0.351 and r= -0.133, p=0.339). In conclusion, there is no significant correlation between PLR and NLR with histopathology of tumor size in patients with breast cancer.

Tumor microenvironment in thyroid cancer: Immune cells, patterns, and novel treatments.

The tumor immune microenvironment of thyroid cancer is the heterogeneous histological space in which tumor cells coexist with host cells. Published data from this review were identified by search and selection database of Pubmed, Elsevier, and Science Direct. Searching was made in two steps using different keywords. In thyroid pathology, the inflammatory response is very important, and might have a key role finding new diagnostic and therapeutic methods, particularly in thyroid cancer. Different immune cells may be more or less present in different types of thyroid cancer and may even have different functions, hence the importance of knowing their presence in different thyroid tumor pathologies. Cancer-related inflammation could be a useful target for new diagnostic and therapeutic strategies by analyzing peritumoral and intratumoral immune cells in different types of thyroid tumors. Moreover, novel strategies for thyroid cancer treatments, such as monoclonal antibodies targeting checkpoint inhibitors, are emerging as promising alternatives.

Prognostic Value of Systemic Inflammatory Markers and Scoring Systems in Predicting Postoperative 30-Day Complications and Mortality in Colorectal Cancer Surgery: A Retrospective Cross-Sectional Analysis.

Cancer-related systemic inflammation causes the increase of proinflammatory markers and acute phase proteins. Activation of systemic inflammatory response has been linked to poorer prognosis in colorectal cancer. This study aims to evaluate the prognostic value of preoperative systemic inflammatory markers and inflammation/nutrition scoring systems in predicting the postoperative early period (first 30 days) complications and mortality outcomes of patients who underwent curative surgery for colorectal cancer in our clinic. This study was designed as a retrospective single-arm cross-sectional study. In this study, 300 patients older than 18 years of age who underwent open and laparoscopic surgery for colorectal cancer were included. Demographic characteristics of the patients, preoperative hemogram and biochemical values, operation characteristics, postoperative tumor pathologies and disease stages were recorded. Neoadjuvant chemoradiotherapy, Systemic Inflammation Score, Modified Glasgow Prognostic Score, Naples Prognostic Score and Prognostic Nutritional Index had a significant effect on the first 30-day mortality (p-values: <0.001, 0.007, <0.001, <0.001, <0.001, respectively). The results suggest that certain preoperative inflammation and nutrition scores might serve as indicators for potential early postoperative adverse outcomes in colorectal cancer surgery.

A practical prognostic peripheral blood-based risk model for the evaluation of the likelihood of a response and survival of metastatic cancer patients treated with immune checkpoint inhibitors

BackgroundLess than half of unselected metastatic cancer patients benefit from the immune checkpoint inhibitor (ICI) therapy. Systemic cancer-related inflammation may influence the efficacy of ICIs and thus, systemic inflammatory markers could have prognostic and/or predictive potential in ICI therapy. Here, we aimed to identify a combination of inflammation-related laboratory parameters to establish a practical prognostic risk model for the pretreatment evaluation of a response and survival of ICI-treated patients with different types of metastatic cancers.MethodsThe study-cohort consisted of a real-world patient population receiving ICIs for metastatic cancers of different origins (n = 158). Laboratory parameters determined before the initiation of the ICI treatment were retrospectively collected. Six inflammation-related parameters i.e., elevated values of neutrophils, platelets, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH), and the presence of anemia, were each scored with one point, giving 0–6 risk points for each patient. The patients with information of all these six parameters (n = 109) were then stratified into low-risk (0–3 points) and high-risk (4–6 points) groups. The overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) according to the risk scores were determined.ResultsThe risk model was strongly associated with the outcome of the patients. The ORR to ICI treatment in the high-risk group was 30.3% in comparison to 53.9% in the low-risk group (p = 0.023). The medians for OS were 10.0 months and 27.3 months, respectively (p < 0.001), and the corresponding medians for PFS were 3.9 months and 6.3 months (p = 0.002). The risk group remained as a significant prognostic factor for both OS (HR 3.04, 95% CI 1.64–5.64, p < 0.001) and PFS (HR 1.79, 95% CI 1.04–3.06, p = 0.035) in the Cox multivariate analyses.ConclusionsWe propose a readily feasible, practical risk model consisted of six inflammation-related laboratory parameters as a tool for outcome prediction in metastatic cancer patients treated with ICIs. The risk model was strongly associated with the outcome of the patients in terms of all the evaluated indicators i.e., ORR, OS and PFS. Yet, further studies are needed to validate the risk model.

Abstract B094: Pentraxin 3 promotes the therapy resistance to sorafenib via regulating apoptosis in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is prevalently regarded as an inflammation-related cancer, characterized by persistent inflammation throughout the tumor microenvironment (TME). Currently, Sorafenib is the first-line targeted therapy drug used for advanced HCC patients. Unfortunately, many patients still face the risk of drug resistance after treatment with sorafenib. Pentraxin 3 (PTX3) has been reported as a secretory protein involved in cancer-related inflammation. It has been found to be overexpressed and acts as an unfavorable prognostic factor in the progression of chronic inflammation-related cancers. A recent study indicated that HCC patients who received sorafenib treatment had significantly higher PTX3 expression. However, the detailed role of PTX3 in these sorafenib-treated HCC patients still remains unclear. Therefore, it is intriguing whether elevated PTX3 contributes to sorafenib resistance in HCC patients. In this study, we observed that PTX3 is responsive to sorafenib, and there is a positive correlation between PTX3 expression and sorafenib resistance. Depletion of PTX3 led to increased sensitivity of HCC cells to sorafenib. For the underlying mechanism, sorafenib-induced PTX3 was found to promote resistance by regulating the anti-apoptotic protein MCL-1 and the pro-apoptotic protein BAX. In vivo experiments also revealed that combined treatment of sorafenib and a PTX3 inhibitor significantly reduced the size of HCC tumors, demonstrating that blocking elevated PTX3 increases sensitivity to sorafenib. Overall, targeting PTX3 attenuates resistance to sorafenib through the regulation of apoptosis, providing a novel therapeutic strategy to enhance therapeutic efficacy in HCC patients undergoing sorafenib treatment. Citation Format: Ping-Wen Chen. Pentraxin 3 promotes the therapy resistance to sorafenib via regulating apoptosis in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B094.

Breast cancer remotely imposes a myeloid bias on haematopoietic stem cells by reprogramming the bone marrow niche.

Myeloid cell infiltration of solid tumours generally associates with poor patient prognosis and disease severity1-13. Therefore, understanding the regulation of myeloid cell differentiation during cancer is crucial to counteract their pro-tumourigenic role. Bone marrow (BM) haematopoiesis is a tightly regulated process for the production of all immune cells in accordance to tissue needs14. Myeloid cells differentiate during haematopoiesis from multipotent haematopoietic stem and progenitor cells (HSPCs)15-17. HSPCs can sense inflammatory signals from the periphery during infections18-21 or inflammatory disorders22-27. In these settings, HSPC expansion is associated with increased myeloid differentiation28,29. During carcinogenesis, the elevation of haematopoietic growth factors supports the expansion and differentiation of committed myeloid progenitors5,30. However, it is unclear whether cancer-related inflammation also triggers demand-adapted haematopoiesis at the level of multipotent HSPCs. In the BM, HSPCs reside within the haematopoietic niche which delivers HSC maintenance and differentiation cues31-35. Mesenchymal stem cells (MSCs) are a major cellular component of the BM niche and contribute to HSC homeostasis36-41. Modifications of MSCs in systemic disorders have been associated with HSC differentiation towards myeloid cells22,42. It is unknown if MSCs are regulated in the context of solid tumours and if their myeloid supportive activity is impacted by cancer-induced systemic changes. Here, using unbiased transcriptomic analysis and in situ imaging of HSCs and the BM niche during breast cancer, we show that both HSCs and MSCs are transcriptionally and spatially modified. We demonstrate that breast tumour can distantly remodel the cellular cross-talks in the BM niche leading to increased myelopoiesis.

Development of a Prognostic Model for Early Breast Cancer Integrating Neutrophil to Lymphocyte Ratio and Clinical-Pathological Characteristics.

Breast cancer-related inflammation is critical in tumorigenesis, cancer progression, and patient prognosis. Several inflammatory markers derived from peripheral blood cells count, such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII) are considered as prognostic markers in several types of malignancy. We investigate and validate a prognostic model in early patients with breast cancer to predict disease-free survival (DFS) based on readily available baseline clinicopathological prognostic factors and preoperative peripheral blood-derived indexes. We analyzed a training cohort of 710 patients and 2 external validation cohorts of 980 and 157 patients with breast cancer, respectively, with different demographic origins. An elevated preoperative NLR is a better DFS predictor than others scores. The prognostic model generated in this study was able to classify patients into 3 groups with different risks of relapse based on ECOG-PS, presence of comorbidities, T and N stage, PgR status, and NLR. Prognostic models derived from the combination of clinicopathological features and peripheral blood indices, such as NLR, represent attractive markers mainly because they are easily detectable and applicable in daily clinical practice. More comprehensive prospective studies are needed to unveil their actual effectiveness.

Cytotoxic and anti-inflammatory constituents from roots of Hypericum beanii and the antitumor potential under the view of cancer-related inflammation

Hypericum beanii, a traditional folk medicine plant, has been employed in the treatment of various inflammation-related diseases and has demonstrated promising potential as an herbal remedy for cancer. In this study, we isolated 29 compounds from the roots of H. beanii. We evaluated their cytotoxic effects on five human cancer cell lines, which revealed that the ethanol extract, along with compounds 4 and 14, exhibited significant cytotoxic activity. Additionally, we assessed their anti-inflammatory properties by measuring the inhibition of nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophages. Our findings showed that the ethanol extract (IC50 = 7.41 ± 0.38 μg/mL), compound 4 (IC50 = 7.82 ± 0.42 μM), and compound 14 (IC50 = 3.05 ± 0.06 μM) displayed substantial anti-inflammatory activity. ELISA assays and qPCR analysis revealed that compounds 4 and 14 may exert their anti-inflammatory and antitumor effects by inhibiting the expression of iNOS, TNF-α, IL-1β, and IL-6 mRNA, shedding light on their role in cancer-related inflammation.

A Prospective Study on the Roles of the Lymphocyte-to-Monocyte Ratio (LMR), Neutrophil-to-Lymphocyte Ratio (NLR), and Platelet-to-Lymphocyte Ratio (PLR) in Patients with Locally Advanced Rectal Cancer.

Rectal cancer constitutes over one-third of all colorectal cancers (CRCs) and is one of the leading causes of cancer-related deaths in developed countries. In order to identify high-risk patients and better adjust therapies, new markers are needed. Systemic inflammatory response (SIR) markers such as LMR, NLR, and PLR have proven to be highly prognostic in many malignancies, including CRC; however, their roles in locally advanced rectal cancer (LARC) are conflicting and lack proper validation. Sixty well-selected patients with LARC treated at the Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, between August 2017 and December 2020 were prospectively enrolled in this study. The reproducibility of the pre-treatment levels of the SIR markers, their correlations with clinicopathological characteristics, and their prognostic value were evaluated. There was a significant positive correlation between LMR and cancer-related inflammatory infiltrate (r = 0.38, p = 0.044) and PD-L1 expression in tumor cells, lymphocytes, and macrophages (combined positive score (CPS)) (r = 0.45, p = 0.016). The PLR level was correlated with nodal involvement (p = 0.033). The SIR markers proved to be only moderately reproducible and had no significant prognostic value. In conclusion, the LMR was associated with local cancer-related inflammation and PD-L1 expression in tumor microenvironments. The validity of SIR indices as biomarkers in LARC requires further investigation.

The Yin Yang of Complement and Cancer.

Cancer-related inflammation is a crucial component of the tumor microenvironment (TME). Complement activation occurs in cancer and supports the development of an inflammatory microenvironment. Complement has traditionally been considered a mechanism of immune resistance against cancer, and its activation is known to contribute to the cytolytic effects of antibody-based immunotherapeutic treatments. However, several studies have recently revealed that complement activation may exert protumoral functions by sustaining cancer-related inflammation and immunosuppression through different molecular mechanisms, targeting both the TME and cancer cells. These new discoveries have revealed that complement manipulation can be considered a new strategy for cancer therapies. Here we summarize our current understanding of the mechanisms by which the different elements of the complement system exert antitumor or protumor functions, both in preclinical studies and in human tumorigenesis. Complement components can serve as disease biomarkers for cancer stratification and prognosis and be exploited for tumor treatment.

Efficient analysis of toxicity and mechanisms of environmental pollutants with network toxicology and molecular docking strategy: Acetyl tributyl citrate as an example

The study aims to promote network toxicology strategy to efficiently investigate the putative toxicity and underlying molecular mechanisms of environmental pollutants through an example of exploring brain injury induced by ATBC exposure. By utilizing ChEMBL, STITCH, GeneCards, and OMIM databases, we identified 213 potential targets associated with ATBC exposure and brain injury. Further refinements via STRING and Cytoscape software highlight 23 core targets, including AKT1, CASP3, and HSP90AA1. GO and KEGG pathway analysis conducted through DAVID and FUMA databases reveal that core targets of ATBC-induced brain toxicity are predominantly enriched in cancer signaling and neuroactive ligand receptor interaction pathways. Molecular docking was performed with Autodock, which confirmed robust binding between ATBC and core targets. Together, these findings suggest that ATBC may impact the occurrence and development of brain cancer and brain related inflammation, whereas pose risks for cognitive impairment and neurodegeneration, by modulating the apoptosis and proliferation of brain cancer cells, activating inflammatory signaling pathways, and regulating neuroplasticity. This research provides a theoretical basis for understanding the molecular mechanism of ATBC-induced brain toxicity, as well as establishing a foundation for the prevention and treatment of prostatic diseases associated with exposure to plastic products containing ATBC and certain ATBC-overwhelmed environments. Moreover, our network toxicology approach also expedites the elucidation of toxicity pathways for uncharacterized environmental chemicals.

Structural insights into the biological functions of the long pentraxin PTX3.

Soluble pattern recognition molecules (PRMs) are a heterogenous group of proteins that recognize pathogen- and danger-associated molecular patterns (PAMPs and DAMPs, respectively), and cooperate with cell-borne receptors in the orchestration of innate and adaptive immune responses to pathogenic insults and tissue damage. Amongst soluble PRMs, pentraxins are a family of highly conserved proteins with distinctive structural features. Originally identified in the early 1990s as an early inflammatory gene, PTX3 is the prototype of long pentraxins. Unlike the short pentraxin C reactive protein (CRP), whose expression is mostly confined to the liver, PTX3 is made by several immune and non-immune cells at sites of infection and inflammation, where it intercepts fundamental aspects of infection immunity, inflammation, and tissue remodeling. Of note, PTX3 cross talks to components of the complement system to control cancer-related inflammation and disposal of pathogens. Also, it is an essential component of inflammatory extracellular matrices (ECMs) through crosslinking of hyaluronic acid and turn-over of provisional fibrin networks that assemble at sites of tissue injury. This functional diversity is mediated by unique structural characteristics whose fine details have been unveiled only recently. Here, we revisit the structure/function relationships of this long pentraxin in light of the most recent advances in its structural biology, with a focus on the interplay with complement and the emerging roles as a component of the ECM. Differences to and similarities with the short pentraxins are highlighted and discussed.

CRISPR-Cas9 knockout screening identifies KIAA1429 as an essential gene in Ewing sarcoma

BackgroundEwing sarcoma (ES) is an aggressive childhood bone and soft tissue cancer. KIAA1429 is one type of N6-methyladenosine (m6A) writer that plays a tumor-progressive role in various cancers, but the role of KIAA1429 in ES remains to be elucidated. The aim of the study was to investigate the role of KIAA1429 in ES.MethodsWe performed a multi-omic screen including CRISPR-Cas9 functional genomic and transcriptomic approaches, and identified that KIAA1429 played a significant role in ES progression. Gene knockdown, quantitative real-time PCR (Q-RT-PCR), immunoblotting, CellTiter-Glo assays, clonogenic assays, a subcutaneous xenograft model and immunohistochemistry were used to assess the functional role of KIAA1429 in ES. We mainly conducted RNA sequencing (RNA-seq) in ES cells to analyze the downstream regulatory mechanism of KIAA1429. An integrative analysis of chromatin immunoprecipitation sequencing (ChIP-seq) and RNA-seq indicated the upstream regulatory mechanism of KIAA1429.ResultsIn vitro and in vivo CRISPR-Cas9 knockout screening identified KIAA1429 as an ES-dependent gene. Genetic suppression of KIAA1429 inhibited ES cell proliferation and tumorigenicity both in vitro and in vivo. Further studies revealed that KIAA1429 promotes ES tumorigenesis by regulating the ribosome-associated cell cycle and cancer-related inflammation. Interestingly, we found that STAT3 was a target of KIAA1429 and that a STAT3 inhibitor reduced KIAA1429 transcript levels, indicating positive feedback between KIAA1429 and STAT3. Finally, we found that NKX2-2 bound to the KIAA1429 promoter and transactivated KIAA1429.ConclusionOur study systematically analyzed ES-dependent epigenetic/transcriptional regulatory genes and identified KIAA1429 as a biomarker of tumor progression in ES, providing a potential therapeutic target for treating ES.

Gut microbiota and microbiota-derived metabolites in colorectal cancer: enemy or friend.

Colorectal cancer (CRC) is a highly prevalent gastrointestinal cancer worldwide. Recent research has shown that the gut microbiota plays a significant role in the development of CRC. There is mounting evidence supporting the crucial contributions of bacteria-derived toxins and metabolites to cancer-related inflammation, immune imbalances, and the response to therapy. Besides, some gut microbiota and microbiota-derived metabolites have protective effects against CRC. This review aims to summarize the current studies on the effects and mechanisms of gut microbiota and microbiota-produced metabolites in the initiation, progression, and drug sensitivity/resistance of CRC. Additionally, we explore the clinical implications and future prospects of utilizing gut microbiota as innovative approaches for preventing and treating CRC.