Research on the Internal Flow Field of Left Atrial Appendage and Stroke Risk Assessment with Different Blood Models.

Extant clinical research has underscored that patients suffering from atrial fibrillation (AF) bear an elevated risk for stroke, predominantly driven by the formation of thrombus in the left atrial appendage (LAA). As such, accurately identifying those at an increased risk of thrombosis becomes paramount to facilitate timely and effective treatment. This study was designed to shed light on the mechanisms underlying thrombus formation in the LAA by employing three-dimensional (3D) left atrium (LA) models of AF patients, which were constructed based on Computed Tomography (CT) imaging. The distinct benefits of Computational Fluid Dynamics (CFD) were leveraged to simulate the blood flow field within the LA, using three distinct blood flow models, both under AF and sinus rhythm (SR) conditions. The potential risk of thrombus formation was evaluated by analyzing the Relative Residence Time (RRT) and Endothelial Cell Activation Potential (ECAP) values. The results gleaned from this study affirm that all three blood flow models align with extant clinical guidelines, thereby enabling an effective prediction of thrombosis risk. However, noteworthy differences emerged when comparing the intricacies of the flow field and thrombosis risk across the three models. The single-phase non-Newtonian blood flow model resulted in comparatively lower residence times for blood within the LA and lower values for the Oscillatory Shear Index (OSI), RRT, and ECAP within the LAA. These findings suggest a reduced thrombosis risk. Conversely, the two-phase non-Newtonian blood flow model exhibited a higher residence time for blood and elevated RRT value within the LAA, suggesting an increased risk for thrombosis.

Left atrial appendage closure in patients with reversed chicken-wing morphology: Anatomical features and procedural strategy.

Background: Left atrial appendage (LAA) closure (LAAC) in atrial fibrillation (AF) patients with the reversed chicken-wing (RCW) LAA is challenging. Aims: To elucidate the LAAC strategy of the RCW-LAA. Methods: A total of 802 AF patients who were enrolled in the LAACablation registry for LAAC procedure were included, 55 of whom presented with the RCW-LAA. The WATCHMAN device was implanted using the standard protocol when the sheath depth was no less than the device depth (the simple group). For those with a sheath depth of less than the device depth (the complex group), device deployment was attempted with acceptable protrusion or after a repeated atrial transseptal puncture (re-ATP) at a more inferior and anterior position. The anatomical and procedural features were compared between groups and before and after the re-ATP. Results: The success rate of LAAC was significantly lower in patients with the RCW-LAA than with the other morphologies (92.7% vs. 98.8%, p = 0.001). Compared with the simple group, the complex group had shorter root depth and shorter neck length, and more LAAs in the complex group were at lower position (all p < 0.05). The sheath depth after the re-ATP was significantly greater than that before the re-ATP (18.8 ± 3.4 mm vs. 14.7 ± 2.6 mm, p < 0.001). For the patients who underwent re-ATP, the sheath went significantly deeper in successful procedures than in aborted procedures (19.7 ± 3.3 mm vs. 15.8 ± 1.8 mm, p = 0.040). Conclusions: The anatomical features of the RCW-LAA were related to the complexity of the LAAC procedure. The re-ATP at an inferior and anterior location could increase the success rate of LAAC. ClinicalTrialsgov: NCT03788941.

Assessing patient safety culture in obstetrics ward: A pilot study using a modified Manchester Patient Safety Framework in China.

AIM: The primary objective of this study was to assess the patient safety culture in a general hospital in Shanghai, China, through a modified Manchester Patient Safety Framework (MaPSaF). DESIGN: This study has a qualitative interview design. Data were collected through group interviews and analyses performed through content analysis. METHODS: The MaPSaF was translated into Chinese and used to assess the patient safety culture in a large general hospital in Shanghai, China. Group interviews using the MaPSaF were conducted with 15 nurses in the obstetric ward. Participants rated their safety practice individually on each of the nine MaPSaF safety culture dimensions. The dimensions and scores were then collectively discussed and a practice-wide consensus score for each dimension was agreed. Discussions were recorded, transcribed and analysed to assess patient safety in the obstetric ward. RESULTS: It took about 2 hr to complete the discussion focusing on patients' safety employing the MaPSaF. Most participants recognized the process as acceptable and useful. The MaPSaF directed team discussion about patient safety issues and facilitated communication, prompting some practice changes. All participants responded positively to the discussion and perceived MaPSaF as a good safety culture assessment tool, with clear, comprehensive and understandable entries. The process demonstrated that the department of obstetrics in the hospital already had a positive patient safety culture, but certain areas were highlighted as still needing improvement. Based on participants' positive experience and perception of the MaPSaF, it can be concluded that there is potential benefit in its adaptation and use in obstetrics wards of Chinese hospitals. The MaPSaF has the potential to strengthen existing safety cultures and improve general safety through collaborative measures.

Numerical study of the risk of thrombosis in the left atrial appendage of chicken wing shape in atrial fibrillation.

Atrial fibrillation (AF) is a common and life-threatening disease. For the patients with AF, more than 90% of the thrombi are formed in the left atrial appendage (LAA), thrombus dislodgement can cause vascular embolism, making them is becoming a high-risk group for stroke. Therefore, identifying the patients with high risk of thrombosis is crucial for advanced stroke warning. To better investigate the mechanism behind thrombus formation in the LAA, this study reconstructed the 3-D Left Atrium (LA) models of six AF volunteer patients by corresponding Computed Tomography (CT) images. Combine the advantages of Computational Fluid Dynamics (CFD), the blood flow field in LA both in AF and sinus heart rate states were studied. The risk of thrombus was evaluated based on the blood viscosity, shear rate thrombus prediction model and Time Average Wall Shear Stress (TAWSS), Oscillatory Shear Index (OSI), and Relative Residence Time (RRT) values. The results showed that the left atrium had lower blood flow velocity and TAWSS values at the LAA in both AF and sinus rhythm, thus the LAA is the most thrombogenic region in the LA. Besides, the RRT value of LAA was generally higher in AF than in sinus rhythm. Therefore, AF carries a higher risk of thrombosis.

Clonal Distribution and Intratumor Heterogeneity of the TCR Repertoire in Papillary Thyroid Cancer With or Without Coexistent Hashimoto's Thyroiditis.

The intratumor heterogeneity (ITH) of the amount and TCR repertoires of tumor infiltrating lymphocytes (TILs) in PTC with and without coexistent Hashimoto's thyroiditis (HT) are unclear. Here, we investigated the amount of T cells in tumor and corresponding normal tissues by immunohistochemical staining on 80 tumor samples and 40 normal samples from 40 patients. The immune repertoire of T cells was identified on 24 tumor samples and 12 normal samples from 12 patients using TCR high-throughput sequencing. The results demonstrated that the numbers of CD3+, CD4+ and CD8+ T cells in PTC without coexistent HT (PTC-WO) were significantly lower than those in PTC with existing HT (PTC-W). In PTC-W, the density of CD4+ TILs were generally higher when compared with CD8+ TILs. Furthermore, we found that the numbers of CD3+ T cells and their CD4+, CD8+ subtypes in tumor samples were generally higher than those in normal tissue in PTC-WO and moreover, the number of CD3+ T cells was negatively associated with TCR clonality in PTC-WO. In addition, although ITH of the TCR repertoire truly existed in PTC-W and PTC-WO, the TCR repertoires between distinct regions of the non-adjacent tumor foci were presented with a higher degree of similarity than those between tumor and matched normal tissue in PTC-WO, yet the similarity of intratumor repertoires was not significantly higher than those between tumor and corresponding normal samples in PTC-W. This research comprehensively delineated the quantity and TCR repertoire ITH of T cells in PTC-W and PTC-WO, suggesting that TILs might be reactive to tumor antigens in PTC-WO. Moreover, multiregion biopsies should be performed to precisely identify the immune background in PTC-W and PTC-WO.

Translation, Cultural Adaptation, Reliability, and Validity Testing of a Chinese Version of the Self-Administered Mediterranean Diet Scale.

Mediterranean Diet management for people with cardiovascular disease (CVD) or CVD risk is supported by evidence. However, there is no valid Chinese language instrument for the measurement of adherence to this diet. The objective of this study was to generate a Chinese version of the Mediterranean Diet Scale (MDS-Chinese) and to validate a self-administered version with Chinese participants with CVD or CVD risk. The MDS-Chinese was created by translation and cultural adaptation and tested for psychometric properties. A panel of 10 experts in the field, who evaluated the MDS-Chinese content, showed that the content validity index ranged from 0.88 to 1.00. Sixteen native Chinese speakers with CVD or CVD risk evaluated the clarity of the MDS-Chinese, and the resulting instruction and items clarity scores ranged from 9.2 to 10.0. A total of 326 participants completed the MDS-Chinese and a Chinese version of the Coronary Artery Disease Education Questionnaire-Short Version (CADE-Q SV). Analysis indicated that the MDS-Chinese has 4 factors, and the Pearson's correlation between the MDS-Chinese and CADE-Q SV was 0.73. Fifty randomly selected participants completed the MDS-Chinese again with a 1-week interval to assess reliability. Internal consistency was acceptable (Cronbach's α was 0.62) and the inter-class correlation reliability coefficients (ICC) for each item ranged from 0.73 to 0.88. This study showed that the MDS-Chinese has acceptable reliability and validity for use among those in the Chinese population with CVD or CVD risk. Given that diet is one of the key secondary prevention strategies for management in cardiac rehabilitation, the MDS-Chinese instrument may be a useful and convenient tool for use with those in the Chinese population with CVD or with high risk of CVD, to monitor the level of Mediterranean diet (MD) adherence, information which is important for clinical practice. In addition, the establishment of the MDS-Chinese gives a fundamental tool for diet-related CVD research in the Chinese population. Moreover, employment of the MDS-Chinese in the Chinese community may improve awareness of the importance of a healthy diet in CVD prevention and management. Clinical Trial Registration: http://www.chictr.org.cn/enIndex.aspx, identifier: ChiCTR2000032810.

Research on the difference between patients with coronary heart disease and healthy controls by surface enhanced Raman spectroscopy.

Coronary heart disease (CHD) is one of the primary causes of death globally. There are several diagnostic techniques for CHD at present, but they are invasive and with limited accuracy. In the work, measurement of human urine based on surface-enhanced Raman spectroscopy (SERS) was proposed to diagnose CHD. Urine samples of 157 CHD patients and 63 healthy controls (HC) were investigated by SERS. Statistical analysis of the measured data was then performed. It was found that there were intensity differences in nine Raman peaks (1223/1243/1272/1463/1481/1516/1536/1541/1550 cm-1) between CHD and HC in their average SERS spectrum. Furthermore, principal component analysis (PCA)-linear discriminant analysis (LDA) was then utilized to establish a prediction model to classify CHD and HC. It revealed that the accuracy, specificity and sensitivity of the prediction model validated by leave-one-patient-out cross validation (LOPOCV) were 84.09%, 92.06% and 80.89%, respectively. Therefore, the proposed method can be employed as a non-invasive, rapid and accurate tool for CHD diagnosis in clinical application.

TfR1 binding with H-ferritin nanocarrier achieves prognostic diagnosis and enhances the therapeutic efficacy in clinical gastric cancer.

H-ferritin (HFn) nanocarrier is emerging as a promising theranostic platform for tumor diagnosis and therapy, which can specifically target tumor cells via binding transferrin receptor 1 (TfR1). This led us to investigate the therapeutic function of TfR1 in GC. The clinical significance of TfR1 was assessed in 178 GC tissues by using a magneto-HFn nanoparticle-based immunohistochemistry method. The therapeutic effects of doxorubicin-loaded HFn nanocarriers (HFn-Dox) were evaluated on TfR1-positive GC patient-derived xenograft (GC-PDX) models. The biological function of TfR1 was investigated through in vitro and in vivo assays. TfR1 was upregulated (73.03%) in GC tissues, and reversely correlated with patient outcome. TfR1-negative sorted cells exhibited tumor-initiating features, which enhanced tumor formation and migration/invasion, whereas TfR1-positive sorted cells showed significant proliferation ability. Knockout of TfR1 in GC cells also enhanced cell invasion. TfR1-deficient cells displayed immune escape by upregulating PD-L1, CXCL9, and CXCL10, when disposed with IFN-γ. Western blot results demonstrated that TfR1-knockout GC cells upregulated Akt and STAT3 signaling. Moreover, in TfR1-positive GC-PDX models, the HFn-Dox group significantly inhibited tumor growth, and increased mouse survival, compared with that of free-Dox group. TfR1 could be a potential prognostic and therapeutic biomarker for GC: (i) TfR1 reversely correlated with patient outcome, and its negative cells possessed tumor-aggressive features; (ii) TfR1-positive cells can be killed by HFn drug nanocarrier. Given the heterogeneity of GC, HFn drug nanocarrier combined with other therapies toward TfR1-negative cells (such as small molecules or immunotherapy) will be a new option for GC treatment.

Downregulation of TfR1 promotes progression of colorectal cancer via the JAK/STAT pathway.

Background: Colorectal cancer (CRC) is one of the most prevalent gastrointestinal malignancies. The incidence of CRC has been rapidly increasing in China. Transferrin receptor 1 (TfR1) is a key regulator of cellular iron homeostasis. Several studies have demonstrated TfR1 overexpression in a variety of human tumors, but the association between TfR1 and CRC remains unclear. Methods: TfR1 expression was evaluated in six CRC cell lines and tumor tissues. A total of 201 CRC patients were included for immunohistochemistry and 19 pairs of frozen tissues were used for real-time PCR. Cell proliferation, cell cycle, cell migration and invasion, and in vivo carcinogenesis were tested after downregulation of TfR1 by lentivirus. Protein microarray and Western blot analyses were used to explore the underlying mechanisms of TfR1 in CRC. Results: TfR1 expression was higher in CRC tissues than in normal tissues (57.2% vs 22.9%, P＜0.001). TfR1 expression was obviously higher in CRC tissues with well differentiation (P＝0.008), no lymph node metastasis (P＝0.002), no distant metastasis (P＝0.006), no vascular invasion (P＜0.001) and early TNM stage (P＝0.013). CRC patients with TfR1-positive expression had a better survival than those with TfR1-negative expression (P＝0.044). Downregulation of TfR1 expression inhibited cell proliferation, promoted cells from G1 phase to S phase and facilitated cell migration and invasion. Knockdown of TfR1 also suppressed tumor growth in BALB/C-nu mice. Protein microarray and Western blot analyses showed that the Janus protein tyrosine kinase/signal transducer and activator of transcription pathway was activated along with downregulation of TfR1 expression. Conclusion: Though TfR1 was overexpressed in colorectal cancer tissues, there was evidence that downregulation of TfR1 could promote cancer progression.

Influence of drugs on the prospective diagnostic method for coronary heart disease with urine.

The morbidity of coronary heart disease (CHD) with high risks has been rising in recent years. A novel and noninvasive method based on surface-enhanced Raman spectroscopy (SERS) was proposed by Yang et al. (Analyst 143: 2235, 2018) to prospectively diagnose the arterial blockage by detecting platelet-derived growth factor-BB (PDGF-BB) in urine. Clinically, anti-platelet drugs (such as aspirin, statins and clopidogrel) are often used for ordinary CHD patients or patients with percutaneous coronary intervention (PCI). Therefore, whether the previous developed method can be applied to the CHD patients on long-term medication (more than 6 months) or post-PCI patients was investigated here. Firstly, urine samples of 13 CHD patients on long-term medication (aspirin, rosuvastatin, clopidogrel bisulfate) and 13 post-PCI patients were measured by the proposed method. Clinical data of coronary angiography results provided by Xin Hua Hospital and Yangpu District Central Hospital Antu Branch revealed that these 26 patients were with serious arterial blockage, however, characteristic Raman peak at 1509 cm-1 attributed to PDGF-BB was not observed in the SERS spectra of these 26 patients. In addition, an eight-day follow-up investigation was performed on a CHD patient with PCI three years ago and on long-term medication. It was found that the Raman peak at 1509 cm-1 could be only observed in the third and fourth day after suspending the drugs. Furthermore, SERS spectra of mixed solutions of PDGF-BB and aspirin, rosuvastatin, mixed solutions of these two drugs and clopidogrel bisulfate were analyzed. The Raman peak at 1509 cm-1 was not found in all these spectra, it indicated that all the three kinds of drugs could influence on the SERS signal of PDGF-BB. Therefore, the previous developed method is not suitable for CHD patients on long-term medication and post-PCI patients.

Interactions between human hemoglobin subunits and peroxiredoxin 2.

Red blood cells (RBCs) are exposed to exogenous reactive oxygen species in the circulatory system. To this end, the interactions between the different hemoglobin (Hb) subunits and peroxiredoxin 2, which is a ubiquitous member of the antioxidant enzymes that also controls the cytokine-induced peroxide levels, were assessed. We predicted by the increment of diversity with quadratic discriminant analysis (IDQD) that peroxiredoxin2 (Prx2) could interact with the hemoglobin alpha, beta and gamma subunits but not with the delta subunit. Coimmunoprecipitation (co-IP), electrospray ionization quadrupole time of flight (ESI-Q-TOF) mass spectrometry, Western blotting and X-ray absorption fine structure (XAFS) spectroscopy were performed to verify these predictions. The results showed that Prx2 was a member of the beta-globin immunoprecipitating complex that existed in hemoglobin A, hemolysate-hemoglobin A, hemoglobin A-hemoglobin A2, hemolysate-hemoglobin A-hemoglobin A2 and hemoglobin A2 but not in hemolysate-hemoglobin A2. Adding Prx2 to hemoglobin A altered the second shell of iron embedded in hemoglobin A. Therefore, Prx2 interacts with hemoglobin A (Alpha2Beta2) and hemoglobin F (Alpha2Gamma2) but not with hemoglobin A2 (Alpha2Delta2).

Effectiveness of Intensive Endoscopic Screening for Esophageal Cancer in China: A Community-Based Study.

Evidence is required to evaluate the effectiveness of population-level endoscopic screening for esophageal cancer (EC). In this study, 5,632 permanent residents aged 25-65 years from 6 villages in Hua County, Henan Province, China, were defined as the screening cohort and were offered intensive endoscopic screening. Residents of all 914 remaining villages in Hua County were included as the control cohort, and age-sex standardization was used to calculate the expected numbers of EC and upper gastrointestinal (GI) tract cancer cases and deaths in the screening cohort. The effectiveness of screening was assessed by comparing observed numbers of cases and deaths with expected numbers after 9-year follow-up of these screened subjects (2007-2016). In the screening cohort, 23 upper GI cancers (including 16 ECs) and 10 upper GI cancer deaths (including 5 EC deaths) were identified, and 47% (standardized incidence ratio = 0.53, 95% confidence interval (CI): 0.33, 0.87) and 66% (standardized mortality ratio = 0.34, 95% CI: 0.14, 0.81) reductions in cumulative EC incidence and mortality were found. For upper GI cancers, incidence and mortality were lowered by 43% (standardized incidence ratio = 0.57, 95% CI: 0.38, 0.86) and 53% (standardized mortality ratio = 0.47, 95% CI: 0.25, 0.88), respectively. This study showed that upper GI tract endoscopy is an effective population-level screening test for EC in high-risk regions.

TCR repertoire intratumor heterogeneity of CD4+ and CD8+ T cells in centers and margins of localized lung adenocarcinomas.

Intratumor heterogeneity (ITH) of T cell receptor (TCR) repertoire in different T-cell subsets and locations in lung adenocarcinomas was unclear. Here, we investigated percentages and TCR repertoire of freshly isolated CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) in tumor centers and margins by flow cytometry on 80 tumor samples from 20 patients and high-throughput TCR sequencing on 27 and 25 samples of CD4+ and CD8+ TILs from seven patients. Our results demonstrated that amount and TCR repertoire diversity of CD4+ TILs were significantly higher than those of CD8+ TILs and moreover substantial ITH regarding amount and TCR repertoire of CD4+ and CD8+ TILs were observed. Additionally, ITH of CD4/CD8 T-cell ratio and CD8+ TIL repertoire across center regions was lower than that across margin regions. The amount and TCR repertoire ITH of CD4+ and CD8+ TILs and mean clonality of CD8+ TILs in tumor centers were associated with relapse. Our study provides insights into amount and TCR repertoire ITH of CD4+ and CD8+ TILs in tumor centers and margins as well as corresponding association with prognosis in lung adenocarcinoma patients, suggesting potential clinical significance of TCR repertoire.

Enhancement of Sensitivity to Chemo/Radiation Therapy by Using miR-15b against DCLK1 in Colorectal Cancer.

Chemo-/radiotherapy resistance is the main cause accounting for most treatment failure in colorectal cancer (CRC). Tumor-initiating cells (TICs) are the culprit leading to CRC chemo-/radiotherapy resistance. The underlying regulation mechanism of TICs in CRC remains unclear. Here we discovered that miR-15b expression positively correlated with therapeutic outcome in CRC. Expression of miR-15b in pretreatment biopsy tissue samples predicted tumor regression grade (TRG) in rectal cancer patients after receiving neoadjuvant radiotherapy (nRT). Expression of miR-15b in post-nRT tissue samples was associated with therapeutic outcome. DCLK1 was identified as the direct target gene for miR-15b and its suppression was associated with self-renewal and tumorigenic properties of DCLK1+ TICs. We identified B lymphoma Mo-MLV insertion region l homolog (BMI1) as a downstream target regulated by miR-15b/DCLK1 signaling. Thus, miR-15b may serve as a valuable marker for prognosis and therapeutic outcome prediction. DCLK1 could be a potential therapeutic target to overcome chemo-/radioresistance in CRC.

Antitumor effects of Xi Huang pills on MDA­MB­231 cells in vitro and in vivo.

The management of patients with triple­negative breast cancer is challenging due to the lack of effective therapeutic options, aggressive behavior and relatively poor prognosis. Xi Huang pills (XHP) are a well­known traditional Chinese medicine that demonstrate anticancer activities. The aim of the present study was to investigate the antitumor effects of XHP on MDA­MB­231 cells in vitro and in vivo, and its potential underlying molecular mechanisms. In the present study, an MTT assay was used to evaluate the antiproliferative activity of XHP on MDA­MB­231 cells. In order to investigate the effects further, cell cycle distribution, apoptosis and mitochondrial membrane potential assays were performed, as well as western blot analyses. In addition, a tumor xenograft model was employed to investigate the effects of XHP in vivo. The results of the MTT assay demonstrated that the viability of MDA­MB­231 cells was markedly inhibited by XHP in a dose­ and time­dependent manner. The inhibitory effect of XHP on the viability of MDA­MB­231 cells was greater when compared with MCF­10A cells. An increase in apoptosis and loss of mitochondrial membrane potential was observed following 4, 8 and 12 mg/ml XHP treatment of MDA­MB­231 cells. The protein expression levels of cleaved caspase­3 were increased by 1.62­, 2.13­ and 2.19­fold, respectively, when compared with the untreated controls, whereas no effects on the expression of B­cell lymphoma 2 (Bcl­2) or Bcl­2­associated X protein (Bax) were observed. The results of the cell cycle distribution assay analysis demonstrated that XHP treatment arrested cells at the G2/M phase. In addition, XHP treatment decreased the expression of cyclin A and increased the expression of p21Cip1. In vivo experiments revealed that XHP inhibited the growth of MDA­MB­231 xenograft tumors without body weight loss, and demonstrated similar effects on the protein expression levels of cleaved caspase 3, cyclin A and p21Cip1 as observed in vitro. In conclusion, the viability of MDA­MB­231 cells was inhibited by XHP in a dose­dependent, time­dependent and cell­selective manner in vitro, and the potential underlying mechanisms may involve apoptosis and cell cycle arrest at the G2/M phase. XHP may induce apoptosis in MDA­MB­231 cells via the intrinsic pathway, which does not involve the Bcl­2/Bax ratio. G2/M phase arrest may have been due to the integrated action of decreased cyclin A expression and increased p21Cip1 expression. In addition, XHP inhibited the growth of xenograft tumors in the absence of body weight loss in vivo.

Association between LAPTM4B gene polymorphism and susceptibility to and prognosis of diffuse large B-cell lymphoma.

Lysosomal protein transmembrane 4ß (LAPTM4B) is an oncogene that is overexpressed in a number of various types of human cancer. There are two known alleles of LAPTM4B: LAPTM4B*1 and LAPTM4B*2. The present study assessed the association between LAPTM4B polymorphisms and the susceptibility to diffuse large B-cell lymphoma (DLBCL) and its prognosis. LAPTM4B genotypes were determined using polymerase chain reaction analysis in 164 DLBCL and 350 healthy control cases. The association between LAPTM4B polymorphisms and the risk of DLBCL was analyzed using unconditional logistic regression. Differences in patient survival were calculated using Kaplan-Meier analysis. The present study indicated no significant differences (P>0.05) in the frequency of LAPTM4B*2 alleles between DLBCL cases (26.5%) and controls (24.1%). The risk of DLBCL was slightly increased in cases with the LAPTM4B*1/2 genotype [odds ratio (OR)=1.160; 95% confidence interval (CI)=0.781-1.724] or the LAPTM4B*2/2 genotype (OR=1.446; 95% CI=0.648-3.227) compared with those with the LAPTM4B*1/1 genotype. There was no significant association between the presence of the LAPTM4B*2 allele and overall survival (OS) and disease-free survival (DFS) in patients with DLBCL (P=0.399 and 0.520, respectively). However, there was a tendency for patients with LAPTM4B*2 and International Prognostic Index (IPI) score 3-5 to have longer OS and DFS (P=0.126 and 0.109, respectively). These findings suggest that genetic polymorphisms of LAPTM4B is not a risk factor for the development of DLBCL, but the LAPTM4B*2 allele may a better prognostic indicator in patients with IPI score 3-5 in DLBCL.

Plasma CAMK2A predicts chemotherapy resistance in metastatic triple negative breast cancer.

BACKGROUND: Chemotherapy resistance is a great obstacle in effective treatment for metastatic triple negative breast cancer (TNBC). The ability to predict chemotherapy response would allow chemotherapy administration to be directed toward only those patients who would benefit, thus maximizing treatment efficiency. Differentially expressed plasma proteins may serve as putative biomarkers for predicting chemotherapy outcomes. PATIENTS AND METHODS: In this study, 26 plasma samples (10 samples with partial response (S) and 16 samples with progression disease (R)) from patients with metastatic TNBC were measured by Tandem Mass Tag (TMT)-based proteomics analysis to identify differentially expressed proteins between the S and R group. Potential proteinswere validated with enzyme-linked immunosorbent assay (ELISA) in another 67 plasma samples. RESULTS: A total of 320 plasma proteins were identified, and statistical analysis showed that 108 proteins were significantly dysregulated between R and S groups in the screening stage. Bioinformatics revealed relevant pathways and regulatory networks of the differentially expressed proteins. Three differentially expressed proteins were validated by ELISA with 67 samples from TNBC patients. The R group had significantly higher plasma CAMK2A level than the S group (P=0.0074). The ROC curve analysis showed an AUC of 0.708, with sensitivity 48.4% and specificity 86.1%. In multivariate logistic regression analysis, the level of plasma CAMK2A was also significant for chemotherapeutic response (P=0.009, OR=0.152). Furthermore, the patients with higher CAMK2A level had shorter OS than those with lower CAMK2A level, which amounted to 13.9 and 28.9 months, respectively (P=0.034). In the multivariate Cox regression analysis, CAMK2A level still had significant effect on OS (P=0.031, HR=1.865). CONCLUSION: TMT-based proteomic analysis was able to identify potential biomarkers in plasma that predicted chemotherapy resistance in the metastatic TNBC. The plasma of CAMK2A level may serve as apotential predictive and prognostic biomarker for chemotherapy in metastatic TNBC.

Functional analysis of BRCT missense mutations in BRCA1-mutated Chinese Han familial breast cancer.

Breast cancer 1 (BRCA1) is one of the most common tumor suppressor genes in breast cancer. The BRCT domain of BRCA1 has been shown to have a critical role in tumor suppression. In a previous study, two de novo BRCT missense mutations of BRCA1, G1763V and L1786P were identified from Chinese females with familial breast cancer. In the present study, the function of these two novel mutations were assessed by bioinformatics analysis and a series of experiments investigating cell proliferation, cell cycle and chemotherapy combination. Although bioinformatics analysis indicated that the mutants may be deleterious, a series of experiments revealed that the two mutants significantly reduced the growth and increased cell apoptosis similar to the function of BRCA1 wild type. Furthermore, no synergistic effect between the Olaparib and BRCA1 mutation was noted on cell apoptosis. These results demonstrated that these two mutations did not affect the tumor suppressor function of BRCA1. It was concluded that not all BRCA1 missense mutations are pathogenic and that any new BRCA1 mutation should be assessed for its effect on the tumor suppressor function of BRCA1.

FCGR3A 158V/F polymorphism and response to frontline R-CHOP therapy in diffuse large B-cell lymphoma.

The influence of Fc gamma receptor IIIA (FCGR3A) 158V/F polymorphisms on the response to rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone; R-CHOP) therapy in diffuse large B-cell lymphoma (DLBCL) is uncertain. Thus, a retrospective study and a meta-analysis were performed to examine the possible correlation between FCGR3A 158V/F polymorphism and the response rate of R-CHOP regimen in patients with newly diagnosed DLBCL. The genotypes of FCGR3A 158V/F in 164 newly diagnosed DLBCL patients treated with R-CHOP were determined in this retrospective study. Additionally, a meta-analysis of current and previously published studies was conducted. Overall response rate (complete and partial response, ORR) and complete response rate (CR) were evaluated. The results of our retrospective study showed lack of correlation between FCGR3A 158V/F polymorphism and ORR (p=0.78) or CR (p=0.76) with R-CHOP therapy. A meta-analysis of 731 cases also showed lack of significant association of ORR and CR in all genetic models with FCGR3A 158V/F polymorphism. In survival analysis, the homozygous F genotype correlated with a shorter progression-free survival than that of non-F/F genotype (p=0.05), this was significant for the non-GC subset of DLBCL (p=0.04), but no association was found between overall survival and FCGR3A 158V/F polymorphism. Further analysis with nonsuperiority test (p<0.0001) suggested that FCGR3A 158V/F polymorphism was not associated with better ORR or CR in newly diagnosed DLBCL patient treated with R-CHOP. No clear relationship was found between FCGR3A 158V/F polymorphism and response to frontline R-CHOP therapy in patients with DLBCL.