Prognostic Marker For Poor Survival Research Articles

MAT1A activation of glycolysis to promote NSCLC progression depends on stabilizing CCND1

Non-small cell lung cancer (NSCLC) remains a cause for concern as the leading cause of cancer-related death worldwide. Amidst ongoing debates on the role and mechanisms of methionine adenosyltransferase 1A (MAT1A) in cancer, our study sheds light on its significance in NSCLC. Leveraging TCGA database and immunohistochemical staining, we systematically analyzed MAT1A expression in NSCLC, uncovering its marked upregulation. To unravel the functional and mechanistic underpinnings, we implemented stable knockdown of MAT1A in NSCLC cell lines. Our findings converged to demonstrate that suppression of MAT1A expression effectively impeded the proliferation and migratory capabilities of NSCLC cells, while concurrently enhancing apoptosis. Mechanistically, we discovered that MAT1A depletion accelerated the degradation of CCND1, a key cell cycle regulator, through S-phase kinase-associated protein 2 (SKP2)-mediated ubiquitination. Notably, CCND1 emerged as a crucial MAT1A partner, jointly orchestrating glycolytic metabolism in NSCLC cells. This intricate interplay suggests that MAT1A promotes NSCLC progression by safeguarding CCND1 protein stability and activating glycolytic pathways, thereby sustaining tumorigenesis. In summary, our study not only identifies MAT1A as a prognostic marker for poor survival in NSCLC patients but also elucidates its mechanistic contributions to cancer progression. These findings pave the way for the development of targeted therapies aimed at disrupting the deleterious MAT1A-CCND1-glycolysis axis in NSCLC.

TERT Expression and Clinical Outcome in Pulmonary Carcinoids.

The clinical course of pulmonary carcinoids ranges from indolent to fatal disease, suggesting that specific molecular alterations drive progression toward the fully malignant state. A similar spectrum of clinical phenotypes occurs in pediatric neuroblastoma, in which activation of telomerase reverse transcriptase (TERT) is decisive in determining the course of disease. We therefore investigated whether TERT expression defines the clinical fate of patients with pulmonary carcinoid. TERT expression was examined by RNA sequencing in a test cohort and a validation cohort of pulmonary carcinoids (n = 88 and n = 105, respectively). A natural TERT expression cutoff was determined in the test cohort on the basis of the distribution of TERT expression, and its prognostic value was assessed by Kaplan-Meier survival estimates and multivariable analyses. Telomerase activity was validated by telomere repeat amplification protocol assay. Similar to neuroblastoma, TERT expression exhibited a bimodal distribution in pulmonary carcinoids, separating tumors into TERT-high and TERT-low subgroups. A natural TERT cutoff discriminated unfavorable from favorable clinical courses with high accuracy both in the test cohort (5-year overall survival [OS], 0.547 ± 0.132 v 1.0; P < .001) and the validation cohort (5-year OS, 0.788 ± 0.063 v 0.913 ± 0.048; P < .001). In line with these findings, telomerase activity was largely absent in TERT-low tumors, whereas it was readily detectable in TERT-high carcinoids. In multivariable analysis considering TERT expression, histology (typical v atypical carcinoid), and stage (≤IIA v ≥IIB), high TERT expression was an independent prognostic marker for poor survival, with a hazard ratio of 5.243 (95% CI, 1.943 to 14.148; P = .001). Our data demonstrate that high TERT expression defines clinically aggressive pulmonary carcinoids with fatal outcome, similar to neuroblastoma, indicating that activation of TERT may be a defining feature of lethal cancers.

Neuronal CFL1 upregulation in head and neck squamous cell carcinoma enhances tumor-nerve crosstalk and promotes tumor growth.

Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer type, marked by a pronounced nerve density within the tumor microenvironment and a high rate of perineural invasion (PNI). Growing evidence suggests that the nervous system plays a vital role in HNSCC progression. Yet, the mechanisms governing cancer-nerve interactions remain largely elusive. Our research revealed that cofilin-1 (CFL1) is significantly overexpressed in HNSCC and correlates with both PNI and unfavorable prognosis. Utilizing multiplex fluorescent immunohistochemistry, we have localized CFL1 chiefly to the nerves adjacent to tumor sites. Significantly, it is the elevated expression of CFL1 in neuronal structures, rather than in the tumor cells, that aligns with diminished patient survival rates. We observed that HNSCC cells induced the expression of neuronal CFL1 and that the conditional knockout of neuronal CFL1 impedes tumor-nerve interactions. Both Gene Ontology functional enrichment analyses and Gene Set Enrichment Analysis demonstrate that CFL1 expression in HNSCC is associated with specific biological processes, including "RIBOSOME," "PROTEASOME," and "cadherin binding." In summary, HNSCC promotes the expression of CFL1 in nerves, which is essential for cancer-nerve interactions. The neuronal CFL1 is associated with PNI and may be a potential molecular prognostic marker of poor survival in HNSCC.

Prognostic significance of prognostic nutritional index and hemoglobin to red cell distribution width ratio in metastatic colorectal cancer patients

Aims: Malnutrition and systemic inflammation are poor prognostic factors in cancer. Prognostic nutritional index (PNI) and Hemoglobin to red blood cell distribution witdh (HRR) are considered indicators of malnutrition and systemic inflammation. We aimed to investigate the prognostic importance of PNI and HRR on metastatic colorectal cancer survival.&#x0D; Methods: We retrospectively reviewed all patients diagnosed with metastatic colorectal cancer treated at Kayseri City Training and Research Hospital and Erciyes University Medical School. PNI is calculated as (serum albumin (g/L) +5 x total lymphocyte count (10⁹/L)). And HRR was calculated as the ratio of hemoglobin (g/dl) and RDW (%). PNI was divided into two groups based on the cut off points 46.175 as PNI high and low. And we compared these two groups according to general characteristics and overall survival. We performed another comparision between HRR low and high groups based on the cut off points 0.8675 according to general characteristics and overall survival. Kaplan Meier method was used to analyse overall survival and compared survival rates with the log-rank test.&#x0D; Results: We reviewed 346 metastatic colorectal cancer patients and we included 145 of them who fit to inclusion criteria to the study. Univariate analysis revealed that presence of initially metastatic disease, right located tumor, low HRR, low PNI were independent prognostic markers of poor overall survival. In multivariate analysis, presence of initially metastatic disease and low PNI remain statistically significant independent prognostic markers of poor survival. The median overall survival was statistically longer in HRR and PNI low groups than high groups.&#x0D; Conclusion: Both PNI and HRR are associated with poor overall survival in metastatic colorectal cancer.

Abstract 6341: Preclinical development of a monoclonal antibody targeting CD70 as cancer immunotherapy

Abstract CD70 is a novel immune checkpoint highly expressed on cancers of kidney, blood and lymphoid tissues, mesothelium and gastrointestinal system. High expression of CD70 is a prognostic marker for poor survival in patients with ovarian carcinoma, pancreatic cancer and mesothelioma, etc. Several CD70 antibodies are under early stages of clinical trials for oncology indications. We have developed IMM40H, a humanized IgG1 antibody that differentially induces phagocytosis and cytotoxicity in CD70-expressing cancer cells. Results of in vitro study have demonstrated that, in comparison with cusatuzumab, IMM40H possesses better CD70 binding (kD= 3.22E-11M) and functional inhibition ability, as well as more potent activities of ADCC (antibody-dependent cellular cytotoxicity, EC50 = 0.5 -2.0ng/ml) and CDC (complement-dependent cytotoxicity, EC50 = 170 ng/mL) against certain cancer cells. IMM40H also induces strong ADCP (antibody-dependent cellular phagocytosis) activity (EC50 = 0.02nM). At doses between 0.3 mg/kg to 10mg/kg, IMM40H significantly reduced tumor volume in mouse models of multiple myeloma, lymphoma and kidney cancer. Notably, in a U266 multiple myeloma model, IMM40H, at the dose of 0.3 mg/kg, completely inhibited tumor growth in a way that therapeutic effects appeared significantly earlier than that of cusatuzumab at a higher dose of 1 mg/kg. Therapeutic effects of IMM40H at the dose of 3 mg/kg also appeared earlier than that of bortezomib at the dose of 0.5 mg/kg. Interestingly, combination of IMM40H and IMM01 (a SIRPα-IgG1 Fc fusion protein targeting CD47) generated significant therapeutic synergy in models of A498 kidney cancer and Raji lymphoma. Importantly, maximum tolerated dose of IMM40H exceeds 100 mg/kg (IV, single dose) in cynomolgus monkeys and no significant adverse reaction was observed at a dose range of 3 to 30 mg/kg (IV, QW, 5 times) in monkeys. Taken together, our data show that targeting CD70 on tumor cells using IMM40H antibody may serve as a potent immunotherapy for multiple cancer indications. IND of IMM40H has been approved in China and US. This antibody is now in a phase 1 study in patients with advanced malignancies expressing CD70. Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Gui Zhao, Ruliang Zhang, Fan Zhang, Frank X. Gan. Preclinical development of a monoclonal antibody targeting CD70 as cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6341.

A controlling nutritional status score is an independent predictor for patients with newly diagnosed nasal-type extranodal NK/T-cell lymphoma based on asparaginase-containing regimens.

The controlling nutritional status (CONUT) score is a nutritional index that combines serum albumin, total cholesterol, and lymphocyte counts. The potential value of CONUT score for predicting clinical outcomes in patients with nasal-type extranodal NK/T-cell lymphoma (ENKTL) has not been explored. This study included 374 ENKTL patients treated with asparaginase-containing regimens from September 2012 to September 2017. Clinical characteristics, treatment efficacy, prognostic factors, and the predictive value of CONUT score were analyzed. The complete response (CR) and overall response rate (ORR) were 54.8% and 74.6%, respectively. Patients with CONUT scores <2 had higher CR and ORR compared to patients with scores ≥2 (69.1% vs. 48.9% for CR, p= 0.001; 90.0% vs. 74.6% for ORR, p< 0.001). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 61.9% and 57.3%, respectively. Patients with CONUT scores <2 had better survival outcomes than those with scores ≥2 (5-year OS, 76.1% vs. 56.0%, p< 0.001; 5-year PFS, 74.4% vs. 50.1%, p< 0.001). CONUT score ≥2 was identified as an independent poor prognostic factor for both OS and PFS. A CONUT score ≥2 was also associated with poorer survival outcomes in low-risk ENKTL patients. A CONUT score ≥2 is a prognostic marker for poor survival in patients with ENKTL and could be used to stratify risk in low-risk patients.

The prognostic value and biological significance of gap junction beta protein 2 (GJB2 or Cx26) in cervical cancer.

ObjectiveTo evaluate the prognostic value and explore the biological significance of gap junction protein beta 2 (GJB2 or Cx26) in cervical cancer (CC).MethodsWe first compared GJB2 expression between CC and normal tissues using public databases and immunohistochemistry (IHC). Based on The Cancer Genome Atlas data (TCGA cohort, n = 304) and tissue microarray samples (OBC cohort, n = 111), we explored the prognostic value of GJB2 for CC patients using bioinformatics analysis and IHC scoring. To explore the biological significance of GJB2, Gene set enrichment analysis (GSEA) and Gene Ontology (GO) were performed. The impact of GJB2 on the immune microenvironment was analyzed by CIBERSORTx and ESTIMATE algorithms. We finally investigated the relationship between GJB2 and drug sensitivity based on the Genomics of Drug Sensitivity in Cancer (GDSC).ResultsThe expression of GJB2 was significantly increased in CC over normal tissues. Both the TCGA and OBC cohort found that patients with high GJB2 expression had shorter overall survival (OS) time, and high GJB2 expression was the independent risk factor for prognosis (TCGA: HR, 2.566; 95% CI, 1.066–6.180; p = 0.036; OBC: HR, 2.198; 95% CI, 1.019–4.741; p = 0.045). GJB2 was correlated with patient clinical factors such as tumor size and differentiation grade. The p53 signaling pathway and toll-like receptor pathway may be regulated by GJB2. The abundance of various immune cells was significantly different between the low and high GJB2 expression groups. The ImmuneScore was significantly increased in the high GJB2 expression group. In addition, the expression level of GJB2 was positively correlated with the natural log of the half-maximal inhibitory concentration (LN_IC50) value of cisplatin/paclitaxel (Spearman r = 0.238/0.153, p < 0.001).ConclusionGJB2 can serve as a potential prognostic marker of poor survival and a therapeutic target in CC. Moreover, GJB2 may affect the immune microenvironment and is correlated with chemoresistance.

Prognostic value of soluble programmed cell death ligand-1 in patients with non-small-cell lung cancer: a meta-analysis.

Background: Previously published data was collected and a meta-analysis was conducted to precisely identify the prognostic and clinicopathological significance of soluble programmed cell death ligand-1 (sPD-L1) in patients with non-small-cell lung cancer (NSCLC). Materials & methods: Combined hazard ratios (HRs), odds ratios and 95% confidence intervals were used to assess the correlation between sPD-L1 expression and prognosis in patients with NSCLC. Results: A total of 11 studies with 976 patients were included in this meta-analysis. High levels of sPD-L1 were associated with poor overall and progression-free survival (HR: 2.65, 95% CI: 2.32-3.02; p<0.001 vs HR: 2.02, 95% CI: 1.24-3.29; p =0.005). sPD-L1 level was not significantly correlated with sex, smoking status, age, Eastern Cooperative Oncology Group performance status, subtype or EGFR mutation. Conclusion: High levels of sPD-L1 are a prognostic marker for poor survival in patients with NSCLC.

Abstract 635: Concordance between dogs and humans: The use of AI in evaluating clinical cancer genomic datasets

Abstract Spontaneous tumors in dogs are highly similar to human cancers histologically, genetically, molecularly and clinically. In this presentation we explore similarities found across species when associating cancer biomarkers and outcomes. Our findings validate concordance across the cancer journeys. This is important to deepen the field of comparative oncology and affirming spontaneous cancer in dogs as an ideal ‘model’ for precision oncology, building upon recent work in tumor biology concordance. Our machine learning analysis prognosis and predictive effect of genomic alterations in 1303 client-owned tumor-bearing dogs identified TP53 and PTPRD as prognostic markers for poor survival in dogs with an overall survival hazard ratio (OS HR) of 1.732, 1.914, respectively (P&amp;lt;0.001 and P=0.023). These results are aligned with non-small cell lung cancer, metastatic breast cancer and pancreatic cancer in people correlated with poor survival when carrying TP53 mutation, and PTPRD also correlated with poor survival in gliomas. Besides that, we also identified ALB1 and PIK3CA prognostic markers for poor survival in canine tumors with an overall survival hazard ratio (OS HR) of 1.707, 1.689, respectively (P=0.01, and P=0.002). This data reaffirms the similarity between canine and human cancers not just in the genomic profiles but also the tumor biology and treatment strategy for both species. Among tumor types, lymphoma and hemangiosarcoma showed the worst survival times (N=32, OS HR=1.929, P=0.002, and N=202, OS HR=1.743, P&amp;lt;0.001). Interestingly, we also identified that dogs with RET mutations respond better to toceranib, a veterinary oral multikinase inhibitor against RET, VEGFR2, PDGFR, FLT3 and c-KIT; this is in concordance with sunitinib a tyrosine kinase inhibitor that target RET used in humans thyroid carcinomas and other tumors carrying RET mutations. To the best of our knowledge, this is the largest canine tumor clinical genomic dataset analysis. Applying real-world evidence and data tools in the FidoCure® dataset, we successfully identified associations between gene mutations and survival associated with response to target therapy treatment. These associations can benefit dogs by enabling better therapeutic recommendations and also benefit human cancer research since canine models recapitulate human disease with intact immune systems and similar tumor genomic profiles, confirmed by the FidoCure® database, accelerating clinical studies of novel treatments that currently have significant barriers to study at scale. Citation Format: Kevin Wu, Lucas Rodrigues, Gerald Post, Garrett Harvey, Aubrey Miller, Lindsay Lambert, Christina Lopes, Benjamin Lewis, James Zou. Concordance between dogs and humans: The use of AI in evaluating clinical cancer genomic datasets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 635.

Molecular mechanisms of tumour budding and its association with microenvironment in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide. Poor survival of CRC associated with the development of tumour metastasis led to the investigation of the potential biomarkers to predict outcomes in CRC patients. Tumour budding (TB) is a well-known independent prognostic marker for poor survival and disease metastasis. Therefore, it has been suggested that TB status is included in routine clinicopathological factors for risk assessment in CRC. In contrast with a vast majority of studies regarding the prognostic power of TB, there is no clear evidence pertaining to the underlying molecular mechanism driving this phenotype, or an understanding of TB relationship with the tumour microenvironment (TME). The aim of the present study is to present a comprehensive review of TB and tumour cell signalling pathways together with the cross-talk of immune cells that could drive TB formation in CRC.

Abstract P3-05-03: KMT2D as a novel therapeutic target for HER2+ breast cancers

Abstract Background: Breast cancer is the second leading cause of cancer-related deaths among women in the US. Major factors that contribute to breast cancer carcinogenesis include disruptions in both genetic and epigenetic processes. Histone modifications and DNA-methylation are common epigenetic changes that have been implicated in several breast cancers, including an aggressive subset known as human epidermal growth factor receptor 2 (HER2+) breast cancers. One prognostic marker for poor survival in women with HER2+ breast cancer is high RNA expression of the critical epigenetic regulator, Histone-lysine methyltransferase 2D (KMT2D). KMT2D belongs to a family of histone modifying proteins which plays an essential role in regulating developmental processes. Specifically, KMT2D is a histone methyltransferase that monomethylates histone 3 lysine 4 at enhancers throughout the genome and is required for transcriptional activation. Interestingly, in HER2+ cells (BT474), KMT2D mRNA was found to be significantly increased in stem-like tumor initiating cells (TICs) compared to bulk cells. BT474 cells that have acquired resistance to trastuzumab (BTR) from prolonged treatment express higher levels of KMT2D than those of the isogenic parental sensitive cells (BTS). Furthermore, siRNA-specific knockdown of KMT2D significantly decreased bulk cell proliferation in both BTS and BTR cells, and significantly inhibited TIC survival in BTS cells. Thus, we hypothesized that KMT2D is a critical epigenetic regulator that contributes to resistance by promoting bulk cell proliferation and TIC survival. Methods: RNA-sequencing was performed in BTS and BTR cells-expressing or depleted for KMT2D. Differentially regulated genes were identified and pathway analysis was performed. Chromatin immunoprecipitation (ChIP) PCR and sequencing were performed to identify novel KMT2D-bound regions in both BTS and BTR cells. SiRNA induced silencing was also utilized to study various gene functions in BT474 cells. Results: We identified and confirmed by RT-qPCR several differentially expressed genes that were positively and negatively regulated by KMT2D, suggesting they may be critical direct targets of KMT2D. One gene, ITGB6, encodes for integrin subunit beta 6 and was found to be decreased upon KMT2D depletion. ITGB6 regulates multiple processes which contribute to cancer progression and metastases, including cellular proliferation and epithelial-mesenchymal transition. Similar to KMT2D knockdown, ITGB6 knockdown resulted in decreased BTS and BTR bulk cell proliferation and a reduction in TICs. Interestingly, KMT2D enrichment at an ITGB6 enhancer region was lower in resistant cells compared to sensitive cells. Future studies will include knockdown of KMT2D with simultaneous rescue of wild type or a mutant of ITGB6 to determine if KMT2D-mediated increase in ITGB6 is required for HER2+ cell growth and/or TIC survival. Furthermore, our data also suggests an anti-apoptotic and cell-cell adhesion role for KMT2D, which may in part be due to its direct effects on ITGB6. Additional future studies will investigate the mechanism of how KMT2D regulates its target genes through ChIP-sequencing analysis as well as studies to evaluate KMT2D’s role in vivo. Conclusions: Our results suggest a critical role for KMT2D in HER2+ breast cancer progression, and may yield novel therapeutic targets and pathways for the treatment of HER2+ breast cancers. Citation Format: Emily Ma, Andrei Zlobin, Debra Wyatt, Jeffrey Ng, Andrew Dingwall, Clodia Osipo. KMT2D as a novel therapeutic target for HER2+ breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-05-03.

BCAR3 promotes head and neck cancer growth and is associated with poor prognosis

Breast cancer anti-estrogen resistance protein 3 (BCAR3) is involved in anti-estrogen resistance and other important aspects of breast cancer. However, the role of BCAR3 in other solid tumors remains unclear. The relationship between the clinicopathologic characteristics of head and neck squamous cell carcinoma (HNSCC) patients and BCAR3 was analyzed using the Wilcoxon’s signed-rank test and logistic regression. The association between BCAR3 expression and clinicopathologic features and survival was analyzed using Cox regression and the Kaplan–Meier method. In vivo and in vitro assays were performed to validate the effect of BCAR3 on HNSCC growth. BCAR3-related mRNAs were determined by calculating the Pearson’s correlation coefficient based on The Cancer Genome Atlas (TCGA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and gene set enrichment analysis (GSEA) were used to predict the potential functions of BCAR3. BCAR3 expression is overexpressed in HNSCC and was shown to be associated with perineural invasion (PNI) and poor survival. BCAR3 silencing significantly attenuated the proliferation of HNSCC cells, whereas BCAR3 depletion inhibited tumor growth in vitro. GO and KEGG functional enrichment analyses, and GSEA showed that BCAR3 expression in HNSCC was associated with biological processes, such as cell adhesion, actin binding, cadherin binding, and angiogenesis. BCAR3, which promotes HNSCC growth, is associated with perineural invasion and may be a potential molecular prognostic marker of poor survival in HNSCC.

Prognostic Significance of JMJD3 Expression in Pleural Mesotheliomas

Pleural mesothelioma is a disease associated with asbestos exposure and patients often have poor prognosis. Biomarkers that can stratify tumours more efficiently are much sought after to enable more personalized treatment options and predict prognosis. Jumonji domain-containing protein D3 (JMJD3) has variable expression in a range of tumours. However, there has been much discordance in the immunohistochemical labelling of JMJD3 between cancers at different sites and ambiguity exists regarding its functional significance. Recent evidence suggests that although nuclear expression of JMJD3 has a demethylase role in most cancers, there are also demethylase-independent actions of JMJD3 that need to be explored including its cytoplasmic expression. We analysed JMJD3 labelling in 99 pleural mesothelioma tissues and correlated nuclear and cytoplasmic expression with survival outcomes. We found that low nuclear and high cytoplasmic expression were associated with poor survival outcomes in our cohort (p = 0.014 and p = 0.041, respectively). Additionally, we found that low nuclear expression of JMJD3 was frequent in the sarcomatoid subtype (p &lt; 0.001). Finally, we showed that cytoplasmic labelling is an independent prognostic marker of poor survival. Our cohort only contained a small number of tumours with high cytoplasmic expression of JMJD3, and a larger cohort study may provide clearer stratification.

Aspirin-Triggered Resolvin D1 Reduces Proliferation and the Neutrophil to Lymphocyte Ratio in a Mutant KRAS-Driven Lung Adenocarcinoma Model.

Simple SummaryAspirin-triggered resolvin D1 (AT-RvD1) is biosynthesised by leukocytes as a mechanism to resolve inflammation during infection and/or injury. Emerging studies reveal that AT-RvD1 also has anti-cancer properties associated with stimulating macrophage-mediated clearance of tumour debris. No study to date has investigated how AT-RvD1 influences the neutrophil to lymphocyte ratio (NLR) in lung cancer, an established marker of poor prognosis. The biosynthesis of AT-RvD1 is dependent on the ALOX5 gene, and we reveal that ALOX5 mRNA expression was markedly reduced in lung adenocarcinoma tumours. We next utilised an oncogenic KrasG12D lung adenocarcinoma mouse model to investigate the efficacy of AT-RvD1 in vivo. We show for the first time that AT-RvD1 reduces tumour growth in the lungs of KrasG12D mice and alters the immune landscape in tumours by reducing the NLR.Tumour-associated neutrophils (TANs) can support tumour growth by suppressing cytotoxic lymphocytes. AT-RvD1 is an eicosanoid that can antagonise neutrophil trafficking instigated by ALX/FPR2 ligands such as serum amyloid A (SAA). We aimed to establish whether SAA and ALOX5 expression associates with TANs and investigate the immunomodulatory actions of AT-RvD1 in vivo. MPO-positive neutrophils were quantified in tumour blocks from lung adenocarcinoma (n = 48) and control tissue (n = 20) by IHC. Tumour expression of SAA and ALOX5 were analysed by RTqPCR and an oncogenic KrasG12D lung adenocarcinoma mouse model was used to investigate the in vivo efficacy of AT-RvD1 treatment. ALOX5 expression was markedly reduced in lung adenocarcinoma tumours. The SAA/ALOX5 ratio strongly correlated with TANs and was significantly increased in tumours harbouring an oncogenic KRAS mutation. AT-RvD1 treatment reduced tumour growth in KrasG12D mice, which was accompanied by suppressed cellular proliferation within parenchymal lesions. In addition, AT-RvD1 significantly reduced the neutrophil to lymphocyte ratio (NLR), an established prognostic marker of poor survival in adenocarcinoma. This study identifies a novel molecular signature whereby elevated levels of SAA relative to ALOX5 favour accumulation of TANs. Furthermore, the ALOX5/5-LO enzymatic product, AT-RvD1, markedly reduced the NLR and suppressed tumour growth in KrasG12D mice.

IgD Subtype But Not IgM or Non-Secretory Is a Prognostic Marker for Poor Survival Following Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Results From the EBMT CALM (Collaboration to Collect Autologous Transplant Outcomes in Lymphomas and Myeloma) Study

BackgroundThe Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study has provided an opportunity to evaluate the real-world outcomes of patients with myeloma. The aim of this study was to compare the outcome according to the different subtypes of myeloma using CALM data. PatientsThis study compared overall survival (OS), progression-free survival (PFS), and complete remission (CR) and the impact of novel versus non-novel drug containing induction regimens prior to autologous hematopoietic cell transplantation (HCT) of 2802 patients with “usual” and “rare” myelomas. ResultsOur data suggest that IgM and non-secretory myeloma have superior PFS and OS compared with IgD myeloma and outcomes comparable to those for usual myeloma. Patients who received novel agent induction had higher rates of CR prior to transplant. Non-novel induction regimens were associated with inferior PFS but no difference in OS. Although not the primary focus of this study, we show that poor mobilization status is associated with reduced PFS and OS, but these differences disappear in multivariate analysis suggesting that poor mobilization status is a surrogate for other indicators of poor prognosis. ConclusionWe confirm that IgD myeloma is associated with the worst prognosis and inferior outcomes compared with the other isotypes.

Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer.

Rationale: Little is known about the roles of proteoglycans in esophageal cancer. This study aims to investigate the roles and mechanisms of serglycin (SRGN) proteoglycan in promoting metastasis of esophageal squamous cell carcinoma (ESCC).Methods: Reverse phase protein array analysis was used to identify activated signaling pathways in SRGN-overexpressing cells. Chemokine array was used to identify differentially secreted factors from SRGN-overexpressing cells. Binding between SRGN and potential interacting partners was evaluated using proximity ligation assay and co-immunoprecipitation. The glycosaminoglycan (GAG) chains of SRGN were characterized using fluorophore-assisted carbohydrate electrophoresis. Tissue microarray and serum samples were used to determine the correlation of SRGN expression with clinicopathological parameters and patient survival.Results: In vitro and in vivo experiments showed that SRGN promoted invasion and metastasis in ESCC via activating ERK pathway, stabilizing c-Myc and upregulating the secretion of matrix metalloproteinases. SRGN-knockdown suppressed tumorigenic hallmarks. These SRGN-elicited functions were carried out in an autocrine manner by inducing the secretion of midkine (MDK), which was further identified as a novel binding partner of SRGN for the formation of a SRGN/MDK/CD44 complex. In addition, SRGN interacted with MDK and matrix metalloproteinase 2 in ESCC via its GAG chains, which were mainly decorated with chondroitin sulfate comprising of ∆di-4S and ∆di-6S CS. Clinically, high expression of serum SRGN in serum of patients with ESCC was an independent prognostic marker for poor survival.Conclusions: This study provides the first evidence that elevated serum SRGN has prognostic significance in patients with ESCC, and sheds light on the molecular mechanism by which elevated circulating SRGN in cancer patients might promote cancer progression.

Anillin is a prognostic factor and is correlated with genovariation in pancreatic cancer based on databases analysis.

Pancreatic cancer has a low survival rate globally. Anillin (ANLN) is involved in the pathogenesis of pancreatic cancer (PC). The present study used databases and reverse transcription-quantitative PCR to investigate the association between ANLN expression, clinical variables and the survival rate of patients with pancreatic cancer. Gene expression of ANLN in normal and cancer tissues was analyzed using data from The Cancer Genome Atlas, Oncomine and Gene Expression database of Normal and Tumor tissues 2 and ANOVA, and the association between ANLN mRNA expression and ANLN genovariation was analyzed using cBioPortal. The association between ANLN expression and the survival, clinical, pathological and prognostic characteristics of PC was analyzed using Kaplan-Meier (K-M) survival analysis, Kruskal Wallis and Mann Whitney-U tests, and logistic and Cox regression models. Gene Set Enrichment Analysis (GSEA) revealed the molecular pathways underpinning ANLN function in PC. Overexpression of ANLN was observed in PC cells (normal vs. tumor, P<0.01) and tissues (normal vs. tumor, P=0.008). Enhanced ANLN expression was associated with high tumor grade (grade 1 vs. grade 3, odds ratio: 5.662, P<0.001). However, ANLN expression was not associated with other clinical features (all P>0.05). K-M analysis suggested that increased ANLN expression was associated with poor survival (P=0.002). Univariate and multivariate analysis revealed the ANLN is an independent prognostic factor for PC (P<0.001). GSEA demonstrated the p53, cell cycle, DNA replication, mismatch repair, nucleotide excision repair and PC pathways were associated with low expression of ANLN. Overall, ANLN is more highly expressed in PC compared with in normal tissue, and is associated with poor differentiation. The expression of ANLN may be a novel prognostic marker of poor survival. Finally, ANLN exert its functions in PC through the p53, cell cycle, DNA replication, mismatch repair and nucleotide excision repair and pathways.

GJA1 Expression and Its Prognostic Value in Cervical Cancer.

Gap Junction Protein Alpha 1 (GJA1) belongs to the gap junction family and has been widely studied in cancers. We evaluated the role of GJA1 in cervical cancer (CC) using public data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. The difference of GJA1 expression level between CC and normal tissues was analyzed by the Gene Expression Profiling Interactive Analysis (GEPIA), six GEO datasets, and the Human Protein Atlas (HPA). The relationship between clinicopathological features and GJA1 expression was analyzed by the chi-squared test and the logistic regression. Kaplan–Meier survival analysis and Cox proportional hazard regression analysis were used to assessing the effect of GJA1 expression on survival. Gene set enrichment analysis (GSEA) was used to screen the signaling pathways regulated by GJA1. Immune Cell Abundance Identifier (ImmuCellAI) was chosen to analyze the immune cells affected by GJA1. The expression of GJA1 in CC was significantly lower than that in normal tissues based on the GEPIA, GEO datasets, and HPA. Both the chi-squared test and the logistic regression showed that high-GJA1 expression was significantly correlated with keratinization, hormone use, tumor size, and FIGO stage. The Kaplan–Meier curves suggested that high-GJA1 expression could indicate poor prognosis (p = 0.0058). Multivariate analysis showed that high-GJA1 expression was an independent predictor of poor overall survival (HR, 4.084; 95% CI, 1.354-12.320; p = 0.013). GSEA showed many cancer-related pathways, such as the p53 signaling pathway and the Wnt signaling pathway, were enriched in the high-GJA1-expression group. Immune cell abundance analysis revealed that the abundance of CD8 naive, DC, and neutrophil was significantly increased in the high-GJA1-expression group. In conclusion, GJA1 can be regarded as a potential prognostic marker of poor survival and therapeutic target in CC. Moreover, many cancer-related pathways may be the critical pathways regulated by GJA1. Furthermore, GJA1 can affect the abundance of immune cells.

HOXC9 overexpression is associated with gastric cancer progression and a prognostic marker for poor survival in gastric cancer patients.

As a member of the homeobox family, HOXC9 is overexpressed in several malignant tumors and may be regarded as a biomarker for prognostic evaluation. However, the expression pattern and prognostic significance of HOXC9 in gastric cancer have not been detailedly studied. HOXC9 mRNA expression difference in normal tissues and gastric cancer tissues were investigated using RT-PCR, and immunohistochemistry was used to analyze HOXC9 protein expression in precancerous lesions and gastric cancer at different stages, and its clinicopathological characteristics and survival were statistically tested. Compared to the normal gastric mucosa tissues, the expression levels of HOXC9 mRNA in the human gastric cancer tissues were significantly higher. HOXC9 protein levels of gastric cancer were obviously higher than that in other noncancerous tissues (P < 0.001). Positive expression of HOXC9 was associated with tumor size (P = 0.036), lymphatic invasion (P = 0.001), depth of invasion (P < 0.001), lymph-node metastasis (P < 0.001), and higher stage disease (P < 0.001). Furthermore, Kaplan-Meier survival curves showed that HOXC9 expression is inversely correlated with both disease-specific and disease-free 5year survival of patients with gastric cancer (P < 0.001 for both). Strikingly, our multivariate Cox regression analysis revealed that HOXC9 expression was an independent poor prognostic factor in gastric cancer (P < 0.05). HOXC9 expression was observed in a subset of patients with gastric cancer and was associated with an unfavorable prognosis. As well as being a new prognostic indicator, HOXC9 protein could be a useful marker for early diagnosis.

Expression of SIRT1, SIRT3 and SIRT6 Genes for Predicting Survival in Triple-Negative and Hormone Receptor-Positive Subtypes of Breast Cancer.

Triple-negative breast cancer (TNBC) is characterized by aggressive phenotype and a poorer prognosis compared to the estrogen and progesterone receptor positive, Her2 negative (ER + PR + Her2-) breast cancer. Increasing evidence suggests that sirtuins, a family of histone deacetylases, could have an important role in aggressiveness of TNBC's. The current study evaluated the potential clinical relevance of SIRT1, SIRT3 and SIRT6 gene expressions in two prognostically distinctive subtypes of breast cancer, the most aggressive TNBC and the least aggressive ER + PR + Her2- tumors. Total RNAs were isolated from 48 TNBC and 63 ER + PR + Her2- tumor samples. Relative gene expression was determined by SYBR Green RT-PCR and delta-delta Ct method, normalized to GAPDH. Mean gene expression of both SIRT1 and SIRT3 was significantly lower in the TNBC compared to ER + PR + Her2- tumors (p = 0.0001). Low SIRT1 and SIRT6 expressions associated with worse overall survival in ER + PR + Her2- patients (p = 0.039, p = 0.006, respectively), while TNBC patients with high SIRT1 tend to have a poor prognosis (p = 0.057). In contrast, high expression of SIRT3 in TNBC patients associated with higher histological grade (p = 0.027) and worse overall survival (p = 0.039). The Cox regression analysis revealed that low SIRT1 expression could be an independent prognostic marker of poor survival in ER + PR + Her2- breast cancers (HR = 11.765, 95% CI:1.234-100, p = 0.033). Observed differential expression of SIRT1, SIRT3 and SIRT6 genes in TNBC and ER + PR + Her2- subtypes, with opposite effects on patients' survival, suggests context-dependent mechanisms underlying aggressiveness of breast cancer. Further investigations are necessary to evaluate sirtuins as potential biomarkers and therapeutic targets in breast cancer.