Sex differences in the prognostic significance of KRAS codons 12 and 13, and BRAF mutations in colorectal cancer: a cohort study

Background

Activating KRAS and BRAF mutations predict unresponsiveness to EGFR-targeting therapies in colorectal cancer (CRC), but their prognostic value needs further validation. In this study, we investigated the impact of KRAS codons 12 and 13, and BRAF mutations on survival from CRC, overall and stratified by sex, in a large prospective cohort study.

Methods

KRAS codons 12 and 13, and BRAF mutations were analysed by pyrosequencing of tumours from 525 and 524 incident CRC cases in The Malmö Diet and Cancer Study. Associations with cancer-specific survival (CSS) were explored by Cox proportional hazards regression, unadjusted and adjusted for age, TNM stage, differentiation grade, vascular invasion and microsatellite instability (MSI) status.

Results

KRAS and BRAF mutations were mutually exclusive. KRAS mutations were found in 191/ 525 (36.4%) cases, 82.2% of these mutations were in codon 12, 17.3% were in codon 13, and 0.5% cases had mutations in both codons. BRAF mutations were found in 78/524 (14.9%) cases. Overall, mutation in KRAS codon 13, but not codon 12, was associated with a significantly reduced CSS in unadjusted, but not in adjusted analysis, and BRAF mutation did not significantly affect survival. However, in microsatellite stable (MSS), but not in MSI tumours, an adverse prognostic impact of BRAF mutation was observed in unadjusted, but not in adjusted analysis. While KRAS mutation status was not significantly associated with sex, BRAF mutations were more common in women. BRAF mutation was not prognostic in women; but in men, BRAF mutation was associated with a significantly reduced CSS in overall adjusted analysis (HR = 3.50; 95% CI = 1.41–8.70), but not in unadjusted analysis. In men with MSS tumours, BRAF mutation was an independent factor of poor prognosis (HR = 4.91; 95% CI = 1.99–12.12). KRAS codon 13 mutation was associated with a significantly reduced CSS in women, but not in men in unadjusted, but not in adjusted analysis.

Conclusions

Results from this cohort study demonstrate sex-related differences in the prognostic value of BRAF mutations in colorectal cancer, being particularly evident in men. These findings are novel and merit further validation.

     

Pre-treatment prognostic nutritional index may serve as a potential biomarker in urinary cancers: a systematic review and meta-analysis

Background

To investigate the potential prognostic role of pre-treatment prognostic nutritional index (PNI) in urinary cancers.

Methods

Relevant articles were searched comprehensively from PubMed, Embase and Web of Science, up to November 2018. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted to evaluate their associations.

Result

A total of 12 related articles including 6561 patients were ultimately enrolled. Our results indicated that a relatively lower level of pre-treatment PNI was associated with decreased OS, CSS/DSS and DFS/RFS/PFS (pooled HR?=?1.68, 95% CI 1.45–1.95; pooled HR?=?1.57, 95% CI 1.33–1.86; pooled HR?=?1.75, 95% CI 1.53–1.99, respectively). Subsequent stratified analysis by cancer type for OS showed that PNI could also be a predictor no matter in renal cell cancer (RCC) or bladder cancer (BC) (pooled HR?=?1.65, 95% CI 1.37–1.97 and pooled HR?=?1.67, 95% CI 1.20–2.33). Similar results could be found in DFS/RFS/PFS (RCC: HR?=?1.81, 95% CI 1.54–2.13 and BC: HR?=?1.68, 95% CI 1.32–2.12) and in CSS/DSS (RCC: HR?=?1.50, 95% CI 1.23–1.82 and upper tract urothelial carcinoma: HR?=?1.61, 95% CI 1.13–2.28). As for the treatment subgroup, a relatively lower level of PNI could also be a positive predictor for OS (surgery: HR?=?1.64, 95% CI 1.40–1.93; target therapy: HR?=?1.88, 95% CI 1.34–2.63) and DFS/RFS/PFS (surgery: HR?=?1.69, 95% CI 1.47–1.95; target therapy: HR?=?2.14, 95% CI 1.50–3.05).

Conclusion

The outcomes of us shed light on that elevated pre-treatment PNI was positively associated with OS, CSS/DSS and DFS/RFS/PFS, indicating that it could be an independent prognostic factor in urinary cancers.

     

A methodology for elucidating regulatory mechanisms leading to changes in lipid profiles

Introduction

It is difficult to elucidate the metabolic and regulatory factors causing lipidome perturbations.

Objectives

This work simplifies this process.

Methods

A method has been developed to query an online holistic lipid metabolic network (of 7923 metabolites) to extract the pathways that connect the input list of lipids.

Results

The output enables pathway visualisation and the querying of other databases to identify potential regulators. When used to a study a plasma lipidome dataset of polycystic ovary syndrome, 14 enzymes were identified, of which 3 are linked to ELAVL1—an mRNA stabiliser.

Conclusion

This method provides a simplified approach to identifying potential regulators causing lipid-profile perturbations.

     

Characterizing biomarkers in osteosarcoma metastasis based on an ego-network

Objectives

To characterize biomarkers that underlie osteosarcoma (OS) metastasis based on an ego-network.

Results

From the microarray data, we obtained 13,326 genes. By combining PPI data and microarray data, 10,520 shared genes were found and constructed into ego-networks. 17 significant ego-networks were identified with p < 0.05. In the pathway enrichment analysis, seven ego-networks were identified with the most significant pathway.

Conclusions

These significant ego-modules were potential biomarkers that reveal the potential mechanisms in OS metastasis, which may contribute to understanding cancer prognoses and providing new perspectives in the treatment of cancer.

     

RNA binding protein Lin28A promotes osteocarcinoma cells progression by associating with the long noncoding RNA MALAT1

Objectives

To explore the effects of Lin28A on progression of osteocarcinoma (OS) cells.

Results

Lin28A mRNA and protein expressions were significantly increased in OS tissues compared with that in normal adjacent tissues. Expressions of Lin28A and long noncoding RNA MALAT1 were positively correlated. Patients with higher Lin28A expression had shorter overall survival. Moreover, Lin28A knockdown inhibited OS cells proliferation, migration, invasion and promoted cell apoptosis; Lin28A was found to harbor binding sites on MALAT1 sequences and associated with MALAT1, and increased MALAT1 stability and expression. Notably, the inhibition of Lin28A knockdown was attenuated or even reversed by MALAT1 overexpression.

Conclusions

RNA binding protein Lin28A could facilitate OS cells progression by associating with the long noncoding RNA MALAT1.

     

Pseudomyxoma extraperitonei occurring 35 years after appendicectomy: a case report and review of literature

Background

Pseudomyxoma peritonei is a rare condition consisting of mucinous ascites, most commonly arising from mucinous tumors of the appendix and occasionally from the ovary. Very rarely mucinous implants arise in the retroperitoneum without any intra-peritoneal involvement. This has been termed as pseudomyxoma extraperitonei.

Case presentation

We report a case of a 57 year old man who developed pseudomyxoma extraperitonei, 35 years after undergoing an appendicectomy for a perforated appendix.

Conclusions

Pseudomyxoma extraperitonei has been previously reported, however we report the longest incubation period of 35 years for this condition.

     

Type 2 diabetes increases oocyte mtDNA mutations which are eliminated in the offspring by bottleneck effect

Background

Diabetes induces many complications including reduced fertility and low oocyte quality, but whether it causes increased mtDNA mutations is unknown.

Methods

We generated a T2D mouse model by using high-fat-diet (HFD) and Streptozotocin (STZ) injection. We examined mtDNA mutations in oocytes of diabetic mice by high-throughput sequencing techniques.

Results

T2D mice showed glucose intolerance, insulin resistance, low fecundity compared to the control group. T2D oocytes showed increased mtDNA mutation sites and mutation numbers compared to the control counterparts. mtDNA mutation examination in F1 mice showed that the mitochondrial bottleneck could eliminate mtDNA mutations.

Conclusions

T2D mice have increased mtDNA mutation sites and mtDNA mutation numbers in oocytes compared to the counterparts, while these adverse effects can be eliminated by the bottleneck effect in their offspring. This is the first study using a small number of oocytes to examine mtDNA mutations in diabetic mothers and offspring.

     

Immunohistochemical investigation of prognostic biomarkers in resected colorectal liver metastases: a systematic review and meta-analysis

Background

Many studies have investigated the prognostic role of biomarkers in colorectal liver metastases (CRLM). However, no biomarker has been established in routine clinical practice. The aim of this study was to scrutinize the current literature for biomarkers evaluated by immunohistochemistry as prognostic markers in patients with resected CRLM.

Methods

A systematic review was performed according to the PRISMA guidelines. Articles were identified in the PubMed database with selected search terms and by cross-references search. The REMARK quality criteria were applied. Markers were included if they reported the prognostic impact of immunohistochemical markers in a multivariable setting in relation to overall survival (OS). A meta-analysis was conducted when more than one original article provided survival data of a marker.

Results

In total, 26 biomarkers were identified as independent significant markers for OS in resected CRLM. These biomarkers were found to be involved in multiple oncogenic signalling pathways that control cell growth, apoptosis, angiogenesis and evasion of immune detection. Among these biomarker candidates were Ki-67, EGFR, p53, hTERT, CD34, TSP-1, KISS1, Aurora kinase A and CDX2. CD34 and TSP-1 were reported as significantly associated with survival by more than one study and where therefore pooled in a meta-analysis.

Conclusion

A number of independent prognostic biomarkers for resected CRLM were identified. However, most markers were evaluated in a retrospective setting with small patient cohorts, without external validation. Large, prospective, multicentre studies with standardised methods are needed before biomarkers can translated into the clinic.

     

Microarray-based analysis and clinical validation identify ubiquitin-conjugating enzyme E2E1 (<Emphasis Type="Italic">UBE2E1</Emphasis>) as a prognostic factor in acute myeloid leukemia

Background

Previous research suggested that single gene expression might be correlated with acute myeloid leukemia (AML) survival. Therefore, we conducted a systematical analysis for AML prognostic gene expressions.

Methods

We performed a microarray-based analysis for correlations between gene expression and adult AML overall survival (OS) using datasets GSE12417 and GSE8970. Positive findings were validated in an independent cohort of 50 newly diagnosed, non-acute promyelocytic leukemia (APL) AML patients by quantitative RT-PCR and survival analysis.

Results

Microarray-based analysis suggested that expression of eight genes was each associated with 1-year and 3-year AML OS in both GSE12417 and GSE8970 datasets (p?<?0.05). Next, we validated our findings in an independent cohort of AML samples collected in our hospital. We found that ubiquitin-conjugating enzyme E2E1 (UBE2E1) expression was adversely correlated with AML survival (p?=?0.04). Multivariable analysis showed that UBE2E1 ^high patients had a significant shorter OS and shorter progression-free survival after adjusting other known prognostic factors (p?=?0.03). At last, we found that UBE2E1 expression was negatively correlated with patients’ response to induction chemotherapy (p?<?0.05).

Conclusions

In summary, we demonstrated that UBE2E1 expression was a novel prognostic factor in adult, non-APL AML patients.

     

Optimization of fecal sample preparation for untargeted LC-HRMS based metabolomics

Introduction

Collecting feces is easy. It offers direct outcome to endogenous and microbial metabolites.

Objectives

In a context of lack of consensus about fecal sample preparation, especially in animal species, we developed a robust protocol allowing untargeted LC-HRMS fingerprinting.

Methods

The conditions of extraction (quantity, preparation, solvents, dilutions) were investigated in bovine feces.

Results

A rapid and simple protocol involving feces extraction with methanol (1/3, M/V) followed by centrifugation and a step filtration (10 kDa) was developed.

Conclusion

The workflow generated repeatable and informative fingerprints for robust metabolome characterization.

     

Pseudo current density maps of electrophysiological heart,nerve or brain function and their physical basis

Background

In recent years the visualization of biomagnetic measurement data by so-called pseudo current density maps or Hosaka-Cohen (HC) transformations became popular.

Methods

The physical basis of these intuitive maps is clarified by means of analytically solvable problems.

Results

Examples in magnetocardiography, magnetoencephalography and magnetoneurography demonstrate the usefulness of this method.

Conclusion

Hardware realizations of the HC-transformation and some similar transformations are discussed which could advantageously support cross-platform comparability of biomagnetic measurements.

     

Prognostic significance of CXCR7 in cancer patients: a meta-analysis

Background

CXC chemokine receptor 7 (CXCR7) is frequently overexpressed in a variety of tumors. Nevertheless, whether CXCR7 can be used as a tumor prognosis marker has not been systematically assessed. The current meta-analysis was performed to obtain an accurate evaluation of the relationship between CXCR7 level and the prognosis of cancer patients.

Methods

Embase, Web of Science, and PubMed were systematically searched according to a defined search strategy up to June 11, 2018. Then, the required data were extracted from all qualified studies which were screened out based on the defined inclusion and exclusion criteria. Finally, the hazard ratios (HR) with 95% confidence intervals (CI) were used to evaluate the prognostic significance of CXCR7 in tumor patients.

Results

A total of 28 original research studies comprising 33 cohorts and 5685 patients were included in this meta-analysis. The results showed that CXCR7 overexpression was significantly related to worse overall survival (OS) (HR 1.72; 95% CI 1.49–1.99), disease-free survival (DFS) (HR 5.58; 95% CI 3.16–9.85), progression-free survival (PFS) (HR 2.83; 95% CI 1.66–4.85) and recurrence-free survival (RFS) (HR 1.58; 95% CI 1.34–1.88) in cancer patients. Furthermore, for certain types of cancer, significant associations between higher CXCR7 expression and worse OS of glioma (HR 1.77; 95% CI 1.43–2.19), breast cancer (HR 1.45; 95% CI 1.28–1.63), esophageal cancer (HR 2.72; 95% CI 1.11–6.66) and pancreatic cancer (HR 1.46; 95% CI 1.12–1.90) were found. However, for lung cancer and hepatocellular cancer, there was no significant relationship between CXCR7 expression level and OS, (HR 2.40; 95% CI 0.34–17.07) and (HR 1.37; 95% CI 0.84–2.24) respectively.

Conclusions

Increased CXCR7 level could predict poor prognosis of tumor patients and might be regarded as a novel prognostic biomarker for tumor patients.

     

The concentration of D-dimers in portal blood positively correlates with overall survival in patients with non-resectable pancreatic cancer

Background

Several recent studies provide evidence that D-dimer (DD) concentration in peripheral blood correlates negatively with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). Contrarily, there are recent evidence indicating that preoperative plasma fibrinogen, but not D-dimer might represent a prognostic factor in non-metastatic gastrointestinal cancers.

Methods

In a single-center prospective study, we enrolled 62 patients undergoing surgery for pathologically confirmed PDAC without detectable venous thrombosis. Intraoperatively, the sample of the blood from the portal vein was obtained. DD concentration in these samples was measured. Patients were followed postoperatively until time of death from any cause.

Results

We found that OS for patients with portal blood DD values above 2700 (ng/mL) (n?=?22 from 62 patients) was higher by 158% than that for the patients (n?=?42) with DD values ≤?2700 (416 days versus 161 days, p?=?0.05). On the contrary to the studies investigating DD concentration in peripheral blood, we have found that patients with higher DD level in the portal vein had longer mean OS than patients with lower ones.

Conclusions

Further investigation is necessary both to confirm our results in a larger patient population and to elucidate the mechanism for the correlation between portal blood D-dimer concentrations and survival time. Along with other authors, we conclude that portal circulation is characterized by unique, biological environment that requires further evaluation.

     

Monitoring cancer prognosis,diagnosis and treatment efficacy using metabolomics and lipidomics

Introduction

Cellular metabolism is altered during cancer initiation and progression, which allows cancer cells to increase anabolic synthesis, avoid apoptosis and adapt to low nutrient and oxygen availability. The metabolic nature of cancer enables patient cancer status to be monitored by metabolomics and lipidomics. Additionally, monitoring metabolic status of patients or biological models can be used to greater understand the action of anticancer therapeutics.

Objectives

Discuss how metabolomics and lipidomics can be used to (i) identify metabolic biomarkers of cancer and (ii) understand the mechanism-of-action of anticancer therapies. Discuss considerations that can maximize the clinical value of metabolic cancer biomarkers including case–control, prognostic and longitudinal study designs.

Methods

A literature search of the current relevant primary research was performed.

Results

Metabolomics and lipidomics can identify metabolic signatures that associate with cancer diagnosis, prognosis and disease progression. Discriminatory metabolites were most commonly linked to lipid or energy metabolism. Case–control studies outnumbered prognostic and longitudinal approaches. Prognostic studies were able to correlate metabolic features with future cancer risk, whereas longitudinal studies were most effective for studying cancer progression. Metabolomics and lipidomics can help to understand the mechanism-of-action of anticancer therapeutics and mechanisms of drug resistance.

Conclusion

Metabolomics and lipidomics can be used to identify biomarkers associated with cancer and to better understand anticancer therapies.

     

miR-149 promotes human osteocarcinoma progression via targeting bone morphogenetic protein 9 (BMP9)

Objectives

To investigate the roles of miR-149 in the progression of human osteosarcoma (OS).

Results

miR-149 level was upregulated in tissues from OS patients more than in normal subjects. Cell proliferation and apoptosis assays revealed that miR-149 increased cell proliferation and inhibited cell apoptosis in OS cell line (MG63). An increase of Bcl-2 gene expression and a decrease of cleaved-caspase-3, and cleaved-PARP expression were observed in MG63 cells with transfection of miR-149. Additionally, bone morphogenetic protein 9 (BMP9) was identified as a target of miR-149 in MG63 cells, and BMP9 expression was negatively correlated with miR149 level in OS clinical samples. Co-overexpression of BMP9 with miR-149 in MG63 cells prohibited miR-149-mediated promotive effects on OS progression. Importantly, overexpression of miR-149 conferred chemoresistance in MG63 cells.

Conclusions

miR-149 promotes OS progression via targeting BMP9.

     

Associations of branched-chain amino acids with parameters of energy balance and survival in colorectal cancer patients: results from the ColoCare study

Background

Branched-chain amino acids (BCAA) have been previously linked to survival in colorectal cancer (CRC) patients. It is unclear whether BCAAs are prognostic biomarkers or surrogate markers for energy balance.

Objectives

We aimed to determine correlations of BCAAs with markers of energy balance over time and to investigate prognostic significance of BCAAs in CRC.

Methods

We used urinary samples from newly diagnosed CRC patients [n?=?163; (stage I–IV)] from the ColoCare study in Heidelberg, Germany, collected at surgery (n?=?163), 6 (n?=?83) and 12 months follow-up (n?=?54). Isoleucine, leucine, valine, (2Z)-3-methylglutaconic acid (3HM), 2-ethylhydracrylic acid (2EA), 2-methyl-3-hydroxybutyrate (2M3H) were detected using gas-chromatography mass-spectrometry and proton-nuclear-magnetic-resonance spectroscopy. Partial correlation coefficients between BCAAs with body mass index, physical activity (metabolic equivalent) and muscle area were computed and adjusted for sex and age at diagnosis. We used Cox proportional hazard models to investigate overall survival (OS) after 24 months of follow-up.

Results

We did not observe significant correlations between BCAAs and parameters of energy balance at all time points (correlation ranges: BMI: r?=???0.13 to ??0.01; METs: r?=???0.14 to 0.02; dorsal muscle: r?=???0.03 to 0.10). BCAAs were not associated with risk of death in stage I–III (e.g., valine: HR_log2?=?1.62, p?=?0.25) or in stage IV tumors. Elevated concentrations of 2EA and 2M3H were significantly associated with OS, independent of stage (2EA: stage I–III: HR_log2?=?0.42, p?=?0.04; stage IV: HR_log2?=?0.51, p?=?0.01).

Conclusion

Our study suggests that BCAAs in colorectal cancer patients do not reflect parameters of energy balance and may be independently associated with overall survival.

     

A lost opportunity for science: journals promote data sharing in metabolomics but do not enforce it

Introduction

Data sharing is being increasingly required by journals and has been heralded as a solution to the ‘replication crisis’.

Objectives

(i) Review data sharing policies of journals publishing the most metabolomics papers associated with open data and (ii) compare these journals’ policies to those that publish the most metabolomics papers.

Methods

A PubMed search was used to identify metabolomics papers. Metabolomics data repositories were manually searched for linked publications.

Results

Journals that support data sharing are not necessarily those with the most papers associated to open metabolomics data.

Conclusion

Further efforts are required to improve data sharing in metabolomics.

     

Models of cell signaling uncover molecular mechanisms of high-risk neuroblastoma and predict disease outcome

Background

Despite the progress in neuroblastoma therapies the mortality of high-risk patients is still high (40–50%) and the molecular basis of the disease remains poorly known. Recently, a mathematical model was used to demonstrate that the network regulating stress signaling by the c-Jun N-terminal kinase pathway played a crucial role in survival of patients with neuroblastoma irrespective of their MYCN amplification status. This demonstrates the enormous potential of computational models of biological modules for the discovery of underlying molecular mechanisms of diseases.

Results

Since signaling is known to be highly relevant in cancer, we have used a computational model of the whole cell signaling network to understand the molecular determinants of bad prognostic in neuroblastoma. Our model produced a comprehensive view of the molecular mechanisms of neuroblastoma tumorigenesis and progression.

Conclusion

We have also shown how the activity of signaling circuits can be considered a reliable model-based prognostic biomarker.

Reviewers

This article was reviewed by Tim Beissbarth, Wenzhong Xiao and Joanna Polanska. For the full reviews, please go to the Reviewers’ comments section.

     

Metabolomic profiling of maternal hair suggests rapid development of intrahepatic cholestasis of pregnancy

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a common maternal liver disease; development can result in devastating consequences, including sudden fetal death and stillbirth. Currently, recognition of ICP only occurs following onset of clinical symptoms.

Objective

Investigate the maternal hair metabolome for predictive biomarkers of ICP.

Methods

The maternal hair metabolome (gestational age of sampling between 17 and 41 weeks) of 38 Chinese women with ICP and 46 pregnant controls was analysed using gas chromatography–mass spectrometry.

Results

Of 105 metabolites detected in hair, none were significantly associated with ICP.

Conclusion

Hair samples represent accumulative environmental exposure over time. Samples collected at the onset of ICP did not reveal any metabolic shifts, suggesting rapid development of the disease.

     

Prognostic impact of pretreatment lymphocyte-to-monocyte ratio in advanced epithelial cancers: a meta-analysis

Background

There is increasing evidence that inflammation-based biomarkers are associated with tumor microenvironment which plays important roles in cancer progression. A high lymphocyte-to-monocyte ratio (LMR), has been suggested to indicate favorable prognoses in various epithelial cancers. We performed a meta-analysis to quantify the prognostic value of LMR in advanced-stage epithelial cancers undergoing various treatment.

Methods

We searched PubMed, EMBASE, Web of science and Cochrane Library up to July 2018 for relevant studies. We included studies assessing the prognostic impact of pretreatment LMR on clinical outcomes in patients with advanced-stage epithelial cancers. The primary outcome was overall survival (OS) and the secondary outcome was progression free survival (PFS). The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated.

Results

A total of 8984 patients from 35 studies were included. A high pretreatment LMR was associated with favorable OS (HR?=?0.578, 95% CI 0.522–0.641, P?<?0.001) and PFS (HR?=?0.598, 95% CI 0.465–0.768, P?<?0.001). The effect of LMR on OS was observed among various tumor types. A higher pretreatment LMR was associated with improved OS in chemotherapy (n?=?10, HR?=?0.592, 95% CI 0.518–0.676, P?<?0.001), surgery (n?=?10, HR?=?0.683, 95% CI 0.579–0.807, P?<?0.001) and combined therapy (n?=?11, HR?=?0.507, 95% CI 0.442–0.582, P?<?0.001) in the subgroup analysis by different therapeutic strategies. The cut-off value for LMR was 3.0 (range?=?2.35–5.46). Subgroup analysis according to the cut-off value showed a significant prognostic value of LMR on OS and PFS in both subgroups.

Conclusions

A high pretreatment LMR is associated with favorable clinical outcomes in advanced-stage epithelial cancers undergoing different therapeutic strategies. LMR could be used to improve clinical decision-making regarding treatment in advanced epithelial cancers.