Identification and validation of a platelet-related signature for predicting survival and drug sensitivity in multiple myeloma.

Background: Significant progress has been achieved in the management of multiple myeloma (MM) by implementing high-dose therapy and stem cell transplantation. Moreover, the prognosis of patients has been enhanced due to the introduction of novel immunomodulatory drugs and the emergence of new targeted therapies. However, predicting the survival rates of patients with multiple myeloma is still tricky. According to recent researches, platelets have a significant impact in affecting the biological activity of tumors and are essential parts of the tumor microenvironment. Nonetheless, it is still unclear how platelet-related genes (PRGs) connect to the prognosis of multiple myeloma. Methods: We analyzed the expression of platelet-related genes and their prognostic value in multiple myeloma patients in this study. We also created a nomogram combining clinical metrics. Furthermore, we investigated disparities in the biological characteristics, immunological microenvironment, and reaction to immunotherapy, along with analyzing the drug susceptibility within diverse risk groups. Results: By using the platelet-related risk model, we were able to predict patients' prognosis more accurately. Subjects in the high-risk cohort exhibited inferior survival outcomes, both in the training and validation datasets, as compared to those in the low-risk cohort (p < 0.05). Moreover, there were differences in the immunological microenvironments, biological processes, clinical features, and chemotherapeutic drug sensitivity between the groups at high and low risk. Using multivariable Cox regression analyses, platelet-related risk score was shown to be an independent prognostic influence in MM (p < 0.001, hazard ratio (HR) = 2.001%, 95% confidence interval (CI): 1.467-2.730). Furthermore, the capacity to predict survival was further improved when a combined nomogram was utilized. In training cohort, this outperformed the predictive value of International staging system (ISS) alone from a 5-years area under curve (AUC) = 0.668 (95% CI: 0.611-0.725) to an AUC = 0.721 (95% CI: 0.665-0.778). Conclusion: Our study revealed the potential benefits of PRGs in terms of survival prognosis of MM patients. Furthermore, we verified its potential as a drug target for MM patients. These findings open up novel possibilities for prognostic evaluation and treatment choices for MM.

Prognostic significance of ß2-microglobulin decline index in multiple myeloma.

Purpose: To assess the prognostic significance of ß2-microglobulin decline index (ß2M DI) in multiple myeloma (MM). Methods: 150 MM patients diagnosed with MM were enrolled in this study. Cox proportional hazards model was used to analyze the uni- and multivariate prognosis in training cohort (n=105). A new combined prognostic model containing ß2M DI was built up based on the data in training cohort. The validation group was used to verify the model. Results: ß2M DI showed significant correlation with prognosis in both uni- and multivariate analyses and had a good correlation with complete response (CR) rate and deep remission rate. The ROC and calibration curves in validation cohort (n=45) indicated a good predictive performance of the new model. Based on the median risk score of the training group, we classified patients into high- and low- risk groups. In both training and validation groups, patients in the low-risk group had longer overall survival (OS) time than that in the high-risk group (p<0.05). Conclusion: ß2M DI is a good predictive index for predicting treatment response and survival time in MM patients. The prognostic model added with ß2M DI showed a better correlation with OS.

FGF21 ameliorates septic liver injury by restraining proinflammatory macrophages activation through the autophagy/HIF-1α axis.

INTRODUCTION: Sepsis, a systemic immune syndrome caused by severe trauma or infection, poses a substantial threat to the health of patients worldwide. The progression of sepsis is heavily influenced by septic liver injury, which is triggered by infection and cytokine storms, and has a significant impact on the tolerance and prognosis of septic patients. The objective of our study is to elucidate the biological role and molecular mechanism of fibroblast growth factor 21 (FGF21) in the process of sepsis. OBJECTIVES: This study was undertaken in an attempt to elucidate the function and molecular mechanism of FGF21 in therapy of sepsis. METHODS: Serum concentrations of FGF21 were measured in sepsis patients and septic mice. Liver injury was compared between mice FGF21 knockout (KO) mice and wildtype (WT) mice. To assess the therapeutic potential, recombinant human FGF21 was administered to septic mice. Furthermore, the molecular mechanism of FGF21 was investigated in mice with myeloid-cell specific HIF-1α overexpression mice (LyzM-CreDIO-HIF-1α) and myeloid-cell specific Atg7 knockout mice (Atg7△mye). RESULTS: Serum level of FGF21 was significantly increased in sepsis patients and septic mice. Through the use of recombinant human FGF21 (rhFGF21) and FGF21 KO mice, we found that FGF21 mitigated septic liver injury by inhibiting the initiation and propagation of inflammation. Treatment with rhFGF21 effectively suppressed the activation of proinflammatory macrophages by promoting macroautophagy/autophagy degradation of hypoxia-inducible factor-1α (HIF-1α). Importantly, the therapeutic effect of rhFGF21 against septic liver injury was nullified in LyzM-CreDIO-HIF-1α mice and Atg7△mye mice. CONCLUSIONS: Our findings demonstrate that FGF21 considerably suppresses inflammation upon septic liver injury through the autophagy/ HIF-1α axis.

A novel glycolysis-related gene signature for predicting the prognosis of multiple myeloma.

Background: Metabolic reprogramming is an important hallmark of cancer. Glycolysis provides the conditions on which multiple myeloma (MM) thrives. Due to MM's great heterogeneity and incurability, risk assessment and treatment choices are still difficult. Method: We constructed a glycolysis-related prognostic model by Least absolute shrinkage and selection operator (LASSO) Cox regression analysis. It was validated in two independent external cohorts, cell lines, and our clinical specimens. The model was also explored for its biological properties, immune microenvironment, and therapeutic response including immunotherapy. Finally, multiple metrics were combined to construct a nomogram to assist in personalized prediction of survival outcomes. Results: A wide range of variants and heterogeneous expression profiles of glycolysis-related genes were observed in MM. The prognostic model behaved well in differentiating between populations with various prognoses and proved to be an independent prognostic factor. This prognostic signature closely coordinated with multiple malignant features such as high-risk clinical features, immune dysfunction, stem cell-like features, cancer-related pathways, which was associated with the survival outcomes of MM. In terms of treatment, the high-risk group showed resistance to conventional drugs such as bortezomib, doxorubicin and immunotherapy. The joint scores generated by the nomogram showed higher clinical benefit than other clinical indicators. The in vitro experiments with cell lines and clinical subjects further provided convincing evidence for our study. Conclusion: We developed and validated the utility of the MM glycolysis-related prognostic model, which provides a new direction for prognosis assessment, treatment options for MM patients.

Identification and validation of a novel cuproptosis-related gene signature in multiple myeloma.

Background: Cuproptosis is a newly identified unique copper-triggered modality of mitochondrial cell death, distinct from known death mechanisms such as necroptosis, pyroptosis, and ferroptosis. Multiple myeloma (MM) is a hematologic neoplasm characterized by the malignant proliferation of plasma cells. In the development of MM, almost all patients undergo a relatively benign course from monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma (SMM), which further progresses to active myeloma. However, the prognostic value of cuproptosis in MM remains unknown. Method: In this study, we systematically investigated the genetic variants, expression patterns, and prognostic value of cuproptosis-related genes (CRGs) in MM. CRG scores derived from the prognostic model were used to perform the risk stratification of MM patients. We then explored their differences in clinical characteristics and immune patterns and assessed their value in prognosis prediction and treatment response. Nomograms were also developed to improve predictive accuracy and clinical applicability. Finally, we collected MM cell lines and patient samples to validate marker gene expression by quantitative real-time PCR (qRT-PCR). Results: The evolution from MGUS and SMM to MM was also accompanied by differences in the CRG expression profile. Then, a well-performing cuproptosis-related risk model was developed to predict prognosis in MM and was validated in two external cohorts. The high-risk group exhibited higher clinical risk indicators. Cox regression analyses showed that the model was an independent prognostic predictor in MM. Patients in the high-risk group had significantly lower survival rates than those in the low-risk group (p < 0.001). Meanwhile, CRG scores were significantly correlated with immune infiltration, stemness index and immunotherapy sensitivity. We further revealed the close association between CRG scores and mitochondrial metabolism. Subsequently, the prediction nomogram showed good predictive power and calibration. Finally, the prognostic CRGs were further validated by qRT-PCR in vitro. Conclusion: CRGs were closely related to the immune pattern and self-renewal biology of cancer cells in MM. This prognostic model provided a new perspective for the risk stratification and treatment response prediction of MM patients.

Fibroblast growth factor 18 attenuates liver fibrosis and HSCs activation via the SMO-LATS1-YAP pathway.

Liver fibrosis, which is characterized by excessive accumulation of extracellular matrix (ECM) primarily produced by hepatic stellate cells (HSCs), can eventually lead to cirrhosis. Fibroblast growth factor 18 (FGF18) mediates various biological activities. However, the precise role of FGF18 in the pathological process of liver fibrosis and the underlying mechanisms have not been elucidated. In this study, we found that FGF18 was markedly upregulated in carbon tetrachloride (CCl4)-induced fibrotic mouse liver tissues and transforming growth factor ß (TGF-ß) stimulated LX-2 cells. Furthermore, our studies demonstrated that overexpression of FGF18 in the liver significantly alleviated CCl4-induced fibrosis and inhibited the activation of HSCs, while exacerbated by HSC-specific deletion of FGF18. Mechanistically, FGF18 treatment dramatically activated Hippo signaling pathway by suppressing smoothened (SMO) both in vivo and in vitro. Moreover, the interaction between SMO and LATS1 was crucial for the FGF18 induced protective effects. In conclusion, these results indicated that FGF18 attenuates liver fibrosis at least partially via the SMO-LATS1-YAP signaling pathway and therefore may be a potential therapeutic target for liver fibrosis.

Early Enteral Nutrition Prevent Acute Pancreatitis From Deteriorating in Obese Patients.

GOALS: The aim of this study was to determine a potential strategy to prevent acute pancreatitis (AP) from deteriorating in obese patients. BACKGROUND: Nutritional support plays a critical role in the treatment of AP. Early enteral nutrition (EEN) is considered to be able to protect mucosa of AP patients and alleviate inflammatory reactions. Obesity worsen AP prognosis. However, little is known about the effects of EEN in obese patients. STUDY: Prospective randomized control trial. Subjects with moderately severe AP or severe AP were divided into the visceral fat obesity (VFO) group and the non-VFO group by obesity index VFO. The patients received "delayed" enteral nutrition (started enteral nutrition feeding after the first 48 hours after admission to the hospital: group A: patients of non-VFO, n=108; group B: VFO patients, n=88) or EEN (in the VFO subgroup, group C: n=91).Occurrence of complication, clinical outcomes, plasma levels of cytokines, and intestine gut barrier index were measured at different timepoints after admission. RESULTS: VFO was a risk factor for aggravating of AP. EEN prevented the VFO patients from developing pancreatic necrotic infection, the mechanism of which might be related with inhibiting excessive inflammatory reactions, adjusting the imbalance of inflammatory response, and alleviating ischemia of intestine mucosa. CONCLUSIONS: The potential strategy, EEN, was able to prevent AP from deteriorating in obese patients.

The mechanism of SP1/p300 complex promotes proliferation of multiple myeloma cells through regulating IQGAP1 transcription.

Our previous research had firstly shown that MM cells overexpressed IQGAP1 gene and activated Ras/Raf/MEK/ERK pathway. But the mechanism of IQGAP1 overexpression and IQGAP1 gene transcription regulation remains uncertain. The mechanism of IQGAP1 overexpression and transcriptional regulation of IQGAP1 gene in myeloma cells was explored in the study. Through bioinformatics analysis and prediction we predicted and screened transcription factor Sp1 as a possible upstream regulator of IQGAP1.The proliferation, cell cycle and downstream ERK1/2 and p-ERK1/2 proteins were detected after siRNA-IQGAP1 was transfected to myeloma cells. The expression of Sp1, p300, IQGAP1, p-ERK1/2 and ERK1/2 were detected after Sp1 and p300 were inhibited or overexpressed respectively. The dual-luciferase reporter system was used to detect the activity of IQGAP1 gene promoter. CHIP was used to detect the binding of the Sp1 and IQGAP1 promoter regions.CO-IP was used to explore the interaction between Sp1 and p300.The mRNA expression levels of Sp1,p300 and IQGAP1 of the myeloma patients were detected, and the correlation analysis of their mRNA expression levels were carried out. The results showed IQGAP1-siRNA inhibits cell proliferation, cell cycle, IQGAP1 expression and phosphorylation of ERK1/2 protein. Inhibition of Sp1 or p300 down-regulated ERK1/2 and IQGAP1 expression; overexpression of Sp1 or p300 up-regulated ERK1/2 and IQGAP1 expression; Sp1 and p300 had a positive regulation effect on IQGAP1.Over expression of Sp1 or p300 significantly increased activity of IQGAP1 gene promoter. The transcription factor Sp1 plays a regulatory role in the IQGAP1 promoter region. There is an interaction between Sp1 and p300 in myeloma cells. The mRNA expression levels of Sp1, IQGAP1 and p300 in MM samples showed a positive correlation. In summary IQGAP1 is required for cell proliferation in MM cells, and the transcription of Sp1/p300 complex regulates expression of IQGAP1 gene.

NVP-BEZ235-induced autophagy as a potential therapeutic approach for multiple myeloma.

BACKGROUND: The PI3K/Akt/mTOR pathway is constitutively activated in human multiple myeloma (MM) cell lines and in freshly isolated plasmocytes from patients with MM. The mTOR signaling pathway has been designated an attractive anti-tumor target in multiple myeloma. NVP-BEZ235, a novel, dual class I PI3K/mTOR inhibitor, is an imidazoquinoline derivative. NVP-BEZ235 binds to the ATP-binding clefts of PI3K and mTOR kinase, thereby inhibiting their activities. Increasing evidence shows that NVP-BEZ235 is able to effectively and specifically reverse the hyperactivation of the PI3K/mTOR pathway, resulting not only in potent antiproliferative and antitumor activities in a broad range of cancer cell lines and experimental tumors but also in autophagy. METHOD: The antitumor, apoptosis, and autophagy effects of NVP-BEZ235 were measured in three MM cell lines, two leukemia cell lines, and primary CD138+ myeloma cells from MM patients and nude mouse MM models. In addition, the relationships between autophagy, cell death and apoptosis induced by NVP-BEZ235 were analyzed in MM cells. Furthermore, we explored the mechanism of autophagy induced by NVP-BEZ235 in MM cells. RESULTS: NVP-BEZ235 inhibited proliferation and induced apoptosis and autophagy in MM cells and in primary MM cells from patients and nude mouse MM models. Autophagy played an important role in the cell death and apoptosis of MM cell lines induced by NVP-BEZ235, and the mechanism involved the mTOR2-Akt-FOXO3a-BNIP3 pathway. CONCLUSIONS: In this study, NVP-BEZ235 showed the strongest antitumor and autophagy induction activity. Moreover, the mechanism involved the mTOR2-Akt-FOXO3a-BNIP3 pathway. Our study lays a theoretical foundation for NVP-BEZ235 clinical application.

Prognostic significance of the red blood cell distribution width that maintain at high level following completion of first line therapy in mutiple myeloma patients.

To investigate the prognostic value of the red blood cell distribution width(RDW) recovery from low levels at diagnosis after completion of first line therapy in mutiple myeloma (MM)patients,we enrolled 78 consecutive patients with MM and followed up from 2005 to 2016 in our hospital. The RDW was measured following completion of first-line therapy.The log-rank test, univariate analysis, and Cox regression analysis were used to evaluate the relationship between RDW and survival. We found that patients with an RDW ≥ 15.5% at diagnosis, as well as at completion of first-line therapy, had significantly lower progression-free survival (PFS) and overall survival(OS) rates than those with an RDW < 15.5%(P < 0.05).Patients with RDW that maintained more than 15.5% upon completion of therapy showed a shorter OS (P < 0.05) and PFS (P < 0.05) compared with patients with an RDW that decreased to a lower level.The multivariate analysis showed that RDW ≥ 15.5% after the completion of first-line therapy were an independent prognostic marker of poorer OS (P = 0.044) and PFS (P = 0.034). Therefore,we demonstrated that RDW at diagnosis, as well as at completion of first-line therapy is an independent predictor for mutiple myeloma patients.RDW maintained at high level, irrespective of whether RDW decreased to the cutoff value predicted an unfavorable prognosis in patients with MM.

Risk Factors for Worsening of Acute Pancreatitis in Patients Admitted with Mild Acute Pancreatitis.

BACKGROUND The aim of the present study was to investigate risk factors for developing more severe pancreatitis, including moderately severe (MSAP) and severe acute pancreatitis (SAP), in patients admitted with mild acute pancreatitis (MAP). MATERIAL AND METHODS Patients admitted with MAP to our hospital from March 2013 to May 2016 were included and prospectively evaluated. Possible risk factors for developing MSAP or SAP were age, blood glucose level on admission, etiology, sex, Ranson score, amylase level, Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores, C-reactive protein (CRP) level, serum calcium level, visceral fat area (VFA), body mass index (BMI), whether this was the first episode of AP, and method of administration of octreotide. The effects of variables for developing MSAP or SAP were evaluated using univariate and multivariate logistic regression models. Mortality, hospital duration, and rate of ICU transfer of patients were compared between patients who developed MSAP or SAP and patients who did not. RESULTS A total of 602 patients admitted with MAP were recruited into this study (256 men and 346 women). Seventy-four patients (12.3%) developed MSAP or SAP. According to univariate logistic regression analyses, the results indicated that there were 5 significant differences between patients who developed MSAP or SAP and those who did not: VFA (>100 cm²) (p=0.003), BMI (≥25 kg/m²) (p=0.001), Ranson score(p=0.004), APACHE-II (≥5) (p=0.001), and blood glucose level on admission (>11.1 mmol/L) (p=0.040). Further multivariate logistic regression analyses revealed that BMI (≥25 kg/m²) (p=0.005), APACHE-II (≥5) (p=0.001), and blood glucose level on admission (>11.1 mmol/L) (p=0.004) were independent risk factors for developing MSAP or SAP in patients admitted with MAP. Moreover, patients who developed MSAP or SAP had a mortality rate of 5.4%. CONCLUSIONS Significant risk factors for developing MSAP or SAP in patients admitted with MAP included BMI (≥25 kg/m²), APACHE-II (≥5), and blood glucose level on admission (>11.1 mmol/L). These factors should be used in the prediction of more severe pancreatitis in patients admitted with MAP.

Lycorine induces cell death in MM by suppressing Janus Kinase/signal transducer and activator of transcription via inducing the expression of SOCS1.

Despite the use of novel anti-myeloma agents,nearly all patients will eventually relapse or become refractory to drug treatment. New and more effective drugs for multiple myeloma (MM) are urgently needed. The JAK-STAT signaling pathway is important in the proliferation of myeloma cells.Lycorine,a natural alkaloid extracted from amaryllidaceae, has shown anti-tumor effects against a variety of solid tumors. However, its effects on MM remain unclear.In this study,we found that lycorine inhibited cellular viability and induced cell death in MM cell lines and primary myeloma cells which were derived from our four MM patients. The study showed that myeloma cells' cycle was being arrested under the G0/G1 phase followed by the lycorine treatment. Further mechanism analysis demonstrated that lycorine inhibited JAK2/STAT signaling through upregulation of SOCS1 in MM cells and patient MM cells.Importantly, we found that knockdown of HDAC8 resulted in increased expression of SOCS1. Collectively, our findings suggested lycorine acted as a potent novel histone deacetylase inhibitor and inhibited JAK2/STAT signaling through upregulation of SOCS1 in MM cells.

Effects of MicroRNA-132 transfection on the proliferation and apoptosis of human liver cancer cells in vitro and in vivo.

OBJECTIVE: To observe the biological role and underlying mechanism of microRNA-132 (miR-132) in liver cancer cell proliferation and apoptosis. METHODS: The expressions of miR-132 in the cancer tissue and their adjacent tissues from 45 liver cancer patients were detected by real-time quantitative polymerase chain reaction (RT-qPCR). The biological effects of miR-132 transfection on human liver cancer MHCC97H cells were assessed by CCK-8 assay, flow cytometry,in vivo experiment in nude mice, and TUNEL test. Western blotting was used to detect the expressions of p-AKT, Survivin, and Caspase 3 in liver cancer cells. Immunohistochemistry was used to detect the positive expressions of Ki-67,Survivin,and Caspase 3 in the xenograft tumors. RESULTS: The expression level of miR-132 was found to be down-regulated in liver cancer tissues compared with the matched adjacent tissues (P<0.05). After transfection,the expression of miR-132 was significantly higher than blank control group and negative control group (P<0.05). The proliferation of liver cancer cells was inhibited significantly by miR-132 transfection (P<0.05). Transfection of miR-132 arrested cells in the G0/G1 phase and triggered apoptosis of MHCC97H cells (P<0.05). After miR-132 transfection,the expression of Caspase 3 was up-regulated, whereas the expressions of p-AKT and Survivin were down-regulated (P<0.05). In addition,the tumor weight in miR-132 transfection group was significantly decreased in comparison with blank control group and negative control group (P<0.05). Apoptosis occurred more frequently in the miR-132 transfection group than in control groups (P<0.05). Compared with the blank control group and negative control group, the miR-132 transfection group had significantly decreased expression of Survivin but increased positive expression of Ki-67 and Caspase 3(P<0.05). CONCLUSIONS: miR-132 is down-regulated in human liver cancer tissues miR-132 transfection can effectively inhibit proliferation and promote apoptosis of MHCC97H cells in vitro and in vivo. Therefore, miR-132 may become a new target in liver cancer treatment.

[Effect of Ginkgo biloba extract on the function of alveolar polymorphonuclear neutrophils in severe acute pancreatitis rats complicated with lung injury].

OBJECTIVE: To explore the effect of Ginkgo biloba extract (GBE) on the function of alveolar polymorphonuclear neutrophils (PMN) in severe acute pancreatitis (SAP) rats complicated with lung injury (LI). METHODS: Forty-eight adult SD rats were randomly divided into three groups, i.e., the sham-operation group, the SAP group, and the GBE treatment group, 16 in each group. The SAP model was successfully induced by retrograde injection of 5% sodium taurocholate solution into the biliopancreatic duct. Rats in the sham-operation group only received flipping of the duodenum. Those in the GBE treatment group received GBE intervention based on SAP model. Equal volume of normal saline was given to rats in the sham-operation group and the SAP group. Rats were sacrificed at 6 and 12 h after operation respectively. The lung tissue was sampled to evaluate the LI score. The wet/dry ratio (W/D) of lung tissues was detected. The activity of myeloperoxidase (MPO) was measured. Alveolar PMN was harvested by bronchoalveolar lavage. The content of neutrophil elastase (NE) in bronchoalveolar lavage fluid (BALF) was measured by enzyme-linked immunoabsorbent assay (ELISA). The percentage of CD11b/CD18 double positive PMN was detected using flow cytometry. The expression of intercellular adhesion molecule-1 (ICAM-1) and NE protein in the lung tissue was detected by Western blot. RESULTS: Compared with the sham-operation group, significant pathologic lesion occurred in the lung tissue of rats in the SAP group; the pathologic LI score, lung tissue W/D ratio, MPO, and NE content in BALF significantly increased, the expression of ICAM-1 and NE in the lung tissue was obviously up-regulated, and the percentage of CD11b/CD18 double positive PMN significantly increased (P < 0.01). Compared with the SAP group, pathological lesion of the lung tissue was obviously attenuated, and the above indices were all significantly declined in the GBE treatment group (P < 0.01). CONCLUSIONS: Expression of ICAM-1 in the lung tissue and the percentage of D11b/ CD18 double positive PMN were up-regulated in SAP rats complicated with LI, resulting in the adherence of PMN to pulmonary vascular endothelial cells, and then activating PMN to release NE and aggravate LI. GBE could alleviate LI through down-regulating the expression ICAM-1 and CD11b/CD18, and hindering the adherence and activation of PMN to pulmonary vascular endothelial cells.

Quercetin suppresses the proliferation of multiple myeloma cells by down-regulating IQ motif-containing GTPase activating protein 1 expression and extracellular signal-regulated kinase activation.

The flavonoid quercetin has shown anti-tumor effects against a variety of solid tumors. However, its effects on multiple myeloma (MM) remain unclear. In this study we examined the proliferation of human myeloma cell lines U266, KM3 and RPMI8226 and MM derived cells from four patients with MM after quercetin treatment, and detected the expression of IQ motif-containing GTPase activating protein 1 (IQGAP1), a scaffold protein involved in mitogen-activated protein kinase (MAPK) signaling, by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. We found that quercetin inhibited the proliferation of MM cells in a dose- and time-dependent manner, accompanied by reduced IQGAP1 expression at mRNA and protein levels, and reduced extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Furthermore, we found that quercetin inhibited the interaction between IQGAP1 and ERK1/2 in RPMI8226 cells. In summary, our results suggest that quercetin suppresses the proliferation of MM cells by down-regulating IQGAP1 expression and ERK activation, and has potential as a novel agent to target oncogenic kinase cascades for MM therapy.

Treatment selection for gastric cancer with portal hypertension: clinical management.

BACKGROUND: Treatment for gastric cancer with portal hypertension must consider the eradication of the tumor and the change of hemodynamics in portal hypertension (PHT). Few reports have described the surgical procedures and postoperative complications of surgery for gastric cancer associated with PHT. METHODS: The clinical data of 22 patients with PHT undergoing curative surgery for gastric cancer during 5 years were retrospectively analyzed. For 12 patients classified in Child's class A, D2 lymph node (LN) dissection was performed, and 10 patients classified into Child's class B were treated with D1 LN dissection. Surgical treatment included total gastrectomy combined with pericardial devascularization, distal subtotal gastrectomy, distal subtotal gastrectomy combined with splenectomy, and distal subtotal gastrectomy combined with pericardial devascularization with posterior gastric artery and left inferior phrenic artery preserved. A liver biopsy was analyzed in all patients. RESULTS: Postoperative complications developed in 50 % (11/22 patients) and the mortality rate was 9 % (2/22). The rate of postoperative ascites in patients with Child's class A was much lower than in those with Child's class B (P < 0.05). "Operation time," "volume of hemorrhage," "platelet count," and "treatment of PHT" are all risk factors of liver function deterioration. However, there was no significant difference in liver function deterioration rate between patients with Child's class A and Child's class B (P > 0.05). The occurrence rate of complications in patients with PHT was much higher compared to those without with PHT (P < 0.05). CONCLUSIONS: Individualized selection of surgical approaches is crucial for treatment of gastric carcinoma accompanied by PHT. Surgical treatment should be based on preoperative TNM stage, liver function, and degree of PHT.

IQGAP1 plays an important role in the cell proliferation of multiple myeloma via the MAP kinase (ERK) pathway.

The present study was designed to explore the role of IQ motif-containing GTPase activating protein 1 (IQGAP1) in the cell proliferation of multiple myeloma (MM) via the MAP kinase (ERK) pathway. Reverse transcription­polymerase chain reaction (RT-PCR) and western blot analysis were carried out to evaluate the expression of IQGAP1 in RPMI8226, U266 and KM3 cell lines and in primary MM cells from 4 MM patients. shRNA-expressing plasmids were used in RPMI8226 cells to knock down IQGAP1 and an MTT assay was used to examine the proliferative activity of the RPMI8226-shIQGAP1 (clone 1), RPMI8226-shRNA negative and untransfected RPMI8226 cells in subgroups stimulated with VEGF/IL-6 or without. Western blot analyses were then performed to examine the protein levels of p-ERK1/2, ERK1/2, AKT, p-AKT, STAT3, p-STAT3 in the RPMI8226-shIQGAP1 (clone 1), RPMI8226-shRNA negative and untransfected RPMI8226 cells. Co-immunoprecipitation was used to verify the interaction between the IQGAP1 scaffold and the MAP ERK kinase. We found that IQGAP1 was overexpressed in the human myeloma cell lines and in the patient MM cells. The proliferation rate in the RPMI8226 cells was decreased when IQGAP1 was knocked down with shRNA. IQGAP1 was found to affect RPMI8226 cell proliferation by regulation of the MAP kinase (ERK1/2) pathway; IQGAP1 scaffold-MAP kinase (ERK) interaction was noted in the human myeloma RPMI8226 cell lines. In conclusion, IQGAP1 plays an important role in the cell proliferation of MM via the MAP kinase (ERK) pathway.