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Aims: To determine the roles of matrix metallopeptidase-9 (MMP9) on human coronary artery smooth muscle cells (HCASMCs) in vitro, early beginning of atherosclerosis in vivo in diabetic mice, and drug naïve patients with diabetes. Methods: Active human MMP9 (act-hMMP9) was added to HCASMCs and the expressions of MCP-1, ICAM-1, and VCAM-1 were measured. Act-hMMP9 (n=16) or placebo (n=15) was administered to diabetic KK.Cg-Ay/J (KK) mice. Carotid artery inflammation and atherosclerosis measurements were made at 2 and 10 weeks after treatment. An observational study of newly diagnosed drug naïve patients with type 2 diabetes mellitus (T2DM n=234) and healthy matched controls (n=41) was performed and patients had ultrasound of carotid arteries and some had coronary computed tomography angiogram for the assessment of atherosclerosis. Serum MMP9 was measured and its correlation with carotid artery or coronary artery plaques was determined. Results: In vitro, act-hMMP9 increased gene and protein expressions of MCP-1, ICAM-1, VCAM-1, and enhanced macrophage adhesion. Exogenous act-hMMP9 increased inflammation and initiated atherosclerosis in KK mice at 2 and 10 weeks: increased vessel wall thickness, lipid accumulation, and Galectin-3+ macrophage infiltration into the carotid arteries. In newly diagnosed T2DM patients, serum MMP9 correlated with carotid artery plaque size with a possible threshold cutoff point. In addition, serum MMP9 correlated with number of mixed plaques and grade of lumen stenosis in coronary arteries of patients with drug naïve T2DM. Conclusion: MMP9 may contribute to the initiation of atherosclerosis and may be a potential biomarker for the early identification of atherosclerosis in patients with diabetes. [ABSTRACT FROM AUTHOR]

Background: Progression of disease within 24 months (POD24) is a risk factor for poor survival in follicular lymphoma (FL), and there is currently no optimal prognostic model to accurately predict patients with early disease progression. How to combine traditional prognostic models with new indicators to establish a new prediction system, to predict the early progression of FL patients more accurately is a future research direction. Methods: This study retrospectively analyzed patients with newly diagnosed FL patients in Shanxi Provincial Cancer Hospital from January 2015 to December 2020. Data from patients undergoing immunohistochemical detection (IHC) were analyzed using c2 test and multivariate Logistic regression. Also, we built a nomogram model based on the results of LASSO regression analysis of POD24, which was validated in both the training set and validation set, and additional external validation was performed using a dataset (n = 74) from another center, Tianjin Cancer Hospital. Results: The multivariate Logistic regression results suggest that high-risk PRIMA-PI group, Ki-67 high expression represent risk factors for POD24 (P<0.05). Next, PRIMA-PI and Ki67 were combined to build a new model, namely, PRIMA-PIC to reclassify high and low-risk groups. The result showed that the new clinical prediction model constructed by PRIMA-PI with ki67 has a high sensitivity to the prediction of POD24. Compared to PRIMA-PI, PRIMA-PIC also has better discrimination in predicting patient's progression-free survival (PFS) and overall survival (OS). In addition, we built nomogram models based on the results of LASSO regression (histological grading, NK cell percentage, PRIMA-PIC risk group) in the training set, which were validated using internal validation set and external validation set, we found that C-index and calibration curve showed good performance. Conclusion: As such, the new predictive model-based nomogram established by PRIMA-PI and Ki67 could well predict the risk of POD24 in FL patients, which boasts clinical practical value. [ABSTRACT FROM AUTHOR]

Background: Follicular lymphoma (FL), an indolent non-Hodgkin lymphoma (NHL), is generally incurable. Favourable prognosis and durable remission are crucial for FL patients. The genetic mutation spectrum provides novel biomarkers for determining the prognosis of FL patients, but its detection is easily affected by the collection of tumour tissue biopsies. In this study, we aimed to describe the mutational landscape of FL using circulating tumour DNA (ctDNA) samples and to explore the relationship between mutations and prognostic indicators of clinical outcome in patients with newly diagnosed follicular lymphoma and the prognostic value of such mutations. Methods: A total of 28 patients with newly diagnosed FL were included in this study. A targeted NGS-based 59-gene panel was used to assess the ctDNA mutation profiles. Differences in clinical factors between patients carrying mutations and those without mutations were analysed. We also explored the relationship between gene mutation status, mean VAFs (variant allele frequencies) and clinical factors. The Kaplan‒Meier method was applied to analyse the overall survival (OS) and progression-free survival (PFS) of patients carrying mutations and those without mutations. Results: ctDNA mutations were detectable in 21 (75%) patients. The most commonly mutated genes were CREBBP (54%, 15/28), KMT2D (50%, 14/28), STAT6 (29%, 8/28), CARD11 (18%, 5/28), PCLO (14%, 4/28), EP300 (14%, 4/28), BCL2 (11%, 3/28), and TNFAIP3 (11%, 3/28), with a mutation frequency of >10%. Patients with detectable ctDNA mutation tended to present with advanced Ann Arbor stage (III-IV) (p = 0.009), high FLIPI risk (3–5) (p = 0.023) and severe lymph node involvement (No. of involved areas ≥5) (p = 0.02). In addition, we found that the mean VAF was significantly higher in patients with advanced Ann Arbor stage, high-risk FLIPI, elevated lactate dehydrogenase (LDH: 0–248U/L), advanced pathology grade, bone marrow involvement (BMI) and lymph node involvement. Additionally, KMT2D, EP300, and STAT6 mutations were associated with inferior PFS (p < 0.05). Conclusion: We described the ctDNA mutation landscapes in Chinese patients with newly diagnosed FL and found that ctDNA VAF means reflect tumour burden. Moreover, PFS was shorter in patients with KMT2D, EP300 and STAT6 mutations. [ABSTRACT FROM AUTHOR]

Trans-δ-viniferin (TVN), as a natural extract, is a resveratrol dimer with attractive biological activities, particularly its anti-tumor character. However, the mechanism of TVN interfering with cancerous proliferation has not been fully understood. Herein in this study, we found that TVN could trigger cancerous mitochondrial membrane potential (ΔΨm) reduction, with intracellular reactive oxidative species (ROS) level increasing, leading to apoptosis, which makes TVN a promising candidate for lung cancer cells A549 treatment. Therefore, this study provides TVN as an option to meet the demand for higher antitumor availability with lower biotoxicity and other clinical applications. [ABSTRACT FROM AUTHOR]

Background: Follicular lymphoma (FL), an indolent non-Hodgkin lymphoma (NHL), is generally incurable. Favourable prognosis and durable remission are crucial for FL patients. The genetic mutation spectrum provides novel biomarkers for determining the prognosis of FL patients, but its detection is easily affected by the collection of tumour tissue biopsies. In this study, we aimed to describe the mutational landscape of FL using circulating tumour DNA (ctDNA) samples and to explore the relationship between mutations and prognostic indicators of clinical outcome in patients with newly diagnosed follicular lymphoma and the prognostic value of such mutations. Methods: A total of 28 patients with newly diagnosed FL were included in this study. A targeted NGS-based 59-gene panel was used to assess the ctDNA mutation profiles. Differences in clinical factors between patients carrying mutations and those without mutations were analysed. We also explored the relationship between gene mutation status, mean VAFs (variant allele frequencies) and clinical factors. The Kaplan-Meier method was applied to analyse the overall survival (OS) and progression-free survival (PFS) of patients carrying mutations and those without mutations. Results: ctDNA mutations were detectable in 21 (75%) patients. The most commonly mutated genes were CREBBP (54%, 15/28), KMT2D (50%, 14/28), STAT6 (29%, 8/28), CARD11 (18%, 5/28), PCLO (14%, 4/28), EP300 (14%, 4/28), BCL2 (11%, 3/28), and TNFAIP3 (11%, 3/28), with a mutation frequency of >10%. Patients with detectable ctDNA mutation tended to present with advanced Ann Arbor stage (III-IV) (p = 0.009), high FLIPI risk (3-5) (p = 0.023) and severe lymph node involvement (No. of involved areas =5) (p = 0.02). In addition, we found that the mean VAF was significantly higher in patients with advanced Ann Arbor stage, high-risk FLIPI, elevated lactate dehydrogenase (LDH: 0-248U/L), advanced pathology grade, bone marrow involvement (BMI) and lymph node involvement. Additionally, KMT2D, EP300, and STAT6 mutations were associated with inferior PFS (p < 0.05). Conclusion: We described the ctDNA mutation landscapes in Chinese patients with newly diagnosed FL and found that ctDNA VAF means reflect tumour burden. Moreover, PFS was shorter in patients with KMT2D, EP300 and STAT6 mutations. [ABSTRACT FROM AUTHOR]

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). With increasing approval of CAR T-cell products and advances in CAR T cell therapy, CAR T cells are expected to be used in a growing number of cases. However, CAR T-cell-associated toxicities can be severe or even fatal, thus compromising the survival benefit from this therapy. Standardizing and studying the clinical management of these toxicities are imperative. In contrast to other hematological malignancies, such as acute lymphoblastic leukemia and multiple myeloma, anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features, most notably local cytokine-release syndrome (CRS). However, previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL. Consequently, we developed this consensus for the prevention, recognition, and management of these toxicities, on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions. This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management, and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS. [ABSTRACT FROM AUTHOR]

Heroin can cause damage to many human organs, possibly leading to different types of arrhythmias and abnormal electrophysiological function of the heart muscle and the steady state of calcium-ion channels. We explored cardiomyocytes treated with heroin and the effect on calcium-ion channels. Transcriptomics and metabolomics were used to screen for differential genes and metabolite alterations after heroin administration to jointly analyze the effect of heroin on calcium channels in cardiomyocytes. Cardiomyocytes from primary neonatal rats were cultured in vitro and were treated with different concentrations of heroin to observe the changes in morphology and spontaneous beat frequency and rhythm by a patch clamp technique. Transcriptomic studies selected a total of 1,432 differentially expressed genes, 941 upregulated and 491 downregulated genes in rat cardiomyocytes from the control and drug intervention groups. Gene Ontology functional enrichment showed that 1,432 differential genes selected by the two groups were mainly involved in the regulation of the multicellular organismal process, response to external stimulus, myofibril, inflammatory response, muscle system process, cardiac muscle contraction, etc. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that these genes were mainly concentrated in cardiac muscle contraction, osteoclast differentiation, adrenergic signaling in cardiomyocytes, dilated cardiomyopathy, hypertrophic cardiomyopathy, and other important pathways. Metabolomic testing further suggested that cardiomyocyte metabolism was severely affected after heroin intervention. After the treatment with heroin, the L-type calcium channel current I–V curve was up-shifted, the peak value was significantly lower than that of the control group, action potential duration 90 was significantly increased in the action potential, resting potential negative value was lowered, and action potential amplitude was significantly decreased in cardiomyocytes. In this study, heroin could cause morphological changes in primary cardiomyocytes of neonatal rats and electrophysiological function. Heroin can cause myocardial contraction and calcium channel abnormalities, damage the myocardium, and change the action potential and L-type calcium channel. [ABSTRACT FROM AUTHOR]

Background: Characterization of gene mutation profiles can provide new treatment options for patients with diffuse large B-cell lymphoma (DLBCL). However, this method is challenged by the limited source of tissue specimens, especially those of DLBCL patients at advanced stages. Therefore, in the current study, we aimed to describe the gene mutation landscape of DLBCL using circulating tumor DNA (ctDNA) samples obtained from patients' blood samples, as well as to explore the relationship between ctDNA mutations and the prognosis and treatment response of patients with newly diagnosed DLBCL. Methods: A total of 169 newly diagnosed Chinese DLBCL patients were included in this study, among which 85 patients were divided into a training set and 84 were assigned into a validation set. The mutation profile of a 59-gene panel was analyzed by targeted next generation sequencing (NGS) of the patients' ctDNA samples. Differences in clinical factors between patients with and without ctDNA mutations were analyzed. In addition, we also explored gene mutation frequencies between GCB and non-GCB subtypes, and the relationship between gene mutation status, clinical factors, mean VAF (variant allele frequencies) and the patients' overall survival (OS) and progression-free survival (PFS). Results: ctDNA mutations were detected in 64 (75.3%) patients of the training set and 67 (79.8%) patients of the validation set. The most commonly mutated genes in both sets were PCLO, PIM1, MYD88, TP53, KMT2D, CD79B, HIST1H1E and LRP1B, with mutation frequencies of >10%. Patients with detectable ctDNA mutations trended to present advanced Ann Arbor stages (III-IV), elevated LDH (lactate dehydrogenase) levels, shorter OS and PFS, and a lower complete response (CR) rate to the R-CHOP regimen compared with DLBCL patients without ctDNA mutations. In addition, mean VAF (≤4.94%) and PCLO mutations were associated with poor OS and PFS. Conclusion: We investigated the ctDNA mutation landscape in Chinese patients with newly diagnosed DLBCL and found that ctDNA could reflect tumor burden and patients with detectable ctDNA mutations trended to have shorter OS and PFS and a lower CR rate. [ABSTRACT FROM AUTHOR]

Increasing evidence has elucidated that the tumor microenvironment (TME) shows a strong association with tumor progression and therapeutic outcome. We comprehensively estimated the TME infiltration patterns of 111 gastric cancer (GC) and 21 normal stomach mucosa samples based on bulk transcriptomic profiles based on which GC could be clustered as three subtypes, TME-Stromal, TME-Mix, and TME-Immune. The expression data of TME-relevant genes were utilized to build a GC prognostic model--GC_Score. Among the three GC TME subtypes, TME-Stomal displayed the worst prognosis and the highest GC_Score, while TME-Immune had the best prognosis and the lowest GC_Score. Connective tissue growth factor (CTGF), the highest weighted gene in the GC_Score, was found to be overexpressed in GC. In addition, CTGF exhibited a significant correlation with the abundance of fibroblasts. CTGF has the potential to induce transdifferentiation of peritumoral fibroblasts (PTFs) to cancer-associated fibroblasts (CAFs). Beyond characterizing TME subtypes associated with clinical outcomes, we correlated TME infiltration to molecular features and explored their functional relevance, which helps to get a better understanding of carcinogenesis and therapeutic response and provide novel strategies for tumor treatments. [ABSTRACT FROM AUTHOR]

Increased expression of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14) is associated with the development of many cancers. MT1-MMP may promote the entry of yes-associated protein1 (YAP1) into the nucleus by regulating the regulation of β1-integrin. The purpose of this study was to investigate the effects of MT1-MMP, β1-integrin and YAP1 on the prognosis of gliomas. The expression of proteins was detected by bioinformatics and immunohistochemistry. The relationship between three proteins and clinicopathological parameters was analyzed by the χ 2 test. Survival analysis was used to investigate the effects of three proteins on prognosis. The results showed that high expressions of MT1-MMP, β1-integrin and YAP1 were found in glioblastoma (GBM) compared with lower-grade glioma (LGG). There was a significantly positive correlation between MT1-MMP and β1-integrin (r = 0.387), MT1-MMP and YAP1 (r = 0.443), β1-integrin and YAP1 (r = 0.348). Survival analysis showed that patients with overexpression of MT1-MMP, β1-integrin and YAP1 had a worse prognosis. YAP1 expression was the independent prognostic factor for progression-free survival (PFS). There was a statistical correlation between the expression of MT1-MMP and YAP1 and isocitrate dehydrogenase 1 (IDHl) mutation. Thus, this study suggested that MT1-MMP, β1-integrin and YAP1, as tumor suppressors, are expected to be promising prognostic biomarkers and therapeutic targets for glioma patients. [ABSTRACT FROM AUTHOR]

Copy number variations (CNVs) in cell-free DNA (cfDNA) are emerging as noninvasive biomarkers for various cancers. However, multiple-level analysis of cfDNA CNVs for hepatocellular carcinoma (HCC) patients with radical treatments remains uninvestigated. Here, CNVs at genome-wide, chromosomal-arm, and bin levels were analyzed in cfDNA from 117 HCC patients receiving radical treatments. Then, the relationship between cfDNA CNVs and clinical outcomes was explored. Our results showed that a concordant profile of CNVs was observed between cfDNA and tumor tissue DNA. Three genome-wide CNV indicators including tumor fraction (TFx), prediction score (P-score), and stability score (S-score) were calculated and demonstrated to exhibit significant correlation with poorer overall survival (OS) and recurrence-free survival (RFS). Furthermore, the high-frequency cfDNA CNVs at chromosomal-arm level including the loss of 4q, 17p, and 19p and the gain of 8q and 1q clearly predicted HCC prognosis. Finally, a bin-level risk score was constructed to improve the ability of CNVs in predicting prognosis. Altogether, our study indicates that the multiple-level cfDNA CNVs are significantly associated with OS and RFS in HCC patients with radical treatments, suggesting that cfDNA CNVs detected by low-coverage whole-genome sequencing (WGS) may be used as potential prognostic biomarkers of HCC patients. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy and safety of the novel histone deacetylase inhibitor, chidamide, in combination with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (Chi-CHOEP) for untreated peripheral T-cell lymphoma (PTCL). Methods: A prospective, multicenter, single arm, phase 1b/2 study was conducted. A total of 128 patients with untreated PTCL (18-70 years of age) were enrolled between March 2016 and November 2019, and treated with up to 6 cycles with the Chi-CHOEP regimen. In the phase 1b study, 3 dose levels of chidamide were evaluated and the primary endpoint was determination of the maximumtolerated dose and recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 study was 2-year progression-free survival (PFS). Results: Fifteen patients were enrolled in the phase 1b study and the RP2D for chidamide was determined to be 20 mg, twice a week. A total of 113 patients were treated at the RP2D in the phase 2 study, and the overall response rate was 60.2%, with a complete response rate of 40.7%. At a median follow-up of 36 months, the median PFS was 10.7 months, with 1-, 2-, and 3-year PFS rates of 49.9%, 38.0%, and 32.8%, respectively. The Chi-CHOEP regimen was well-tolerated, with grade 3/4 neutropenia occurring in approximately two-thirds of the patients. No unexpected adverse events (AEs) were reported and the observed AEs were manageable. Conclusions: This large cohort phase 1b/2 study showed that Chi-CHOEP was well-tolerated with modest efficacy in previously untreated PTCL patients. [ABSTRACT FROM AUTHOR]

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Objective ‒ The objective of this study was to evaluate the clinicopathological features and treatment of composite lymphoma (CL) with cervical lymph node enlargement. Methods ‒ In this study, two cases of CL are presented. Biopsies of enlarged cervical lymph nodes by excision revealed two distinct types of lymphomas. The diagnoses were confirmed by routine histopathology, immunohistochemistry, in situ hybridization, polymerase chain reactions and flow cytometry. Case 1 was diagnosed with Hodgkin’s lymphoma and cytotoxic T-cell lymphoma complicated by Epstein–Barr virus infection. Case 2 was diagnosed with diffuse large B-cell lymphoma and angioimmunoblastic Tcell lymphoma. Results ‒ Case 1 received one cycle of adriamycin, bleomycin, vincristine and dacarbazine (ABVD regimen) combined with chidamide, followed by one cycle of gemcitabine and dexamethasone (GDP regimen) combined with chidamide, and then oral acyclovir. The patient achieved stable disease, but was lost to follow-up. Case 2 received eight cycles of cyclophosphamide, pirarubicin, vincristine and dexamethasone (CTOP regimen) combined with chidamide, and the patient achieved complete remission. Nine months later, relapse was confirmed. She received chidamide monotherapy for 3 months, which was then terminated. One year later, the patient underwent progressive disease and died. Conclusions ‒ CL is a kind of rare disease. Due to the complexity of CL, clinicians should consider both disease components in order to increase the likelihood of effective treatment. This is important. [ABSTRACT FROM AUTHOR]

Exosomes secreted from the cell to the extracellular environment play an important role in intercellular communication. Next-generation sequencing technology, which has achieved great development recently, allows us to detect more complete data and gain even deeper analyses of RNA transcriptomes. In our research, we extracted exosomes from different gastric cancer cell lines and immortalized normal gastric mucosal epithelial cell line and examined the amounts of exosomal proteins and RNAs. Our data showed that the secreted amount of cancer cell-derived exosomes, which contain proteins and RNAs, was much higher than that of normal cell-derived exosomes. Moreover, next-generation sequencing technology confirmed the presence of small non-coding RNAs in exosomes. Based on publicly available databases, we classified small non-coding RNAs. According to the microRNA profiles of exosomes, hsa-miR-21-5p and hsa-miR-30a-5p were two of the most abundant sequences among all libraries. The expression levels of the two microRNAs, miR-100 and miR-148a, in exosomes were validated through reverse transcription polymerase chain reaction. The reverse transcription polymerase chain reaction result, consistent with the trend of sequencing result, indicated a significant difference in exosomes between gastric cancer and gastric mucosal epithelial cell lines. We also predicted novel microRNA candidates but they need to be validated. This research provided an atlas of small noncoding RNA in exosomes and may make a little contribution to the understanding of exosomal RNA composition and finding parts of differential expression of RNAs in exosomes. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer is one of the most common malignancies worldwide. Recent studies have shown that microRNAs play crucial roles in regulating cellular proliferation process in gastric cancer. MicroRNA-29c (miR-29c) acts as a tumor suppressor in different kinds of tumors.Methods: Quantitative PCR was performed to evaluate miR-29c expression level in 67 patient gastric cancer tissues and 9 gastric cancer cell lines. The effects of miR-29c were explored by proliferation assay, soft agar colony formation assay, apoptosis and cell cycle analysis using flow cytometry. The target gene was predicted by bioinformatic algorithms and validated by dual luciferase reporter assay and Western blot analysis.Results: In this study, we demonstrate that miR-29c is down-regulated in gastric cancer tissues and cell lines. We indicate that overexpression of miR-29c inhibits cell proliferation, promotes apoptosis and arrests cell cycle at G1/G0 phase. We additionally show that miR-29c exerts these effects by targeting Nuclear autoantigenic sperm protein (NASP). Moreover, depletion of NASP can elite the phenotypes caused by miR-29c.Conclusions: These data suggest that miR-29c inhibits proliferation in gastric cancer and could potentially serve as an early biomarker and a novel therapy target. [ABSTRACT FROM AUTHOR]

Background: The efficacy and safety of rituximab-based chemotherapy (R-chemo), the standard regimen for patients with diffuse large B-cell lymphoma (DLBCL), which is more common in Asia than in Western countries, are well confirmed in randomized controlled trials (RCTs). However, the safety and effectiveness of R-chemo in patients who are largely excluded from RCTs have not been well characterized. This real-world study investigated the safety and effectiveness of R-chemo as first-line treatment in Chinese patients with DLBCL.Methods: Treatment-naive DLBCL patients who were CD20 positive and eligible to receive R-chemo were enrolled with no specific exclusion criteria. Data collected at baseline included age, gender, disease stage, international prognostic index (IPI), B symptoms, extranodal involvement, performance status, and medical history. In the present study, data on safety, treatment effectiveness, and HBV infection management were collected 120 days after the last R-chemo administration.Results: Overall, R-chemo was well tolerated. The safety profile of R-chemo in patients with a history of heart or liver disease was well described without any additional unexpected safety concerns. The overall response rate (ORR) in the Chinese patients from this study was 94.2 % (complete response [CR], 55.0 %; CR unconfirmed [CRu] 18.2 %; and partial response [PR], 20.9 %). Compared to patients with no history of disease, the CR and PR rates of patients with a history of heart or liver disease were lower and higher, respectively; this tendency could be in part explained by treatment interruptions in patients with heart or liver diseases. HBsAg positivity and a maximum tumor diameter of ≥7.5 cm negatively correlated with CR + CRu, whereas age and HBsAg positivity negatively correlated with CR.Conclusions: This study further validated the safety and effectiveness of R-chemo in Chinese patients with DLBCL. Patients with a history of heart or liver disease may further benefit from R-chemo if preventive measures are taken to reduce hepatic and cardiovascular toxicity. In addition to IPI and tumor diameter, HBsAg positivity could also be a poor prognostic factor for CR in Chinese patients with DLBCL.Trial Registration: ClinicalTrials.gov # NCT01340443 , April 20, 2011. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effect and safety of autologous peripheral blood stem cell transplantation (APBSCT) in children and adolescents with non-Hodgkin lymphoma (NHL). Ten patients with NHL were analyzed retrospectively. In all the patients, lymph node enlargement was most frequently detected. Patients with a mediastinal mass presented with a cough, palpitation and shortness of breath. Extranodal patients presented with abdominal pain, inability to walk and vaginal bleeding. All patients underwent APBSCT with conditioning regimens BEAM or BuCy. Among them, four patients with B-cell NHL received rituximab in addition to the conditioning regimen. Hematopoietic reconstitution was observed in all patients. Severe toxicity and transplant-related mortality were not observed. Prior to APBSCT, nine patients with a status of complete response (CR) and CR unconfirmed achieved continuing complete remission. Only one patient with partial response succumbed to progressive disease. APBSCT in children and adolescents with NHL is a safe, convenient and efficient treatment. The BEAM conditioning regimen was shown to be effective and tolerable for children and adolescents with NHL. Rituximab is a safe agent in the transplantation. The CR status at the time of transplantation demonstrated a higher survival rate. [ABSTRACT FROM AUTHOR]

The article discusses large B‑cell lymphoma in the leg being a rare heterogeneous malignant situation. It examines primary cutaneous B‑cell lymphoma and the manifestation of the plaques on the legs of elderly people. Also presented is the study of a 51 year old man admitted with a 8‑month history of a progressively enlarging red plaque, a biopsy revealing a dense atypical lymphocytic infiltrate, and the survival time for this disease being 5 years.

Background microRNAs are small noncoding RNAs that modulate a variety of cellular processes by regulating multiple targets, which can promote or inhibit the development of malignant behaviors. Accumulating evidence suggests miR-24 plays important roles in human carcinogenesis. However, its precise biological role remains largely elusive. This study examined the role of miR-24 in gastric cancer (GC). Methods The expression of miR-24 in GC tissues compared with matched non-tumor tissues and GC cells was detected by qRT-PCR. Synthetic short single or double stranded RNA oligonucleotides and lentiviral vectors were used to regulate miR-24 expression in GC cells to investigate its function in vitro and in vivo. Results miR-24 was significantly downregulated in GC tissues compared with matched non-tumor tissues and was associated with tumor differentiation. Ectopic expression of miR-24 in SGC- 7901 GC cells suppressed cell proliferation, migration and invasion in vitro as well as tumorigenicity in vivo by inducing cell cycle arrest in G0/G1 phase and promoting cell apoptosis. Furthermore, we identified RegIV as a target of miR-24 and demonstrated that miR-24 regulated RegIV expression via binding its 3' untranslated region. Conclusions miR-24 functions as a novel tumor suppressor in GC and the anti-oncogenic activity may involve its inhibition of the target gene RegIV. These findings suggest the possibility for miR-24 as a therapeutic target in GC. [ABSTRACT FROM AUTHOR]

Background Elevated MELK expression is featured in multiple tumors and correlated with tumorigenesis and tumor development. This study is aimed to investigate the mechanisms of MELKmediated development of gastric cancer. Methods MELK expression levels in human gastric cancer were determined by quantitative-PCR and immunohistochemistry. The effect of MELK on cell activity was explored by knockdown and overexpression experiments. Cell growth was measured using the CCK-8 assay. Apoptosis and cell cycle distributions were analyzed by flow cytometry. Migration and invasion were tested using a transwell migration assay. Cytoskeletal changes were analyzed by immunofluorescence. To explore the molecular mechanism and effect of MELK on migration and invasion, Western blotting was used to analyze the FAK/Paxillin pathway and pull down assays for the activity of small Rho GTPases. In vivo tumorigenicity and peritoneal metastasis experiments were performed by tumor cell engraftment into nude mice. Results MELK mRNA and protein expression were both elevated in human gastric cancer, and this was associated with chemoresistance to 5-fluorouracil (5-FU). Knockdown of MELK significantly suppressed cell proliferation, migration and invasion of gastric cancer both in vitro and in vivo, decreased the percentages of cells in the G1/G0 phase and increased those in the G2/M and S phases. Moreover, knockdown of MELK decreased the amount of actin stress fibers and inhibited RhoA activity. Finally, knockdown of MELK decreased the phosphorylation of the FAK and paxillin, and prevented gastrin-stimulated FAK/paxillin phosphorylation. By contrast, MELK overexpression had the opposite effect. Conclusions MELK promotes cell migration and invasion via the FAK/Paxillin pathway, and plays an important role in the occurrence and development of gastric cancer. MELK may be a potential target for treatment against gastric cancer. [ABSTRACT FROM AUTHOR]

Background Progesterone is essential for the proliferation and differentiation of mammary gland epithelium. Studies of breast cancer cells have demonstrated a biphasic progesterone response consisting of an initial proliferative burst followed by sustained growth arrest. However, the transcriptional factors acting with the progesterone receptor (PR) to mediate the effects of progesterone on mammary cell growth and differentiation remain to be determined. Recently, it was demonstrated that signal transducer and activator of transcription 6 (Stat6) is a cell growth suppressor. Similar to progesterone-bound PR, Stat6 acts by inducing the expression of the G1 cyclin-dependent kinase inhibitors p21 and p27. The possible interaction between Stat6 and progesterone pathways in mammary cells was therefore investigated in the present study. Methods ChIP and luciferase were assayed to determine whether Stat6 induces p21 and p27 expression by recruitment at the proximal Sp1-binding sites of the gene promoters. Immunoprecipitation and Western blotting were performed to investigate the interaction between Stat6 and PR-B. The cellular DNA content and cell cycle distribution in breast cancer cells were analyzed by FACS. Results We found that Stat6 interacts with progesterone-activated PR in T47D cells. Stat6 synergizes with progesterone-bound PR to transactivate the p21 and p27 gene promoters at the proximal Sp1-binding sites. Moreover, Stat6 overexpression and knockdown, respectively, increased or prevented the induction of p21 and p27 gene expression by progesterone. Stat6 knockdown also abolished the inhibitory effects of progesterone on pRB phosphorylation, G1/S cell cycle progression, and cell proliferation. In addition, knockdown of Stat6 expression prevented the induction of breast cell differentiation markers, previously identified as progesterone target genes. Finally, Stat6 gene expression levels increased following progesterone treatment, indicating a positive auto-regulatory loop between PR and Stat6. Conclusions Taken together, these data identify Stat6 as a coactivator of PR mediating the growth-inhibitory and differentiation effects of progesterone on breast cancer cells. [ABSTRACT FROM AUTHOR]

Background: Fibroblasts play a critical role in tumorigenesis, tumor progression and metastasis. However, their detailed molecular characteristics and clinical significance are still elusive. TAGLN is an actin-binding protein that plays an important role in tumorigenesis. Results: We investigated the interaction between cancer cells and the tumor microenvironment to determine how the fibroblasts from human gastric carcinoma facilitate tumorigenesis through TAGLN. QRT-PCR and Western blot indicated that TAGLN expression was upregulated in gastric carcinoma-associated fibroblasts (CAFs) that promote gastric cancer cell migration and invasion. Using small interfering RNA (siRNA), we found that CAFs enhanced tumor metastasis through upregulated TAGLN in vitro and in vivo. The expression of matrix metalloproteinase-2 (MMP-2) was significantly lower after TAGLN knock-down by siRNA. TAGLN levels were elevated in human gastric cancer stroma than normal gastric stroma and associated with differentiation and lymph node metastasis of gastric cancer. Conclusion: CAFs may promote gastric cancer cell migration and invasion via upregulating TAGLN and TAGLN induced MMP-2 production. [ABSTRACT FROM AUTHOR]

Aim: To investigate the role of bone morphogenetic protein 2 (BMP-2) in regulation of phosphatase and tensin homologue deleted on chromosome ten (PTEN) and apoptosis of pulmonary artery smooth muscle cells (PASMCs) under hypoxia. Methods: Normal human PASMCs were cultured in growth medium (GM) and treated with BMP-2 from 5-80 ng/ml under hypoxia (5% CO2+94% N2+1% O2) for 72 hours. Gene expression of PTEN, AKT-1 and AKT-2 were determined by quantitative RT-PCR (QRT-PCR). Protein expression levels of PTEN, AKT and phosph-AKT (pAKT) were determined. Apoptosis of PASMCs were determined by measuring activities of caspases-3, -8 and -9. siRNA-smad-4, bpV(HOpic) (PTEN inhibitor) and GW9662 (PPARc antagonist) were used to determine the signalling pathways. Results: Proliferation of PASMCs showed dose dependence of BMP-2, the lowest proliferation rate was achieved at 60 ng/ml concentration under hypoxia (82.262.8%). BMP-2 increased PTEN gene expression level, while AKT-1 and AKT-2 did not change. Consistently, the PTEN protein expression also showed dose dependence of BMP-2. AKT activity significantly reduced in BMP-2 treated PASMCs. Increased activities of caspase-3, -8 and -9 of PASMCs were found after cultured with BMP-2. PTEN expression remained unchanged when Smad-4 expression was inhibited by siRNA-Smad-4. bpV(HOpic) and GW9662 (PPARc inhibitor) inhibited PTEN protein expression and recovered PASMCs proliferation rate. Conclusion: BMP-2 increased PTEN expression under hypoxia in a dose dependent pattern. BMP-2 reduced AKT activity and increased caspase activity of PASMCs under hypoxia. The increased PTEN expression may be mediated through PPARc signalling pathway, instead of BMP/Smad signalling pathway. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer is the second most common cause of global cancer-related mortality. Although dedifferentiation predicts poor prognosis in gastric cancer, the molecular mechanism underlying dedifferentiation, which could provide fundamental insights into tumor development and progression, has yet to be elucidated. Furthermore, the molecular mechanism underlying the effects of hexamethylene bisacetamide (HMBA), a recently discovered differentiation inducer, requires investigation and there are no reported studies concerning the effect of HMBA on gastric cancer. Methods: Based on the results of FACS analysis, the levels of proteins involved in the cell cycle or apoptosis were determined using western blotting after single treatments and sequential combinations of HMBA and LiCl. GSK-3β and proton pump were investigated by western blotting after up-regulating Akt expression by Ad-Akt infection. To investigate the effects of HMBA on protein localization and the activities of GSK-3β, CDK2 and CDK4, kinase assays, immunoprecipitation and western blotting were performed. In addition, northern blotting and RNase protection assays were carried out to determine the functional concentration of HMBA. Results: HMBA increased p27Kip1 expression and induced cell cycle arrest associated with gastric epithelial cell differentiation. In addition, treating gastric-derived cells with HMBA induced G0/G1 arrest and up-regulation of the proton pump, a marker of gastric cancer differentiation. Moreover, treatment with HMBA increased the expression and activity of GSK-3β in the nucleus but not the cytosol. HMBA decreased CDK2 activity and induced p27Kip1 expression, which could be rescued by inhibition of GSK-3β. Furthermore, HMBA increased p27Kip1 binding to CDK2, and this was abolished by GSK-3β inhibition. Conclusions: The results presented herein suggest that GSK-3β functions by regulating p27Kip1 assembly with CDK2, thereby playing a critical role in G0/G1 arrest associated with HMBA-induced gastric epithelial cell differentiation. [ABSTRACT FROM AUTHOR]

Tertiary igneous rocks in Qikou Depression, East China are primarily basic rocks. Two types of igneous reservoirs including the effusive basaltic reservoir and the near-surface intrusive doleritic reservoir have been identified so far and each has different reservoir spaces. In this paper, the lithofacies and reservoir properties of Tertiary igneous rocks are described through a systematic analysis of the characteristics of seismic reflection and well logs and selected cores observation. Both of the two types of igneous rocks present strong and low-frequency reflection events on seismic profiles, however, intrusive diabases exhibit the characteristic of strata penetration with a small intersection angle. Effusive basaltic lavas are divided into upper, middle and lower subfacies. This can be distinguished from the well log curves. Observation of sampled cores finds that primary vesicles and amygdales are abundant in the upper and lower subfacies of basaltic lavas. These vesicles can be favourable reservoir space if connected by cracks formed in the late-stage. Intrusive diabases can also be separated into inner subfacies as well as the upper and lower marginal subfacies, of which the former is well crystallized because of slowly cooling, whereas the latter is vitreous due to fast descending temperature at the contact zone between intrusive rocks and host rocks. Hydrothermal metamorphism left the surrounding mudstones metamorphosed to form shrunk fissures and structural fractures as reservoir space, making mudstones of poor porosity and permeability to be metamorphic and have certain reservoir potential. [ABSTRACT FROM AUTHOR]

The study aims to use cholesterol (Chol) + DOTAP liposome (CD liposome) based human vascular endothelial growth factor-165 (VEGF165) gene transfer into skeletal myoblasts (SkMs) for treatment of acute hind limb ischaemia in a rabbit model. The feasibility and efficacy of CD liposome mediated gene transfer with rabbit SkMs were characterized using plasmid carrying enhanced green fluorescent protein (pEGFP) and assessed by flow cytometry. After optimization, SkMs were transfected with CD lipoplexes carrying plasmid-VEGF165 (CD-pVEGF165) and transplanted into rabbit ischaemic limb. Animals were randomized to receive intramuscular injection of Medium199 (M199; group 1), non-transfected SkM (group 2) or CD-pVEGF165 transfected SkM (group 3). Flow cytometry revealed that up to 16% rabbit SkMs were successfully transfected with pEGFP. Based on the optimized transfection condition, transfected rabbit SkM expressed VEGF165 up to day 18 with peak at day 2. SkMs were observed in all cell-transplanted groups, as visualized with 6-diamidino-2-phenylindole and bromodeoxyuridine. Angiographic blood vessel score revealed increased collateral vessel development in group 3 (39.7 ± 2.0) compared with group 2 (21.6 ± 1.1%, P < 0.001) and group 1 (16.9 ± 1.1%, P < 0.001). Immunostaining for CD31 showed significantly increased capillary density in group 3 (14.88 ± 0.9) compared with group 2 (8.5 ± 0.49, P < 0.001) and group 1 (5.69 ± 0.3, P < 0.001). Improved blood flow (ml/min./g) was achieved in animal group 3 (0.173 ± 0.04) as compared with animal group 2 (0.122 ± 0.016; P= 0.047) and group 1 (0.062 ± 0.012; P < 0.001). In conclusion, CD liposome mediated VEGF165 gene transfer with SkMs effectively induced neovascularization in the ischaemic hind limb and may serve as a safe and new therapeutic modality for the repair of acute ischaemic limb disease. [ABSTRACT FROM AUTHOR]

It is well established that agrin, an extracellular matrix protein, plays a crucial role in the formation of neuromuscular junctions. Recent evidence indicates that agrin also contributes to immunological synapse formation. However, little is known about how agrin induces the activation of lymphocytes and whose receptors mediate its regulatory effects on these cells. In the present study, agrin was detected in lymphocytes. Up-regulation of agrin expression was involved in lymphocyte activation whereas down-regulation of its expression led to inhibition of both antigen-specific and nonspecific lymphocyte activation, indicating an intrinsic role for agrin in the activation of lymphocytes. Unexpectedly, unlike that found in muscle cells where there is coexpression of muscle-specific kinase (MUSK) and α-dystroglycan receptors for agrin, only α-dystroglycan could be detected in lymphocytes. Confocal examination showed that α-dystroglycan colocalized with agrin in forming the immunological synapse. Down-regulation of α-dystroglycan expression inhibited lymphocyte activation even in the presence of agrin. However, agrin involved in down-regulation of α-dystroglycan receptors did not increase the inhibitory effect on lymphocytes activation. The anti-α-dystroglycan antibody also induced lymphocytes activation. Taken together, these findings strongly indicate that agrin and α-dystroglycan mediate lymphocyte activation. Furthermore, agrin-involved lymphocyte activation is mediated by α-dystroglycan. [ABSTRACT FROM AUTHOR]