Prostate cancer-associated transcript 6 (PCAT6) promotes epithelial-mesenchymal transition and stemness and worsens prognosis in patients with colorectal cancer.

Approximately 20% of colorectal cancer (CRC) patients are first diagnosed with metastatic colorectal cancer (mCRC) because they develop symptoms at an advanced stage. Despite advancements in treatment, patients with metastatic disease still experience inferior survival rates. Our objective is to investigate the association between long noncoding RNAs (lncRNAs) and prognosis and to explore their role in mCRC. In this study, we find that elevated expression of PCAT6 is independently linked to unfavourable survival outcomes in The Cancer Genome Atlas (TCGA) data, and this finding is further confirmed in CRC samples obtained from Fudan University Shanghai Cancer Center. Cell lines and xenograft mouse models are used to examine the impact of PCAT6 on tumor metastasis. Knockdown of PCAT6 is observed to impede the metastatic phenotype of CRC, as evidenced by functional assays, demonstrating the suppression of epithelial-mesenchymal transition (EMT) and stemness. Our findings show the significance of PCAT6 in mCRC and its potential use as a prognostic biomarker.

ScRNA-seq of gastric cancer tissues reveals differences in the immune microenvironment of primary tumors and metastases.

Gastric carcinoma (GC) is regarded as one of the deadliest cancer characterized by diversity and haste metastasis and suffers limited understanding of the spatial variation between primary and metastatic GC tumors. In this project, transcriptome analysis on 46 primary tumorous, adjacent non-tumorous, and metastatic GC tissues was performed. The results demonstrated that metastatic tumorous tissues had diminished CD8+ T cells compared to primary tumors, which is mechanistically attributed to being due to innate immunity differences represented by marked differences in macrophages between metastatic and primary tumors, particularly those expressing ApoE, where their abundance is linked to unfavorable prognoses. Examining variations in gene expression and interactions indicated possible strategies of immune evasion hindering the growth of CD8+ T cells in metastatic tumor tissues. More insights could be gained into the immune evasion mechanisms by portraying information about the GC ecosystem.

In-situ preparation of lignin/Fe3O4 magnetic spheres as bifunctional material for the efficient removal of metal ions and methylene blue.

In this paper, magnetic composite of lignin/Fe3O4 spheres were synthesized via a straightforward one-step in-situ solvothermal method showing good capacity for adsorbing heavy metal ions and dyes. The physicochemical properties of lignin/Fe3O4 spheres are analyzed using a range of techniques such as SEM, XRD, FTIR, VSM, TG, and BET. Lignin/Fe3O4 spheres exhibited high adsorption capacities of 100.00, 353.36 and 223.71 and 180.18 mg/g for Cu (II), Ni (II) and Cr (VI) metal ions and methylene blue (MB) with equilibrium attained within 60 min. After the recycling experiments, lignin/Fe3O4 spheres still possesses excellent superparamagnetic properties and displays high adsorption capacity. The lignin/Fe3O4 spheres are an efficient and continuous adsorbent to remove heavy metal ions of Cu (II), Ni (II), Cr (VI) and cationic dyes of methylene blue in wastewater, which proves the great potential in practical pollutants treatment applications for water systems.

[Knock-down of ROCK2 gene improves cognitive function and reduces neuronal apoptosis in AD mice by promoting mitochondrial fusion and inhibiting its division].

Objective To explore the effect of knocking down Rho-associated coiled-coil kinase (ROCK2) gene on the cognitive function of amyloid precursor protein/presenilin-1 (APP/PS1) double transgenic mice and its mechanism. Methods APP/PS1 double transgenic mice were randomly divided into AD model group (AD group), ROCK2 gene knock-down group (shROCK2 group), ROCK2 gene knock-down control group (shNCgroup), and wild-type C57BL/6 mice of the same age served as the wild-type control (WT group). Morris water maze and Y maze were employed to test the cognitive function of mice. Neuron morphology was detected by Nissl staining. Immunofluorescence histochemical staining was used to detect the expression of phosphorylated dynamin-related protein 1 (p-Drp1) and mitochondrial fusion 1 (Mfn1). Western blot analysis was used to detect the expression ROCK2, cleaved-caspase-3 (c-caspase-3), B-cell lymphoma 2 (Bcl2), Bcl2-related protein X (BAX), p-Drp1, mitochondrial fission 1 (Fis1), optic atrophy 1 (OPA1), Mfn1 and Mfn2. Results Compared with AD group mice, the expression of ROCK2 in shROCK2 group mice was significantly reduced; the cognitive function was significantly improved with the number of neurons in the hippocampal CA3 and DG areas increasing, and nissl bodies were deeply stained; the expression of c-caspase-3 and BAX was decreased, while the expression of Bcl2 was increased; the expression of mitochondrial division related proteins p-Drp1 and Fis1 were decreased, while the expression of mitochondrial fusion-related proteins OPA1, Mfn1 and Mfn2 were increased. Conclusion Knock-down of ROCK2 gene can significantly improve the cognitive function and inhibit the apoptosis of nerve cells of APP/PS1 mice. The mechanism may be related to promoting mitochondrial fusion and inhibiting its division.

Negative correlation between acetyl-CoA acyltransferase 2 and cetuximab resistance in colorectal cancer.

The emergence of anti-EGFR therapy has revolutionized the treatment of colorectal cancer (CRC). However, not all patients respond consistently well. Therefore, it is imperative to conduct further research to identify the molecular mechanisms underlying the development of cetuximab resistance in CRC. In this study, we find that the expressions of many metabolism-related genes are downregulated in cetuximab-resistant CRC cells compared to their sensitive counterparts. Specifically, acetyl-CoA acyltransferase 2 (ACAA2), a key enzyme in fatty acid metabolism, is downregulated during the development of cetuximab resistance. Silencing of ACAA2 promotes proliferation and increases cetuximab tolerance in CRC cells, while overexpression of ACAA2 exerts the opposite effect. RTK-Kras signaling might contribute to the downregulation of ACAA2 expression in CRC, and ACAA2 predicts CRC prognosis in patients with Kras mutations. Collectively, our data suggest that modulating ACAA2 expression contributes to secondary cetuximab resistance in Kras wild-type CRC patients. ACAA2 expression is related to Kras mutation and demonstrates a prognostic role in CRC patients with Kras mutation. Thus, ACAA2 is a potential target in CRC with Kras mutation.

JUNB mediates oxaliplatin resistance via the MAPK signaling pathway in gastric cancer by chromatin accessibility and transcriptomic analysis.

Currently, platinum-containing regimens are the most commonly used regimens for advanced gastric cancer patients, and chemotherapy resistance is one of the main reasons for treatment failure. Thus, it is important to reveal the mechanism of oxaliplatin resistance and to seek effective intervention strategies to improve chemotherapy sensitivity, thereby improving the survival and prognosis of gastric cancer patients. To understand the molecular mechanisms of oxaliplatin resistance, we generate an oxaliplatin-resistant gastric cancer cell line and conduct assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) for both parental and oxaliplatin-resistant AGS cells. A total of 3232 genomic regions are identified to have higher accessibility in oxaliplatin-resistant cells, and DNA-binding motif analysis identifies JUNB as the core transcription factor in the regulatory network. JUNB is overexpressed in oxaliplatin-resistant gastric cancer cells, and its upregulation is associated with poor prognosis in gastric cancer patients, which is validated by our tissue microarray data. Moreover, chromatin immunoprecipitation sequencing (ChIP-seq) analysis reveals that JUNB binds to the transcriptional start site of key genes involved in the MAPK signaling pathway. Knockdown of JUNB inhibits the MAPK signaling pathway and restores sensitivity to oxaliplatin. Combined treatment with the ERK inhibitor piperlongumine or MEK inhibitor trametinib effectively overcomes oxaliplatin resistance. This study provides evidence that JUNB mediates oxaliplatin resistance in gastric cancer by activating the MAPK pathway. The combination of MAPK inhibitors with oxaliplatin overcomes resistance to oxaliplatin, providing a promising treatment opportunity for oxaliplatin-resistant gastric cancer patients.

Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7.

Receptor tyrosine kinases (RTKs) are a class of membrane spanning cell-surface receptors that transmit extracellular signals through the membrane to trigger diverse intracellular signaling through tyrosine kinases (TKs), and play important role in cancer development. Therapeutic approaches targeting RTKs such as vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), and TKs, such as c-Src, ABL, JAK, are widely used to treat human cancers. Despite favorable benefits in cancer treatment that prolong survival, these tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting RTKs are also accompanied by adverse effects, including cardiovascular toxicity. Mechanisms underlying TKI-induced cardiovascular toxicity remain unclear. The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed chanzyme consisting of a membrane-based ion channel and intracellular α-kinase. TRPM7 is a cation channel that regulates transmembrane Mg2+ and Ca2+ and is involved in a variety of (patho)physiological processes in the cardiovascular system, contributing to hypertension, cardiac fibrosis, inflammation, and atrial arrhythmias. Of importance, we and others demonstrated significant cross-talk between TRPM7, RTKs, and TK signaling in different cell types including vascular smooth muscle cells (VSMCs), which might be a link between TKIs and their cardiovascular effects. In this review, we summarize the implications of RTK inhibitors (RTKIs) and TKIs in cardiovascular toxicities during anti-cancer treatment, with a focus on the potential role of TRPM7/Mg2+ as a mediator of RTKI/TKI-induced cardiovascular toxicity. We also describe the important role of TRPM7 in cancer development and cardiovascular diseases, and the interaction between TRPM7 and RTKs, providing insights for possible mechanisms underlying cardiovascular disease in cancer patients treated with RTKI/TKIs.

The STAT family: Key transcription factors mediating crosstalk between cancer stem cells and tumor immune microenvironment.

Signal transducer and activator of transcription (STAT) proteins compose a family of transcription factors critical for cancer stem cells (CSCs), and they are involved in maintaining stemness properties, enhancing cell proliferation, and promoting metastasis. Recent studies suggest that STAT proteins engage in reciprocal communication between CSCs and infiltrate immune cell populations in the tumor microenvironment (TME). Emerging evidence has substantiated the influence of immune cells, including macrophages, myeloid-derived suppressor cells, and T cells, on CSC survival through the regulation of STAT signaling. Conversely, dysregulation of STATs in CSCs or immune cells contributes to the establishment of an immunosuppressive TME. Thus, STAT proteins are promising therapeutic targets for cancer treatment, especially when used in combination with immunotherapy. From this perspective, we discuss the complex roles of STATs in CSCs and highlight their functions in the crosstalk between CSCs and the immune microenvironment. Finally, cutting-edge clinical trial progress with STAT signaling inhibitors is summarized.

Deficits in ascending pain modulation pathways in breast cancer survivors with chronic neuropathic pain: A resting-state fMRI study.

Purpose: Breast cancer (BC) is the highest frequent malignancy in women globally. Approximately 25-60% of BC patients with chronic neuropathic pain (CNP) result from advances in treating BC. Since the CNP mechanism is unclear, the various treatment methods for CNP are limited. We aimed to explore the brain alternations in BC patients with CNP and the relationship between depression and CNP utilizing resting-state functional magnetic resonance imaging (rs-fMRI). Methods: To collect the data, the female BC survivors with CNP (n = 20) and healthy controls (n = 20) underwent rs-fMRI. We calculated and compared the functional connectivity (FC) between the two groups using the thalamus and periaqueductal gray (PAG) as seed regions. Results: Patients with BC showed increased depression and FC between the thalamus and primary somatosensory cortices (SI). Moreover, the Hospital Anxiety and Depression Scale-Depression (HADS-D) and pain duration were linked positively to the strength of FC from the thalamus to the SI. Furthermore, the thalamus-SI FC mediated the impact of pain duration on HADS-D. Conclusion: In BC patients with CNP, the ascending pain regulation mechanism is impaired and strongly associated with chronic pain and accompanying depression. This research increased our knowledge of the pathophysiology of CNP in patients with BC, which will aid in determining the optimal therapeutic strategy for those patients.

Response to Pyrotinib in a Patient with Metastatic Bladder Urothelial Carcinoma Harboring HER2 V842I Mutation: A Case Report.

Background: The highest incidence of human epidermal growth factor receptor 2 (HER2) mutations has been observed in bladder cancer (BC). However, the function of HER2 mutation in tumor progression and metastasis remains unclear. Currently, no responses to the pan-HER kinase inhibitor were observed in HER2-mutant BC. Case Presentation: We described a patient with metastatic bladder urothelial carcinoma (BUC) carrying a HER2 V842I mutation both in circulating tumor DNA (ctDNA) and biopsy sample. The patient was then treated with a HER2 tyrosine kinase inhibitor, pyrotinib, and responded well. However, the targeting treatment was terminated due to G3 diarrhea. Reduced dose of pyrotinib was later added to late-line treatment, the patient's tumor again responded with a significant decrease in CA199. Conclusion: This is the first reported case of HER2 V842I mutation successfully treated with pyrotinib in BUC, suggesting pyrotinib therapy might serve as a therapeutic option for BUC patients harboring HER2 activating mutation.

Heparanase modulates the prognosis and development of BRAF V600E-mutant colorectal cancer by regulating AKT/p27Kip1/Cyclin E2 pathway.

BRAF V600E-mutant colorectal cancer (CRC) is a rare subtype of colorectal cancer with poor prognosis. Compelling evidence indicates that the heparanase (HPSE) gene has multiple functions in cancer, however, its role in BRAF V600E-mutant CRC remains elusive. Differentially expressed genes between BRAF V600E-mutant and wild-type patients were explored by analyzing public data from The Cancer Genome Atlas and the Gene Expression Omnibus. Clinical samples of 172 patients with BRAF V600E-mutant CRC diagnosed at Zhongshan Hospital Fudan University were collected. Overall survival was analyzed using Kaplan-Meier curves and Cox regression models. Cell models and xenografts were utilized to investigate the effect of HPSE on tumor proliferation. HPSE was significantly highly expressed in the BRAF V600E-mutant group. High HPSE expression level was independently associated with inferior survival in the BRAF V600E-mutant cohort. HPSE knockdown impeded tumor proliferation of BRAF V600E-mutant CRC cells in vitro and in vivo. Mechanistically, HPSE silencing arrested cell cycle in G0/G1 phase by downregulating Cyclin E2 expression via the AKT/p27Kip1 pathway. These findings support a role for HPSE in promoting BRAF V600E-mutant CRC progression, which suggests it holds great promise as a prognostic biomarker and a potential therapeutic target for the aggressive CRC subtype.

Positive Phospho-Focal Adhesion Kinase in Gastric Cancer Associates With Poor Prognosis After Curative Resection.

Gastric cancer (GC) is the fifth most commonly diagnosed cancer and usually has a dismal prognosis. Our previous study highlights the contribution of focal adhesion kinase (FAK) in the tumorigenesis of diffuse gastric cancer (DGC), a subtype of GC according to Lauren classification. The prognostic value of phosphorylated FAK (pFAK) in GC remains to be explored. To explore the prognostic value of pFAK, we retrospectively collected 176 formalin-fixed paraffin-embedded (FFPE) tumor tissues from GC patients who underwent D2 gastrectomy without neoadjuvant treatment. The immunohistochemistry (IHC) staining of pFAK was performed. Survival analysis was performed by Kaplan-Meier and risk factors were evaluated by Cox regression analysis. A pFAK-based nomogram was also constructed for the prediction of overall survival (OS). We demonstrated that the prognosis of pFAK-positive patients was worse than that of the pFAK-negative patients in GC (p = 0.010; hazard ratio [HR] = 1.777, 95% CI 1.131 to 2.791; median OS, 46.6 vs. 86.3 months, respectively), and positive pFAK was also an independent risk factor for the worse prognosis of GC (p = 0.0054; HR = 1.89, 95% CI 1.21-2.96). Moreover, the nomogram based on pFAK and other independent risk factors could improve predictive accuracy for prognosis of GC. In conclusion, through analysis of a large collection of clinically annotated GC samples, we demonstrate that pFAK is a negative prognostic factor in GC, and a nomogram integrating pFAK could help predict OS for GC patients.

Tumor-derived exosomes: immune properties and clinical application in lung cancer.

Lung cancer is the leading cause of cancer-related death worldwide. Despite advances in diagnosis and treatment of lung cancer, the overall survival remains poor. Evidence indicates that lung cancer development is a complex and dynamic process that involves interactions between tumor cells and their microenvironments, including immune cells. Exosomes are small extracellular vesicles secreted by most cell types; they contain functional molecules that allow intercellular communication. Tumor-derived exosomes (TEXs) carry both immunosuppressive and immunostimulatory mediators and may be involved in various immunomodulatory effects. TEXs, which partially mimic profiles of the parent cells, are a potential source of cancer biomarkers for prognosis, diagnosis, and prediction of response to therapy. In addition, TEXs may interfere with immunotherapies, but they also could be used as adjuvants and antigenic components in vaccines against lung cancer. In the context of lung cancer, identifying TEXs and understanding their contribution to tumorigenesis and the response to immunotherapies represents a challenging research area.

Case Report: Complete Response to Antiangiogenesis and Immune Checkpoint Blockade in an Unresectable MMR-Deficient Leiomyosarcoma Harboring Biallelic Loss of PTEN.

BACKGROUND: Leiomyosarcoma (LMS) is a malignant smooth muscle neoplasm, in which the efficacy of immune checkpoint blockade (ICB) is very limited. What is worse, loss of PTEN, known as a negative factor for ICB, frequently occurred in LMS. Seeking new strategies for LMS patients harboring loss of PTEN is important and challenging. CASE PRESENTATION: A 42-year-old Chinese male was diagnosed as having unresectable LMS of the iliopsoas. After the failure of two prior chemotherapy regimens, whole-exome sequencing revealed that tumor tissue had high tumor mutation burden (689 Muts), high microsatellite instability, and some somatic mutations, including PTEN (copy number loss and p.N323fs), MSH6 (p.F1088fs), TP53 p.R273C, ASXL1 p.G645fs, ATR p.S1843P, and CDKN2A p.A118P. Then, antiangiogenic agent (pazopanib or anlotinib) plus pembrolizumab was administered from January 2 to August 6, 2018. However, pazopanib was stopped on June 18 due to the grade 2/3 adverse effect of hand-foot skin reaction, and anlotinib was administered. Considering that the tumor shrunk after immunotherapy, he underwent radical resection on September 6, 2018. The final pathological diagnosis confirmed pathologic complete response (CR). Until the latest follow-up (September 15, 2021), no progressive disease was observed and total disease-free survival has exceeded 36 months. CONCLUSION: We presented a patient with an unresectable mismatch repair (MMR)-deficient LMS harboring biallelic loss of PTEN who achieved CR from a combination strategy of antiangiogenesis plus pembrolizumab. Such a strategy might be a promising strategy to overcome the ICB resistance caused by the loss of PTEN. Such conclusions need to be further confirmed in further investigations.

[Lycium barbarum polysaccharide promotes M2 polarization of BV2 microglia induced by LPS via inhibiting the TLR4/NF-κB signaling pathway].

Objective To investigate the effect of Lycium barbarum polysaccharide (LBP) on the polarization of BV2 microglia from M1 to M2 induced by lipopolysaccharide (LPS) and its mechanism. Methods The BV2 microglia were divided into control group, LPS group, and LBP treatment group (0.6, 0.9, 1.2) g/L. MTT assay was used to observe the cell viability of BV2 cells, and Griess assay was used to detect the release of NO. The levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were detected by ELISA. The expressions of Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), and arginase-1 (Arg1) were detected by immunofluorescence cytochemistry. Western blot was used to evaluate the protein levels of ionized calcium-binding adaptor molecule-1 (Iba-1), TLR4, NF-κB, iNOS, and Arg1. Results There was no significant difference of the cell survival rate after treatment with different doses of LBP. Compared to those in the control group, in LPS group the BV2 microglia were activated with amoeba-like shape and increased release of NO, the expressions of Iba-1, TLR4, NF-κB, iNOS, TNF-α, IL-1ß, and IL-6 were significantly increased, while the expressions of Arg1 and IL-10 was significantly decreased. In LBP group, Iba-1, TLR4, NF-κB, iNOS, TNF-α, IL-1ß, and IL-6 were dramatically decreased and negatively correlated with the dose, while Arg1 and IL-10 were increased and positively correlated with the dose. Conclusion LBP inhibits activation of BV2 microglia induced by LPS and promots the M2 polarization, which may be realized through inhibiting TLR4/NF-κB signaling pathway.

Treatment strategy for myocarditis in patients using immune checkpoint inhibitors or combined anti-vascular endothelial growth factor therapy by clinical severity.

BACKGROUND: Combination of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor (VEGF) therapy has increasingly become a promising strategy in various tumors. However, the combination might be associated with increased cardiotoxicities. Myocarditis is a potentially fatal complication in cancer patients treated with ICI. Currently, there are no clear guidelines for the management of this disease nor data characterizing the clinical course of myocarditis patients due to the combination of ICI and anti-VEGF therapy. PATIENTS AND METHODS: This study included all patients consecutively admitted to Shanghai Zhongshan Hospital, Fudan University for the diagnosis of ICI-associated myocarditis according to Bonaca's criteria. The clinical presentation and outcome of myocarditis patients were collected receiving ICI and anti-VEGF combined therapy. RESULTS: A total of 48 patients were included (23 received combined treatment of ICI and anti-VEGF while 25 received ICI only). No differences in baseline characteristics, clinical course, and outcomes were observed among patients receiving ICI with or without anti-VEGF treatment. The patients were subdivided into 3 groups including 8 fulminant cases, 25 clinically significant cases, and 15 subclinical cases based on clinical severity. The fulminant group was associated with a higher rate of cardiovascular deaths (CVDs) compared with clinically significant and subclinical groups (87.5% versus 4.0% versus 0.0%, p < 0.01). When stratified by the dose of corticosteroids used, cases with high-dose usage were more likely to have a CVD when compared to low dose or no use and intermediate dose groups (0.0% versus 4.0% versus 57.1%, p < 0.01). CONCLUSIONS: No significant differences between myocarditis patients receiving ICI or combined anti-VEGF therapy in terms of clinical presentation and outcome were observed. Treatment strategy for myocarditis in patients using ICI or combined anti-VEGF therapy should be based on clinical severity. Specifically, immunosuppressive therapy besides high-dose corticosteroids is needed for fulminant cases.