Developing a machine learning-based short form of the positive and negative syndrome scale.

BACKGROUND AND HYPOTHESIS: The Positive and Negative Syndrome Scale (PANSS) consists of 30 items and takes up to 50 minutes to administer and score. Therefore, this study aimed to develop and validate a machine learning-based short form of the PANSS (PANSS-MLSF) that reproduces the PANSS scores. Moreover, the PANSS-MLSF estimated the removed-item scores. STUDY DESIGN: The PANSS-MLSF was developed using an artificial neural network, and the removed-item scores were estimated using the eXtreme Gradient Boosting classifier algorithm. The reliability of the PANSS-MLSF was examined using Cronbach's alpha. The concurrent validity was examined by the association (Pearson's r) between the PANSS-MLSF and the PANSS. The convergent validity was examined by the association (Pearson's r) between the PANSS-MLSF and the Clinical Global Impression-Severity, Mini-Mental State Examination, and Lawton Instrumental Activities of Daily Living Scale. The agreement of the estimated removed-item scores with their original scores was examined using Cohen's kappa. STUDY RESULTS: Our analysis included data from 573 patients with moderate severity. The two versions of the PANSS-MLSF comprised 15 items and 9 items were proposed. The PANSS-MLSF scores were similar to the PANSS scores (mean squared error=2.6-24.4 points). The reliability, concurrent validity, and convergent validity of the PANSS-MLSF were good. Moderate to good agreement between the estimated removed-item scores and the original item scores was found in 60% of the removed items. CONCLUSION: The PANSS-MLSF offers a viable way to reduce PANSS administration time, maintain score comparability, uphold reliability and validity, and even estimate scores for the removed items.

Refining the 8th edition TNM classification for EBV related nasopharyngeal carcinoma.

The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed patients with non-metastatic Epstein-Barr virus related nasopharyngeal carcinoma (NPC) from six Chinese centers indicates certain limitations in the current staging system. The 8th edition of the AJCC/UICC TNM classification inadequately differentiates patient outcomes, particularly between T2 and T3 categories and within the N classification. We propose reclassifying cases of T3 NPC with early skull-base invasion as T2, and elevating N1-N2 cases with grade 3 image-identified extranodal extension (ENE) to N3. Additionally, we suggest combining T2N0 with T1N0 into a single stage IA. For de novo metastatic (M1) NPC, we propose subdivisions of M1a, defined by 1-3 metastatic lesions without liver involvement, and M1b, characterized by >3 metastatic lesions or liver involvement. This proposal better reflects responses of NPC patients to the up-to-date treatments and their evolving risk profiles.

Molecular subtypes predict therapeutic responses and identifying and validating diagnostic signatures based on machine learning in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a hematological tumor derived from hematopoietic stem cells. The aim of this study is to analyze the biological characteristics and identify the diagnostic markers of CML. We obtained the expression profiles from the Gene Expression Omnibus (GEO) database and identified 210 differentially expressed genes (DEGs) between CML and normal samples. These DEGs are mainly enriched in immune-related pathways such as Th1 and Th2 cell differentiation, primary immunodeficiency, T cell receptor signaling pathway, antigen processing and presentation pathways. Based on these DEGs, we identified two molecular subtypes using a consensus clustering algorithm. Cluster A was an immunosuppressive phenotype with reduced immune cell infiltration and significant activation of metabolism-related pathways such as reactive oxygen species, glycolysis and mTORC1; Cluster B was an immune activating phenotype with increased infiltration of CD4 + and CD8 + T cells and NK cells, and increased activation of signaling pathways such as interferon gamma (IFN-γ) response, IL6-JAK-STAT3 and inflammatory response. Drug prediction results showed that patients in Cluster B had a higher therapeutic response to anti-PD-1 and anti-CTLA4 and were more sensitive to imatinib, nilotinib and dasatinib. Support Vector Machine Recursive Feature Elimination (SVM-RFE), Least Absolute Shrinkage Selection Operator (LASSO) and Random Forest (RF) algorithms identified 4 CML diagnostic genes (HDC, SMPDL3A, IRF4 and AQP3), and the risk score model constructed by these genes improved the diagnostic accuracy. We further validated the diagnostic value of the 4 genes and the risk score model in a clinical cohort, and the risk score can be used in the differential diagnosis of CML and other hematological malignancies. The risk score can also be used to identify molecular subtypes and predict response to imatinib treatment. These results reveal the characteristics of immunosuppression and metabolic reprogramming in CML patients, and the identification of molecular subtypes and biomarkers provides new ideas and insights for the clinical diagnosis and treatment.

Splicing factor-mediated regulation patterns reveals biological characteristics and aid in predicting prognosis in acute myeloid leukemia.

BACKGROUND: Alternative splicing (AS) of RNA is a fundamental biological process that shapes protein diversity. Many non-characteristic AS events are involved in the onset and development of acute myeloid leukemia (AML). Abnormal alterations in splicing factors (SFs), which regulate the onset of AS events, affect the process of splicing regulation. Hence, it is important to explore the relationship between SFs and the clinical features and biological processes of patients with AML. METHODS: This study focused on SFs of the classical heterogeneous nuclear ribonucleoprotein (hnRNP) family and arginine and serine/arginine-rich (SR) splicing factor family. We explored the relationship between the regulation patterns associated with the expression of SFs and clinicopathological factors and biological behaviors of AML based on a multi-omics approach. The biological functions of SRSF10 in AML were further analyzed using clinical samples and in vitro experiments. RESULTS: Most SFs were upregulated in AML samples and were associated with poor prognosis. The four splicing regulation patterns were characterized by differences in immune function, tumor mutation, signaling pathway activity, prognosis, and predicted response to chemotherapy and immunotherapy. A risk score model was constructed and validated as an independent prognostic factor for AML. Overall survival was significantly shorter in the high-risk score group. In addition, we confirmed that SRSF10 expression was significantly up-regulated in clinical samples of AML, and knockdown of SRSF10 inhibited the proliferation of AML cells and promoted apoptosis and G1 phase arrest during the cell cycle. CONCLUSION: The analysis of splicing regulation patterns can help us better understand the differences in the tumor microenvironment of patients with AML and guide clinical decision-making and prognosis prediction. SRSF10 can be a potential therapeutic target and biomarker for AML.

Ferroptosis-related molecular patterns reveal immune escape, inflammatory development and lipid metabolism characteristics of the tumor microenvironment in acute myeloid leukemia.

Background: An increasing number of studies have revealed the influencing factors of ferroptosis. The influence of immune cell infiltration, inflammation development and lipid metabolism in the tumor microenvironment (TME) on the ferroptosis of tumor cells requires further research and discussion. Methods: We explored the relationship between ferroptosis-related genes and acute myeloid leukemia (AML) from the perspective of large sample analysis and multiomics, used multiple groups to identify and verify ferroptosis-related molecular patterns, and analyzed the sensitivity to ferroptosis and the state of immune escape between different molecular pattern groups. The single-sample gene set enrichment analysis (ssGSEA) algorithm was used to quantify the phenotypes of ferroptosis-related molecular patterns in individual patients. HL-60 and THP-1 cells were treated with ferroptosis inducer RSL3 to verify the therapeutic value of targeted inhibition of GPX4. Results: Three ferroptosis-related molecular patterns and progressively worsening phenotypes including immune activation, immune exclusion and immunosuppression were found with the two different sequencing approaches. The FSscore we constructed can quantify the development of ferroptosis-related phenotypes in individual patients. The higher the FSscore is, the worse the patient's prognosis. The FSscore is also highly positively correlated with pathological conditions such as inflammation development, immune escape, lipid metabolism, immunotherapy resistance, and chemotherapy resistance and is negatively correlated with tumor mutation burden. Moreover, RSL3 can induce ferroptosis of AML cells by reducing the protein level of GPX4. Conclusions: This study revealed the characteristics of immunity, inflammation, and lipid metabolism in the TME of different AML patients and differences in the sensitivity of tumor cells to ferroptosis. The FSscore can be used as a biomarker to provide a reference for the clinical evaluation of the pathological characteristics of AML patients and the design of personalized treatment plans. And GPX4 is a potential target for AML treatment.

A novel fatty acid metabolism-related signature identifies features of the tumor microenvironment and predicts clinical outcome in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is the most common malignancy of the hematological system, and there are currently a number of studies regarding abnormal alterations in energy metabolism, but fewer reports related to fatty acid metabolism (FAM) in AML. We therefore analyze the association of FAM and AML tumor development to explore targets for clinical prognosis prediction and identify those with potential therapeutic value. METHODS: The identification of AML patients with different fatty acid metabolism characteristics was based on a consensus clustering algorithm. The CIBERSORT algorithm was used to calculate the proportion of infiltrating immune cells. We used Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis to construct a signature for predicting the prognosis of AML patients. The Genomics of Drug Sensitivity in Cancer database was used to predict the sensitivity of patient samples in high- and low-risk score groups to different chemotherapy drugs. RESULTS: The consensus clustering approach identified three molecular subtypes of FAM that exhibited significant differences in genomic features such as immunity, metabolism, and inflammation, as well as patient prognosis. The risk-score model we constructed accurately predicted patient outcomes, with area under the receiver operating characteristic curve values of 0.870, 0.878, and 0.950 at 1, 3, and 5 years, respectively. The validation cohort also confirmed the prognostic evaluation performance of the risk score. In addition, higher risk scores were associated with stronger fatty acid metabolisms, significantly higher expression levels of immune checkpoints, and significantly increased infiltration of immunosuppressive cells. Immune functions, such as inflammation promotion, para-inflammation, and type I/II interferon responses, were also significantly activated. These results demonstrated that immunotherapy targeting immune checkpoints and immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) and M2 macrophages, are more suitable for patients with high-risk scores. Finally, the prediction results of chemotherapeutic drugs showed that samples in the high-risk score group had greater treatment sensitivity to four chemotherapy drugs in vitro. CONCLUSIONS: The analysis of the molecular patterns of FAM effectively predicted patient prognosis and revealed various tumor microenvironment (TME) characteristics.

Inflammatory response mediates cross-talk with immune function and reveals clinical features in acute myeloid leukemia.

Accumulated genetic mutations are an important cause for the development of acute myeloid leukemia (AML), but abnormal changes in the inflammatory microenvironment also have regulatory effects on AML. Exploring the relationship between inflammatory response and pathological features of AML has implications for clinical diagnosis, treatment and prognosis evaluation. We analyzed the expression variation landscape of inflammatory response-related genes (IRRGs) and calculated an inflammatory response score for each sample using the gene set variation analysis (GSVA) algorithm. The differences in clinical- and immune-related characteristics between high- and low-inflammatory response groups were further analyzed. We found that most IRRGs were highly expressed in AML samples, and patients with high inflammatory response had poor prognosis and were accompanied with highly activated chemokine-, cytokine- and adhesion molecule-related signaling pathways, higher infiltration ratios of monocytes, neutrophils and M2 macrophages, high activity of type I/II interferon (IFN) response, and higher expression of immune checkpoints. We also used the Genomics of Drug Sensitivity in Cancer (GDSC) database to predict the sensitivity of AML samples with different inflammatory responses to common drugs, and found that AML samples with low inflammatory response were more sensitive to cytarabine, doxorubicin and midostaurin. SubMap algorithm also demonstrated that high-inflammatory response patients are more suitable for anti-PD-1 immunotherapy. Finally, we constructed a prognostic risk score model to predict the overall survival (OS) of AML patients. Patients with higher risk score had significantly shorter OS, which was confirmed in two validation cohorts. The analysis of inflammatory response patterns can help us better understand the differences in tumor microenvironment (TME) of AML patients, and guide clinical medication and prognosis prediction.

Optimization of urinary small extracellular vesicle isolation protocols: implications in early diagnosis, stratification, treatment and prognosis of diseases in the era of personalized medicine.

Extracellular vesicles isolation from urine was severely interfered by polymeric Tamm-Harsefall protein due to its ability to entrap exosome. Studies had been reported to optimize the extraction of urine extracellular vesicles by using reducing agents, surfactants, salt precipitation or ultrafiltration, but rarely based on highly specific purification methods. We optimized the density gradient centrifugation method for the isolation of urinary small extracellular vesicles (sEV) and compared seven differential centrifugation protocols to obtain the high-yield and high-purity sEV isolation procedures. Our study showed Tris sucrose gradient centrifugation at 25°C had more concentrated distribution of exosomal marker in the gradient compared to Tris sucrose gradient centrifugation at 4°C and PBS sucrose gradient centrifugation. Dissolving the 16000 g pellet using Tris, Nonidet™ P 40 or Dithiothreitol then pooling the supernatants did not increase the exosomal markers and number of nanoparticles in sEV preparation compared to the control and PBS groups. Differential centrifugation at room temperature without ultrafiltration recovered more exosome-like vesicles, exosomal markers and nanoparticles than that at 4°C or combining ultrafiltration. Differential centrifugation at RT without ultrafiltration and salt precipitation recovered the highest number of nanoparticles than other protocols. However, differential centrifugation at RT combining 100 kd ultrafiltration obtained the highest purity of sEV calculated by Nanoparticle number/Total protein. In conclusion, we had established two urinary sEV isolation procedures that can recovered higher yield of sEV and more pure preparation of sEV. It is not recommended to treating 16000 g pellet with reducing agents or surfactants to increase the yield of sEV.

Transcriptome profiling reveals the high incidence of hnRNPA1 exon 8 inclusion in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a malignancy that evolves through a multi-step process. Alternative splicing of several genes has been linked to the progression of the disease, but involvement of alternations in splicing profiles has not been reported. RNA-seq of peripheral blood mononuclear cell (PBMC) samples characterized the differentially expressed and spliced transcripts in five CML chronic phase (CP) and five blast phase (BP) patients, and five healthy controls. Global splicing alteration analysis detected 6474 altered splicing events altered between CML and healthy samples, including many of the previously reported splicing variants and showing a more profound altered splicing deregulation in BP samples. Functional clustering of differentially spliced genes in CP revealed a preferred enrichment relating to cell signaling, while the spliceosome pathway was most overrepresented in BP samples. One differentially spliced spliceosome gene hnRNPA1 showed two splice isoforms; the longer isoform contained exon 8 was preferentially expressed in the BP patients, and the short one excluding exon 8 was specific to healthy controls. Our findings suggested that alternative splicing deregulation played a central role during the progression of CML from CP to BP, and the longer isoform of hnRNPA1 might represent a diagnostic marker and therapeutic target for CML.

Correction of Bcl-x splicing improves responses to imatinib in chronic myeloid leukaemia cells and mouse models.

Imatinib mesylate (IM) resistance has become a major clinical problem for chronic myeloid leukaemia (CML). It is known that Bcl-x splicing is deregulated and is involved in multiple malignant cancer initiation and chemotherapy resistance, including CML. The aim of the present study was to correct the abnormal splicing of Bcl-x in CML and investigate the subsequent malignant phenotype changes, especially response to IM. The aberrant Bcl-x splicing in CML cells was effectively restored using vivo-Morpholino Antisense Oligomer (vMO). CCK-8 cell viability assay and flow cytometry showed that restoring of Bcl-x splicing increases IM-induced growth inhibition and apoptosis of K562 cells. Moreover, a more significant similar phenomenon was observed in imatinib-resistant CML cell lines K562/G01. Finally, establishment of CML xenograft model had also proved that correcting Bcl-x splicing in vivo can also enhance the anti-tumor effect of IM. Our findings suggest that vMO co-operating with IM can effectively increase the sensitivity of CML cells to IM both in vitro and in vivo, and Bcl-x splicing could become good candidates for chemotherapy-sensitized target in IM-resistant CML.

K562 cell-derived exosomes suppress the adhesive function of bone marrow mesenchymal stem cells via delivery of miR-711.

A failure of bone marrow mesenchymal stem cells (BM-MSCs) to adhere to hematopoietic cells is an essential cause of the progression of chronic myelogenous leukemia and is also a cause of failure of bone marrow (BM) transplantation, but the exact mechanisms of this have not been fully elucidated. Recent studies have indicated that microRNAs (miRNAs) are contained in leukemia-derived exosomes and are involved in modulating the BM microenvironment. In this study, we found that K562 cell-derived exosomes transfer miR-711 to BM-MSCs and suppress the adhesive function of BM-MSCs. Using qRT-PCR, we also confirmed a significantly higher level of miR-711 in exosomes derived from K562 cells than in exosomes derived from parental cells. The BM-MSCs co-cultured with exosomes derived from K562 cells showed a lower adhesion rate than did controls. We further demonstrated that exosomal transfer of miR-711 induced decreased adhesive abilities by inhibiting expression of adhesion molecule CD44 in BM-MSCs. In conclusion, our study reveals that K562 cell-derived exosomal miR-711 can be transferred to BM-MSCs and weaken adhesive abilities by silencing the expression of the adhesion molecule CD44.

Elevated FPR confers to radiochemoresistance and predicts clinical efficacy and outcome of metastatic colorectal cancer patients.

Association of chronic inflammation, primary tumor sidedness, adjuvant therapy and survival of metastatic colorectal cancer (mCRC) remains unclear. Circulating inflammatory cell, fibrinogen (Fib), albumin (Alb), pre-albumin (pAlb), Alb/Fib (AFR) and Fib/pAlb (FPR) were detected, and clinical outcome was obtained to determine the predictive, prognostic and monitoring roles of them in discovery and validation cohort. We found that elevated FPR, low AFR and poor survival was observed in right-sided mCRC comparing to the left-sided disease, elevated FPR harbored the highest areas under curve to independently predict poor progression-free survival and overall survival in overall and left-sided mCRC case in two cohorts. No survival difference was examined between the two-sided patients in subgroups stratified by FPR. Radiochemoresistance was observed in high FPR case. However, the patient could benefit from bevacizumab plus radiochemotherapy. Low FPR patient showed the best survival with treatment of palliative resection plus radiochemotherapy. Moreover, circulating FPR was significantly increased ahead imaging confirmed progression and it reached up to the highest value within three months before death. Additionally, c-indexes of the prognostic nomograms including FPR were significantly higher than those without it. These findings indicated that FPR was an effective and independent factor to predict progression, prognosis and to precisely identify the patient to receive optimal therapeutic regimen.

Clinical and imaging manifestations of primary cardiac angiosarcoma.

BACKGROUND: To investigate the CT manifestations of primary cardiac angiosarcoma. METHODS: The clinical and CT data for 9 patients with cardiac angiosarcoma were retrospectively analyzed. RESULTS: The lesions in all nine cases were located in the right atrium. In two cases, the involved lesion led downward to the tricuspid valve and right ventricle, and the dynamic cine showed that the lesion affected the opening and closing of the tricuspid valve. In three cases, the lesion involvement led to a thickened pericardium, accompanied by pericardial effusions. On CT plain scans, six patients showed homogeneous density, while three showed inhomogeneous density, two of which were associated with bleeding. On enhanced CT scans, seven patients showed heterogeneous centripetal enhancement, and some angiograms showed lesions with tortuous small blood vessels. The remaining two cases showed early stage rapid inhomogeneous enhancement. Five cases showed multiple metastatic nodules in the lungs at the time of initial diagnosis; four of these showed distinct sharp edges in multiple pulmonary nodules. CONCLUSIONS: Cardiac angiosarcoma has a predilection site and is prone to invading adjacent structures, manifesting as malignant pericardial and pleural effusions. The CT enhancement manifestations are mostly inhomogeneous and centripetal with ground-glass opacity peripheral to the intrapulmonary metastases.

Circulating fibrinogen to pre-albumin ratio is a promising biomarker for diagnosis of colorectal cancer.

BACKGROUND: Inflammation and nutrition are closely associated with initiation and progression of colorectal cancer (CRC). This study aimed to investigate the diagnostic value of the FAR (FAR = 100*Fibrinogen/Albumin) and FPR (FPR = Fibrinogen/pre-Albumin) in CRC. METHODS: Neutrophil-to-lymphocyte ratio (NLR), FPR, and FAR were calculated in 455 newly diagnosed CRC patients, 455 healthy individuals, and 455 benign controls with colorectal polyp. The diagnostic value of biomarker for CRC was evaluated by receiver operating characteristic curve (ROC). Logistic regression analysis was adopted to assess the risk factors for telling CRC apart from benign disease. Moreover, the combined biomarkers were used for discriminating between CRC and benign disease. RESULTS: Neutrophil-to-lymphocyte ratio, FAR, and FPR were significantly higher in CRC patients compared with the benign or healthy controls (P < 0.05). ROC analysis showed that the diagnostic efficacy of FAR and FPR were better than NLR for CRC. Besides, FPR, NLR, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA199) were markedly associated with differentiation of benign disease and CRC in the logistic regression analysis. And the combination of FPR, CEA, and CA199 had the maximum area under the ROC curve (AUC) in separating CRC from benign disease (AUC = 0.845, Sensitivity = 67.9%, Specificity = 85.3%, Positive Predictive Value = 83.5%, Negative Predictive Value = 70.9%). CONCLUSIONS: Fibrinogen/pre-Albumin could be a useful CRC diagnostic biomarker, and the combination of FPR, CEA, and CA199 could significantly improve the diagnostic efficacy in discriminating CRC from the benign colorectal disease.

Preoperative fibrinogen to prealbumin ratio as a novel predictor for clinical outcome of hepatocellular carcinoma.

AIM: To investigate prognostic value of preoperative inflammatory biomarkers in hepatocellular carcinoma (HCC). PATIENTS & METHODS: Preoperative circulating fibrinogen, prealbumin, fibrinogen to prealbumin ratio (FPR), neutrophil to lymphocyte ratio, derived neutrophil to lymphocyte ratio, lymphocyte to monocyte ratio, platelet to lymphocyte ratio were detected and calculated in 230 HCC patients. X-tile software, Kaplan-Meier curve, Cox regression, time-dependent receiver-operating characteristic were used to explored prognostic roles of them in HCC. RESULTS: Multivariate Cox regression showed that high FPR was significantly associated with decreased recurrence-free survival (p = 0.034) and overall survival (p < 0.001) within HCC patients. FPR generated the largest area under curve of time-dependent receiver-operating characteristic comparing to the other biomarkers. Overall survival of HCC patients receiving chemotherapy was superior to the cases without receiving chemotherapy only in high FPR subgroup (p = 0.028). CONCLUSION: Preoperative FPR was superior to other biomarkers to independently predict survival of HCC patients, and it could identify the patients who could benefit from adjuvant chemotherapy.

The predictive and prognostic role of a novel ADS score in esophageal squamous cell carcinoma patients undergoing esophagectomy.

BACKGROUND: Chronic inflammation is deemed to play a significant effect on initiation and progression of esophageal squamous cell carcinoma (ESCC). In current study, we investigated the prognostic and predictive role of albumin (Alb) to fibrinogen (Fib) ratio (AFR) and a novel AFR-Alb-derived neutrophil/lymphocyte ratio (dNLR) score (ADS) in ESCC patients undergoing esophagectomy and compared them with Fib, Alb, neutrophil to lymphocyte ratio (NLR), dNLR, platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR). MATERIALS AND METHODS: A total of 153 clinical confirmed ESCC patients undergoing esophagectomy between January 2011 and December 2013 were included in present study. We detected preoperative Alb, Fib and neutrophil, monocyte, lymphocyte and platelet count, and obtained overall survival (OS) by 3 years' follow-up in the cases. X-tile software, Kaplan-Meier curve, Cox regression and predicted nomogram were used to evaluate the predictive and prognostic role of them in ESCC patients. RESULTS: The optimal cut-off values of Fib, Alb, AFR, NLR, dNLR, PLR and LMR were 3.2 mg/dL, 38.2 g/L, 9.3, 2.1, 4.3, 145.9 and 2.3, respectively. High levels of Fib [(adjusted hazard ratio (HR) = 2.148, 95% confidential interval (CI) (1.229-3.753)], dNLR (adjusted HR = 2.338, 95% CI 1.626-5.308) and PLR (adjusted HR = 1.964, 95% CI 1.129-3.415) as well as low AFR (adjusted HR = 2.381, 95% CI 1.152-4.926) and Alb (adjusted HR = 2.398, 95% CI 1.342-4.273) were significantly associated with decreased OS in ESCC patients. The survival predictive areas under the time-dependent receiver operating characteristics curve of AFR, dNLR and Alb were higher than Fib and PLR, respectively. High ADS score was significantly associated with short 3 years' OS of ESCC patients (adjusted HR = 2.94, 95% CI 1.70-5.08). Moreover, OS of ESCC patients receiving adjuvant radio-chemotherapy was longer than those without the treatment in high ADS score subgroup (p = 0.001), however, no significant survival difference was observed in the patients with or without treatment radio-chemotherapy (p = 0.297). Additionally, a significant difference was observed in c-index values of the nomograms including or without ADS (0.720 vs. 0.670, p < 0.05). CONCLUSIONS: Preoperative ADS was a prospective biomarker to predict clinical efficacy of adjuvant radio-chemotherapy and clinical prognosis of ESCC patients undergoing esophagectomy, and the score could apparently improve predicted efficacy of the nomogram.

Preoperative circulating FPR and CCF score are promising biomarkers for predicting clinical outcome of stage II-III colorectal cancer patients.

INTRODUCTION: Inflammation and nutrition are considered as two important causes leading to the progression and poor survival of colorectal cancer (CRC). The objective of this study is to investigate the prognostic significance of preoperative albumin-to-fibrinogen ratio (AFR), fibrinogen-to-pre-albumin ratio (FPR), fibrinogen (Fib), albumin (Alb), and pre-albumin (pre-Alb) in CRC individuals. MATERIALS AND METHODS: In this study, 3 years' follow-up was carried out in 702 stage I-III resected CRC patients diagnosed between January 2008 and December 2013. The optimal cutoff points and prognostic values of AFR, FPR, Fib, Alb, pre-Alb, and a novel carcinoembryonic antigen (CEA)-carbohydrate antigen 19-9 (CA199)-FPR (CCF) score were assessed by X-tile software, Kaplan-Meier curve, and Cox regression model. We established the CRC prognostic nomogram, and its predictive efficacy was determined by Harrell's concordance index (c-index). RESULTS: Our results showed that high FPR was obviously correlated with poor survival of CRC patients. The prognostic predictive efficacy of CCF score was superior to FPR, CEA, CA199, CEA-CA199 (CCI), and CEA-FPR (CFI) score. Moreover, stage II-III patients harboring high FPR or elevated CCF (score≥1) could benefit from adjuvant chemotherapy, rather than those with low FPR or CCF (score=0). Additionally, the c-index (0.728) of the nomogram containing CCF score was significantly higher than that (0.626) without it (p<0.01). CONCLUSION: These findings illustrated that FPR and CCF score were promising biomarkers to predict the prognosis of CRC and to classify the stage II-III patients who could benefit from the adjuvant chemotherapy.

Albumin-to-fibrinogen ratio as a promising biomarker to predict clinical outcome of non-small cell lung cancer individuals.

Chronic inflammation is one of the critical causes to promote the initiation and metastasis of solid malignancies including lung cancer (LC). Here, we aimed to investigate the prognostic roles of albumin (Alb)-to-fibrinogen (Fib) ratio (AFR), Fib and Alb in LC and to establish a novel effective nomogram combined with AFR. Four hundred twelve LC patients diagnosed between February 2005 and December 2014 were recruited in this prospective study. The prognostic roles of AFR, Fib, Alb, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR) were identified by X-tile software, Kaplan-Meier curve, Cox regression model, and time-dependent ROC. Pretreatment high circulating Fib, low AFR, and Alb were significantly associated with increased risk of death for LC patients, especially for non-small cell lung cancer (NSCLC) patients in all stages. The area under curves (AUCs) of AFR, Fib, and NLR were higher than them within Alb and PLR for predicting the survival of NSCLC patients. Moreover, we found that clinical outcome of high AFR patient with chemo-radiotherapy was superior to low AFR patient; overall survival rate of stage II-III NSCLC patients undergoing chemo-radiotherapy was significantly lower than the surgical patients with treatment of adjuvant chemo-radiotherapy(P = 0.001) in low AFR subgroup. On the contrary, clinical outcome of the patients receiving chemo-radiotherapy was the same to the patients undergoing surgery and adjuvant chemo-radiotherapy (P = 0.405) in high AFR subgroup. In addition, c-index of predicted nomogram including AFR (0.717) for NSCLC patients with treatment of chemo-radiotherapy was higher than that without AFR (0.707). Our findings demonstrated that circulating pretreatment AFR might be a potential biomarker to predict clinical efficacy of surgical resection and adjuvant chemo-radiotherapy and be a prognostic biomarker for NSCLC individuals.

Exosomes derived from imatinib-resistant chronic myeloid leukemia cells mediate a horizontal transfer of drug-resistant trait by delivering miR-365.

Chronic myeloid leukemia (CML) is a malignant disorder of hematopoietic stem/progenitor cells. Majority of patients can be effectively treated with tyrosine kinase inhibitors (TKIs) such as imatinib, but a portion of patients will develop drug resistance. Accumulated evidences have identified exosomes in cancer as promoters of tumor progression. Herein, we found that exosomes derived from imatinib resistant CML cells can be internalized into sensitive CML cells and confer drug-resistance traits. We also demonstrated a significant higher level of miR-365 in exosomes derived from drug-resistant CML cells compared with those from sensitive ones using microarray and qRT-PCR. The imatinib sensitive CML cells transfected with pre-miR-365 displayed lower chemosensitivity and apoptosis rate compared with controls. We further confirmed that exosomal transfer of miR-365 induced drug resistance by inhibiting expression of pro-apoptosis protein in sensitive CML cells. In conclusion, our study reveals that exosomes mediate a horizontal transfer of drug-resistant trait in chronic myeloid leukemia cell by delivering miR-365.