Comprehensive pan-cancer analysis reveals prognostic implications of TMEM92 in the tumor immune microenvironment.

BACKGROUND: Transmembrane protein 92 (TMEM92) has been implicated in the facilitation of tumor progression. Nevertheless, comprehensive analyses concerning the prognostic significance of TMEM92, as well as its role in immunological responses across diverse cancer types, remain to be elucidated. METHODS: In this study, data was sourced from a range of publicly accessible online platforms and databases, including TCGA, GTEx, UCSC Xena, CCLE, cBioPortal, HPA, TIMER2.0, GEPIA, CancerSEA, GDSC, exoRBase, and ImmuCellAI. We systematically analyzed the expression patterns of TMEM92 at both mRNA and protein levels across diverse human organs, tissues, extracellular vesicles (EVs), and cell lines associated with multiple cancer types. Subsequently, analyses were conducted to determine the relationship between TMEM92 and various parameters such as prognosis, DNA methylation, copy number variation (CNV), the tumor microenvironment (TME), immune cell infiltration, genes with immunological relevance, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and half-maximal inhibitory concentration (IC50) values. RESULTS: In the present study, we observed a pronounced overexpression of TMEM92 across a majority of cancer types, which was concomitantly associated with a less favorable prognosis. A notable association emerged between TMEM92 expression and both DNA methylation and CNV. Furthermore, a pronounced relationship was discerned between TMEM92 expression, the TME, and the degree of immune cell infiltration. Intriguingly, while TMEM92 expression displayed a positive correlation with macrophage presence, it inversely correlated with the infiltration level of CD8 + T cells. Concurrently, significant associations were identified between TMEM92 and the major histocompatibility complex, TMB, MSI, and MMR. Results derived from Gene Set Enrichment Analysis and Gene Set Variation Analysis further substantiated the nexus of TMEM92 with both immune and metabolic pathways within the oncogenic context. CONCLUSIONS: These findings expanded the understanding of the roles of TMEM92 in tumorigenesis and progression and suggest that TMEM92 may have an immunoregulatory role in several malignancies.

[Research progress in strigolactones and application prospect in medicinal plants].

Strigolactones(SLs) are a class of sesquiterpenoids derived from the carotenoid biosynthesis pathway with the core carbon skeleton consisting of tricyclic lactone(ABC tricyclic ring) and α,ß-unsaturated furan ring(D ring). SLs are widely distributed in higher plants and are symbiotic signals between plants and Arbuscular mycorrhiza(AM), which play key roles in the evolution of plant colonizing terrestrial habitats. As a new type of plant hormone, SLs possess such important biological functions as inhibiting shoot branching(tillers), regulating root architecture, promoting secondary growth, and improving plant stress resistance. Therefore, SLs have attracted wide attention. The biological functions of SLs are not only closely related to the formation of "excellent shape and quality" of Chinese medicinal materials but also have important practical significance for the production of high-quality medicinal materials. However, SLs have been currently widely studied in model plants and crops such as Oryza sativa and Arabidopsis thaliana, and few related studies have been reported on SLs in medicinal plants, which need to be strengthened. This review focused on the latest research progress in the isolation and identification, biological and artificial synthesis pathways, biosynthesis sites and transport modes, signal transduction pathways and mechanisms, and biological functions of SLs, and prospected the research on the regulation mechanism of SLs in the growth and development of medicinal plants and their related application on targeted regulation of Chinese herbal medicine production, which is expected to provide some references for the in-depth research on SLs in the field of Chinese medicinal resources.

FBXO22 Mediates the NGF/TRKA Signaling Pathway in Bone Metastases in Prostate Cancer.

Prostate cancer (PC) is a malignancy with high morbidity and mortality. Bone metastasis is the main driver of short survival time and difficulties in the treatment and prevention of PC. The goal of this study was to explore the biological function of E3 ubiquitin ligase F-box only protein 22 (FBXO22) in PC metastasis and its specific regulation mechanism. According to transcriptome sequencing, FBXO22 was overexpressed in PC tissues (versus adjacent tissues) and bone tissues (versus biopsied bone tissues without bone metastases). Fbxo22 down-regulation reduced bone metastases and macrophage M2 polarization in mice. FBXO22 was down-regulated in macrophages, and polarization was observed by flow cytometry. Macrophages were co-cultured with PC cells and osteoblasts to assess PC cell and osteoblast activity. FBXO22 knockdown restored osteoblast capacity. FBXO22 ubiquitinated and degraded Krüppel-like factor 4 (KLF4), which regulated the nerve growth factor (NGF)/tropomyosin receptor kinase A pathway by repressing NGF transcription. Silencing of KLF4 mitigated the metastasis-suppressing properties of FBXO22 knockdown, whereas NGF reversed the metastasis-suppressing properties of KLF4 in vitro and in vivo. Cumulatively, these data indicate that FBXO22 promotes PC cell activity and osteogenic lesions by stimulating macrophage M2 polarization. It also degrades KLF4 in macrophages and promotes NGF transcription, thereby activating the NGF/tropomyosin receptor kinase A pathway.

Transcriptome analysis reveals differentially expressed genes involved in somatic embryogenesis and podophyllotoxin biosynthesis of Sinopodophyllum hexandrum (Royle) T. S. Ying.

Sinopodophyllum hexandrum (Royle) T. S. Ying, an important source of podophyllotoxin (PTOX), has become a rare and endangered plant because of over-harvesting. Somatic embryogenesis (SE) is the main way of seedling rapid propagation and germplasm enhancement, but the regeneration of S. hexandrum has not been well established, and the PTOX biosynthesis abilities at different SE stages remain unclear. Therefore, it is extremely important to elucidate the SE mechanism of S. hexandrum and clarify the biosynthesis variation of PTOX. In this study, the transcriptomes of S. hexandrum at different SE stages were sequenced, the contents of PTOX and 4'-demethylepipodophyllotoxin were assayed, and the transcript expression patterns were validated by qRT-PCR. The results revealed that plant hormone (such as auxins, abscisic acid, zeatin, and gibberellins) related pathways were significantly enriched among different SE stages, indicating these plant hormones play important roles in SE of S. hexandrum; the expression levels of a series of PTOX biosynthesis related genes as well as PTOX and 4'-demethylepipodophyllotoxin contents were much higher in embryogenic callus stage than in the other stages, suggesting embryogenic callus stage has the best PTOX biosynthesis ability among different SE stages. This study will contribute to germplasm conservation and fast propagation of S. hexandrum, and facilitate the production of PTOX.

A patient with advanced lung squamous cell carcinoma who failed to benefit from albumin bound paclitaxel plus pembrolizumab achieved partial response with second-line treatment of docetaxel plus pembrolizumab: a case report.

BACKGROUND: Lung cancer, including squamous cell lung cancer and non-squamous non-small cell lung cancer (NSCLC), is the leading cause of cancer-related deaths. At present, for squamous cell lung cancer patients who have progressed on first-line chemotherapy plus immunotherapy, immunotherapy applied across the line is still inconclusive. Therefore, treatment for such patients is often challenging. CASE DESCRIPTION: We present a 53-year-old male patient who found lung mass in August 2021, without symptoms of cough, expectoration or hemoptysis. Through imaging examinations, we found he got tumor of upper lobe in right lung, with left lung metastasis and lymph node metastasis in the right hilar. Bronchoscopy biopsy showed poorly differentiated squamous cell carcinoma of the right lung. Gene screening showed TP53 mutation. The patient was diagnosed as stage IVA (cT2aN1M1b) squamous cell carcinoma. He was administered four cycles of first-line albumin-binding paclitaxel + carboplatin combined with pembrolizumab. Reexamination of chest CT (2022-01-10) showed both right lung lesions and right hilar lymph nodes were progressed after progression free survival (PFS) of four months. After received two cycles of second-line therapy (docetaxel + carboplatin combined with pembrolizumab), the lung lesions shrunk significantly with efficacy of partial response (PR). As of 2022-05-18, he received a total of five cycles of second-line regimen. During this period, the disease was stable. No adverse events related to chemotherapy or immunotherapy were observed during the treatment. This is the first report of a successful case with an advanced lung squamous cell carcinoma patient who achieved disease remission after first-line progressed disease and second-line immunotherapy combined with chemotherapy. This case suggests that for such patients who fail to response to the first-line albumin-bound paclitaxel combined with immunotherapy, may get favorable response to docetaxel combined with immunotherapy. We need further investigations to validate that. CONCLUSIONS: This case suggested advanced lung squamous cell carcinoma patients who have failed to respond to first-line albumin paclitaxel combined with immunotherapy may still benefit from second-line docetaxel combined with immunotherapy. In addition, presentation of the TP53 mutation may be useful in predicting patients who may be responsive to docetaxel plus immunotherapy.

Immune checkpoint inhibitors for treatment of small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Small cell lung cancer (SCLC) is a very aggressive and proliferative disease, with little progress being having made for its treatment in decades. Our goal was to evaluate the effect of immune checkpoint inhibitors (ICIs) and identify optimal first-line interventions for the treatment of SCLC. METHODS: A systematic literature search of the Cochrane Library, PubMed and oncology conference proceedings were conducted. Randomized trials evaluating ICIs for SCLC were included. We use the risk of bias tool in RevMan 5.3 to assess the quality of studies. We used Stata version 15.0 to carry out data direct comparison and R version 4.0.2 to conduct the Bayesian network analysis. RESULTS: A total of 16 relevant clinical trials comprising 4,476 patients were included. We found the magnitude of efficacy for ICIs as first-line therapy conferred a statistically significant benefit in overall survival (OS) and progression-free survival compared to chemotherapy alone. The results were 0.82 (95% CI, 0.76-0.89, P<0.001) and 0.80 (95% CI, 0.74-0.86, P<0.001). For objective response rate (ORR), the result (1.13, 95% CI, 0.97-1.31, P=0.109) was not significant. In the second-line and maintenance treatment, no additional benefit was observed. With regard to safety, results showed that for all grades of AEs and grades 3-4 AEs, the pooled results were 1.36 (95% CI: 0.50-3.70; P=0.543) and 1.35 (95% CI: 0.58-3.15; P=0.484) respectively. In addition, the indirect comparison results showed that nivolumab combined with chemotherapy led to the most significant improvement in OS, while durvalumab combined with chemotherapy was a more efficacious therapy for improving ORR compared with the other interventions; the probability were the best treatments was 73.93% and 81% respectively. DISCUSSION: Our results showed ICIs combined with etoposide and platinum-based drugs as first-line treatment of SCLC have benefits for patients and there was no evidence of a significant difference in efficacy among the different ICI drugs used for the first-line therapy. As for toxicity, the ICIs did not increase the frequency AEs for patients. However, as some studies are ongoing and the full data have still not been reported, our conclusions may not be completely representative.

lncRNA TUG1 Expression in NSCLC and Its Clinical Significance.

BACKGROUND: This study was aimed at exploring the expression of lncRNA TUG1 in non-small cell lung cancer (NSCLC) and analyzing the correlations between TUG1 expression and an NSCLC patient's clinical and pathological parameters and prognosis. METHODS: This study included 132 NSCLC patients who were admitted between January 2012 and May 2013 in our hospital. Expression levels of TUG1 expression in the resected cancer tissue and normal adjacent tissue (NAT) were assessed using the ISH and RT-qPCR assays to analyze the correlations between TUG1 expression in NSCLC tissue and an NSCLC patient's clinical and pathological parameters and prognosis. RESULTS: Compared to NAT, NSCLC tissue has a lower expression level of TUG1. The TUG1 expression further decreases as NSCLC progressed to a later stage, indicating a statistically significant difference (p < 0.01 or p < 0.001). High TUG1 expression is not strongly associated with age, gender, smoking history, or the degree of differentiation of NSCLC (p > 0.05) but exhibits close correlations with tumor size, TNM stage, and lymph node metastasis (p < 0.05). Patients with a higher level of TUG1 expression have a higher survival rate and a longer survival time than those with lower TUG1 expression. The inter-group differences were statistically significant (p < 0.05). CONCLUSION: Considering TUG1 presence in the development and progression of NSCLC, hopefully, it can be used as a tumor marker in the diagnostic workup of patients with NSCLC.

Long non-coding RNA TUG1 enhances chemosensitivity in non-small cell lung cancer by impairing microRNA-221-dependent PTEN inhibition.

Long non-coding RNA taurine up-regulated gene 1 (TUG1) emerges as new players in gene regulation in several cancers; however, its mechanism of action in non-small cell lung cancer (NSCLC) has not been well-studied. Herein, we determined expression pattern of TUG1 in NSCLC and further identified its effect on the chemosensitivity of NSCLC. Low expression of TUG1 was found in NSCLC tissues obtained from non-responders to platinum-based chemotherapy and reflected poor overall survival. TUG1 overexpression was shown to inhibit cell proliferation, migration, invasion, but facilitate apoptosis and autophagy in NSCLC cells resistant to cisplatin (DDP). Smaller size of tumor xenografts of DDP resistant NSCLC cells in the presence of TUG1 demonstrated enhancement of chemosensitivity by TUG1 in vivo. High expression of miR-221 and low expression of PTEN were determined in cancer tissues obtained from non-responders to platinum-based chemotherapy and reflected poor overall survival. TUG1 inhibited miR-221 that targeted PTEN, as evidenced by an elevated expression of PTEN in the presence of miR-221 or the absence of TUG1. Our present study reveals a model of enhancement of chemosensitivity that consists of TUG1, miR-221 and PTEN. Modulation of their levels may offer a new approach for improving anti-tumor efficacy for chemotherapeutic agents in NSCLC.

Synergistic combination therapy of lung cancer: Cetuximab functionalized nanostructured lipid carriers for the co-delivery of paclitaxel and 5-Demethylnobiletin.

Lung cancer remains the leading cause of cancer associated deaths worldwide. Recent efforts have been focused on combinational and nanoparticulate therapies that can efficiently deliver multiple therapeutics. Herein, we reported cetuximab (CET) functionalized, paclitaxel (PTX) and 5-Demethylnobiletin (DMN) co-loaded nanostructured lipid carriers (NLCs) (CET-PTX/DMN-NLCs). The morphology, particle size, zeta potential, stability and drug release were tested. Cellular uptake, cell viability, synergistic effects and in vivo anti-tumor effects were evaluated on human lung adenocarcinoma cells (A549 cells), human embryonic lung cells (MRC-5 cells) and A549 paclitaxel-resistant cells bearing mice models. NLCs had sizes of around 130 nm and zeta potentials of +20-30 mV. The release of drugs from NLCs was relatively fast at the first 12 h and then became slow until completion of sustained release behavior. Cells uptake of CET-PTX/DMN-NLCs (65.8%) was remarkably higher than that of PTX/DMN-NLCs (35.5%) in A549 cells. The combination treatment with PTX and DMN synergistically decreases the viability of cells than the single PTX-NLCs and DMN-NLCs. CET-PTX/DMN-NLCs exhibited the most remarkable in vivo tumor inhibition efficiency, which suspended the tumor growth from 1010.23 to 211.18 mm3 at the end of the study. The highest tumor accumulation amount and low toxicity made CET-PTX/DMN-NLCs a promising system for the synergistic combination therapy of lung cancer.

Analysis of soluble urokinase plasminogen activator receptor in multiple myeloma for predicting prognosis.

Multiple myeloma is a type of malignancy, which affects the plasma cells of the bone marrow. Recent studies have found that malignant plasma cells may express urokinase plasminogen activator (uPA) and uPA receptor (uPAR), and that initiation of proteolytic events by this system contributes to the process of invasion and destruction of the bone marrow. Studies have also suggested that the level of the soluble form of uPAR (suPAR) may act as a marker for prognosis in patients with multiple myeloma, and that there is an association between uPAR/suPAR expression, and clinical characteristics, efficacy of treatment in disease control and patient survival. In order to investigate this, the present study used flow cytometry to detect the monoclonal antibodies associated with multiple myeloma, specifically, uPAR (CD87), CD56 and CD38. Patients with multiple myeloma were divided into the following groups: The effective groups (remission and stable disease) and the ineffective group (progressive disease). suPAR expression in the effective groups was 257.6±32.47 pg/ml and 331.0±99.80 pg/ml respectively, which was not significantly different from that of the normal control group (P>0.05). By contrast, the suPAR level in the invalid group was 562.2±291.0 pg/ml, which was significantly different from the levels in the normal control group (P<0.01) and the effective groups (P<0.05). suPAR levels were positively correlated with disease stage (P<0.01), renal function (P<0.05), C-reactive protein (P<0.005), ß2-microglobulin (P<0.001), extramedullary involvement (P<0.001), chromosome 13 deletion (P<0.01) and survival >2 years (P<0.01). They were was negatively correlated with hemoglobin concentration. No correlation was observed between uPAR expression and suPAR levels. The present study also indicated that the stage of disease and suPAR expression were independent factors, which predicted survival of <2 years. In conclusion, high suPAR expression appears to predict disease progression, a shortened survival period and early extramedullary infiltration.

Bortezomib prevents oncogenesis and bone metastasis of prostate cancer by inhibiting WWP1, Smurf1 and Smurf2.

Prostate cancer is the most common malignancy diagnosed in males, and bone metastases remain a significant source of morbidity and mortality in this population. Ubiquitin ligase E3s and proteasomes were thought to play essential roles in the development of cancers, therefore, they were proposed as therapy targets for the treatment of solid and hematological malignancies. Bortezomib, well-known as a proteasome inhibitor, has been observed with exact anticancer effect both in cell and animal models for several solid tumor types, including prostate cancer. To explore activities of the ubiquitin ligase E3s WWP1, Smurf1 and Smurf2 in oncogenesis and bone metastasis of prostate cancer, as well as in the functional mechanism of bortezomib in preventing prostate cancer, transcription and expression levels of WWP1, Smurf1 and Smurf2 genes in cell lines or tissues of benign prostate hyperplasia and human prostate cancer with and without bone metastasis were tested. Moreover, human prostate cancer PC3 cell lines were treated with bortezomib at different concentration gradients and then their proliferation at different time points, mRNA and protein levels were investigated. The results indicated that transcription and expression levels of WWP1, Smurf1 and Smurf2 genes in prostate cancer without bone metastasis were significantly higher compared to those in benign prostate hyperplasia (P<0.05), whereas significantly lower than prostate cancer metastatic to bone (P<0.05). Furthermore, bortezomib reduced the transcription and expression levels of WWP1, Smurf1 and Smurf2 genes in prostate cancer cell lines in a dose-dependent manner, thus, inhibiting the proliferation of prostate cancer cells. Elevated transcription and expression levels of ubiquitin ligase E3s WWP1, Smurf1 and Smurf2 genes may be the mechanisms of occurrence, development and metastasis of prostate cancer. In addition, bortezomib can prevent prostate cancer and its bone metastasis by downregulating WWP1, Smurf1 and Smurf2.

Effect of neoadjuvant chemotherapy combined with hyperthermic intraperitoneal perfusion chemotherapy on advanced gastric cancer.

Neoadjuvant and hyperthermic intraperitoneal chemotherapies have been shown to be effective in the treatment of resectable advanced gastric cancer. The aim of the present study was to investigate the clinical efficiency and security of neoadjuvant chemotherapy in combination with hyperthermic intraperitoneal chemotherapy for the treatment of postoperative advanced gastric cancer. A total of 192 patients diagnosed with advanced gastric cancer were randomly divided into the following four groups (n=48 per group): Control, neoadjuvant chemotherapy, hyperthermic intraperitoneal perfusion chemotherapy and joint groups. The joint group received neoadjuvant chemotherapy combined with hyperthermic intraperitoneal perfusion chemotherapy. Complications, adverse reactions, recurrence rates within 2 years and the 1- and 3-year survival rates following surgery were observed. No significant differences were observed in the occurrence rates of I-II degree myelosuppression, III-IV degree myelosuppression, I-II degree nausea or III-IV degree nausea and vomiting among the four groups (P>0.05). The median progression-free survival times were 26, 31, 33 and 28 months in the control, neoadjuvant chemotherapy, hyperthermic intraperitoneal perfusion chemotherapy and joint groups, respectively (P<0.001). Compared with the control group, the recurrence-free 2-year survival rate of the joint group was significantly lower (P=0.04). The difference among the median survival times of the four groups was statistically significant (P=0.001). The 1-year survival rate of the joint group was significantly higher when compared with the control group and the difference was statistically significant (P=0.03). However, no statistically significant difference was identified among the 1-year survival rates of the four groups (P>0.05). Compared with the control group, the 3-year survival rates of the other three groups were significantly higher (P<0.05). Therefore, the results of the present study indicated that neoadjuvant chemotherapy combined with hyperthermic intraperitoneal perfusion chemotherapy for the treatment of advanced gastric cancer is well tolerated and exhibits improved compliance and efficiency.