The immune profile of small HER2-positive breast cancers: a secondary analysis from the APT trial.

BACKGROUND: Previous data suggest that the immune microenvironment plays a critical role in human epidermal growth factor receptor 2 (HER2) -positive breast cancer; however, there is little known about the immune profiles of small HER2-positive tumors. In this study, we aimed to characterize the immune microenvironment of small HER2-positive breast cancers included in the Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer (APT) trial and to correlate the immune markers with pathological and molecular tumor characteristics. PATIENTS AND METHODS: The APT trial was a multicenter, single-arm, phase II study of paclitaxel and trastuzumab in patients with node-negative HER2-positive breast cancer. The study included 406 patients with HER2-positive, node-negative breast cancer, measuring up to 3 cm. Exploratory analysis of tumor infiltrating lymphocytes (TIL), programmed death-ligand 1 (PD-L1) expression (by immunohistochemistry), and immune gene signatures using data generated by nCounter PanCancer Pathways Panel (NanoString Technologies, Seattle, WA), and their association with pathological and molecular characteristics was carried out. RESULTS: Of the 406 patients, 328 (81%) had at least one immune assay carried out: 284 cases were evaluated for TIL, 266 for PD-L1, and 213 for immune gene signatures. High TIL (≥60%) were seen with greater frequency in hormone-receptor (HR) negative, histological grades 2 and 3, as well in HER2-enriched and basal-like tumors. Lower stromal PD-L1 (≤1%) expression was seen with greater frequency in HR-positive, histological grade 1, and in luminal tumors. Both TIL and stromal PD-L1 were positively correlated with 10 immune cell signatures, including Th1 and B cell signatures. Luminal B tumors were negatively correlated with those signatures. Significant correlation was seen among these immune markers; however, the magnitude of correlation did not indicate a monotonic relationship between them. CONCLUSION: Immune profiles of small HER2-positive breast cancers differ according to HR status, histological grade, and molecular subtype. Further work is needed to explore the implication of these findings on disease outcome. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00542451.

Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study.

PURPOSE: HER2-targeted therapies have substantially improved the outcome of patients with breast cancer, however, they can be associated with cardiac toxicity. Guidelines recommend holding HER2-targeted therapies until resolution of cardiac dysfunction. SAFE-HEaRt is the first trial that prospectively tests whether these therapies can be safely administered without interruptions in patients with cardiac dysfunction. METHODS: Patients with stage I-IV HER2-positive breast cancer candidates for trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with left ventricular ejection fraction (LVEF) 40-49% and no symptoms of heart failure (HF) were enrolled. All patients underwent cardiology visits, serial echocardiograms and received beta blockers and ACE inhibitors unless contraindicated. The primary endpoint was completion of the planned HER2-targeted therapies without developing either a cardiac event (CE) defined as HF, myocardial infarction, arrhythmia or cardiac death or significant asymptomatic worsening of LVEF. The study was considered successful if planned oncology therapy completion rate was at least 30%. RESULTS: Of 31 enrolled patients, 30 were evaluable. Fifteen patients were treated with trastuzumab, 14 with trastuzumab and pertuzumab, and 2 with TDM-1. Mean LVEF was 45% at baseline and 46% at the end of treatment. Twenty-seven patients (90%) completed the planned HER2-targeted therapies. Two patients experienced a CE and 1 had an asymptomatic worsening of LVEF to ≤ 35%. CONCLUSION: This study provides safety data of HER2-targeted therapies in patients with breast cancer and reduced LVEF while receiving cardioprotective medications and close cardiac monitoring. Our results demonstrate the importance of collaboration between cardiology and oncology providers to allow for delivery of optimal oncologic care to this unique population.

Network change in the ipsilesional cerebellum is correlated with motor recovery following unilateral pontine infarction.

BACKGROUND AND PURPOSE: Patients with acute pontine infarcts generally have good short-term motor outcomes; however, the mechanisms underlying this recovery of function remain unclear. METHODS: Twenty well-recovered patients with acute pontine infarcts and 20 well-recovered patients with acute striato-capsular infarcts were recruited. Fugl-Meyer assessment and resting-state functional magnetic resonance imaging were performed 1, 4 and 12 weeks after onset. Patients were further assigned to better and worse recovery subgroups according to the degree of motor recovery at the twelfth week after stroke. Voxel-wise degree centrality (DC)-behavior correlation analysis was used to identify brain regions related to changes in motor function within 12 weeks after stroke. RESULTS: A significant correlation was found between DC and Fugl-Meyer scores within 12 weeks in the ipsilesional cerebellar crus I and crus II in patients with pontine infarction and in the ipsilesional middle temporal gyrus in patients with striato-capsular infarction (all P < 0.001, AlphaSim corrected). The mean DC in these areas was higher both in the better and worse recovery subgroups at the fourth than at the first week (all P < 0.05). In addition, the mean DC values in these areas were higher in patients with better recovery at the twelfth than at the first week (P < 0.05), but such change was not found in patients with worse recovery. CONCLUSIONS: These results indicate that network changes in the ipsilesional cerebellum are correlated with motor recovery following pontine infarction. Motor recovery mechanisms may vary between pontine and striato-capsular infarcts, according to lesion location.

Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study.

Background: Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. Patients and methods: BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive. Results: Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively). Conclusion: Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab. Clinical Trial Information: NCT02132949.

Efficacy and safety of fosaprepitant in the prevention of nausea and vomiting following highly emetogenic chemotherapy in Chinese people: A randomized, double-blind, phase III study.

The prevention of chemotherapy-induced nausea and vomiting was one of the most challenging supportive care issues in oncology, especially to highly emetogenic chemotherapy (HEC). A total of 645 patients were randomized into fosaprepitant group (fosaprepitant/placebo 150 mg d1 in combination with granisetron and dexamethasone) or aprepitant group (aprepitant/placebo 125 mg d1; 80 mg d2-d3 plus granisetron and dexamethasone).The primary endpoint was the percentage of patients who had a complete response (CR) over the entire treatment course (0-120 hr, overall phase [OP]). It was assessed by using a non-inferiority model, with a non-inferiority margin of 10%. The difference of the CR rate was compared between two groups with chi-square analysis. Six hundred and twenty-six patients were included in the per protocol analysis. The percentage of patients with a CR in the fosaprepitant group was not inferior to that in the aprepitant group (90.85% versus 94.17%, p = .1302) during OP. Whether the cisplatin-based chemotherapy or not, the CR rate of the fosaprepitant group was not inferior to that of the aprepitant group. Both regimens were well tolerated. The most common adverse event was constipation. Fosaprepitant provided effective and well-tolerated control of nausea and vomiting associated with HEC in Chinese patients.

Weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-overexpressing metastatic breast cancer: overall survival and updated progression-free survival results from a phase II study.

We previously reported progression-free survival (PFS) results on a phase II trial of weekly paclitaxel, trastuzumab, and pertuzumab in patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer (MBC) treated in the first- and second-line setting. Here, we report results for overall survival (OS) and updated PFS after an additional year of follow-up. Patients with HER2-positive MBC with 0-1 prior treatment were eligible. Treatment consisted of paclitaxel (80 mg/m(2)) weekly, and trastuzumab (loading dose 8 mg/kg â†’ 6 mg/kg) and pertuzumab (loading dose 840 mg â†’ 420 mg) every 3 weeks, all given intravenously. Primary endpoint was 6-month PFS. Secondary endpoints included median PFS, 6-month and median OS. Evaluable patients received at least one full dose of treatment. From January 2011 to December 2013, 69 patients were enrolled: 51 (74 %) and 18 (26 %) treated in first- and second-line metastatic settings, respectively. As of July 1, 2015, the median follow-up was 33 months (range 3-49 months; 67 patients were evaluable for efficacy). The median OS was 44 months (95 % CI 37.5-NR) overall and 44 months (95 % CI 38.3-NR) and 37.5 months (95 % CI 30.3-NR) for patients with 0 and 1 prior metastatic treatment, respectively; 6-month OS was 98 % (95 % CI 90-1). The 6-month PFS was 86 % (95 % CI 75-93) overall and 89 % (95 % CI 76-95) and 78 % (95 % CI 51-91) for patients with 0 and 1 prior therapy, respectively; and median PFS was 21.4 months (95 % CI 14.1-NR) overall and 25.7 months (95 % CI 14.1-NR) and 16.9 months (95 % CI 8.5-NR) for patients with 0-1 prior treatment, respectively. Treatment was well tolerated. Updated analysis demonstrates that weekly paclitaxel, when added to trastuzumab and pertuzumab, is associated with a favorable OS and PFS and offers an alternative to docetaxel-based therapy. http://www.ClinicalTrials.gov NCT0127604.

[Traffic accidentability and risky driving behavior in young people in New Caledonia. Results of study Situation Sociale et Comportements de Santé des Jeunes en Nouvelle-Calédonie]. / Accidentalité et prise de risque sur la route en Nouvelle-Calédonie. Résultats de l'étude Situation sociale et comportements de santé des jeunes en Nouvelle-Calédonie.

BACKGROUND: New Caledonia has one of the highest global rates of death from road accidents: 240 deaths per million inhabitants in 2011 with a majority of young people. However, research on driving behaviors has remained rare. METHODS: A cross-sectional survey based on face-to-face questionnaire with 1400 male and female youth aged 16 to 25 was conducted in 2007. It was used to measure the frequency of accidents and to compute a score of driving behaviors and their associations with socio-demographic characteristics, lifestyles as well as other health behaviors. RESULTS -  CONCLUSION: A total of 10.6% of boys and 6.5% of girls reported a car accident in the previous twelve months period. Among male participants risky driving behavior was associated with having a degree (ORa=2, 95% CI [1.1-3.8]), sport practices (ORa=3.7, 95% CI [1.9-7.05]), involvement in a fight in the last twelve months (ORa=2.2, 95% CI [1.4-3.4]) and precocity of cannabis use (ORa=1.8, 95% CI [1.2-2.8]). Youth living in couple and those with children presented with higher risk-taking scores. Among female participants, young age at cannabis initiation (ORa=3.1, 95% CI [1.5-6.4]) and at sexual debut (ORa=2.4, 95% CI [1.1-5.1]) were associated with driving risk-taking. Finally, younger age at first alcohol intoxication was associated with risky behavior on the road in both sexes. These results highlighted the multidimensional nature of risk-taking behaviors on the road and showed that they are part of, for boys and girls, a larger pattern of risky behaviors. Such results suggest to include behaviors on the road in a comprehensive approach of prevention.

Increased spontaneous neuronal activity in structurally damaged cortex is correlated with early motor recovery in patients with subcortical infarction.

BACKGROUND AND PURPOSE: Secondary cortical thinning and volumetric atrophy in the motor-related cortex can inhibit early functional recovery after subcortical infarction. However, the relationship between the spontaneous neuronal activity in these cortices and motor recovery in patients with focal cerebral infarct remains unknown. METHODS: Structural magnetic resonance imaging (MRI) and resting-state functional MRI were conducted 1, 4 and 12 weeks after onset in 22 patients with an acute subcortical infarct and in 22 normal subjects. Group differences in cortical thickness and in the amplitude of low-frequency fluctuation (ALFF) in motor-related areas were evaluated, and the relationships between ALFF, cortical thickness changes and changes in the Fugl-Meyer scores of physical performance were further analyzed. RESULTS: In patients with subcortical infarction, progressively decreasing cortical thickness was found over the observation period ipsilesionally in the primary motor cortex (PMC), supplementary motor cortex (SMC) and precuneus (all P < 0.05). Contralesionally, progressive increases in cortical thickness were detected in SMC and insula (all P < 0.05). Increases in ALFF were observed only in PMC (bilaterally) and only at 12 weeks after stroke (all P < 0.05). The cortical thickness changes in the contralesional SMC (rs = 0.483, P = 0.023) and the ALFF changes in bilateral PMC (ipsilesional, rs = 0.51, P = 0.015; contralesional, rs = 0.463, P = 0.03) were positively correlated with changes in the Fugl-Meyer scores. CONCLUSIONS: These results suggest that increased spontaneous neuronal activity of the PMC, a region structurally damaged secondarily to ischaemic lesion, may contribute to early motor recovery in patients with subcortical infarction.

MiR-30a suppresses non-small cell lung cancer progression through AKT signaling pathway by targeting IGF1R.

MicroRNAs play critical roles in the development and progression of human cancers. Although miR—30a has been suggested to function as a tumor repressor in several tumors, its role in non—small cell lung cancer (NSCLC) has not been investigated in detail. This study investigated the expression and role of miR—30a in human NSCLC. The expression of miR—30a is significantly decreased in clinical NSCLC tissues and cell lines. Overexpression of miR—30a inhibited NSCLC cell proliferation, G1/S and S/G2 transition in vitro, whereas suppression of miR—30a facilitated NSCLC cell proliferation, G1/S and S/G2 transition. Using a luciferase reporter assay, insulin—like growth factor 1 receptor (IGF1R) was determined to be a direct target of miR—30a. Furthermore, silencing IGF1R resulted in the same biologic effects of miR—30a overexpression in NSCLC cells, which included suppressed NSCLC cell proliferation and trigering cell cycle arrest through PI3K/AKT signaling pathway by inhibiting cell cycle regulators (CDK2, CDK4, Cyclin A2 , Cyclin D1). These results demonstrate that miR—30a influences NSCLC progression through PI3K/AKT signaling pathway by targeting IGF1R in A549 cells, which suggest miR—30a as a novel strategy for NSCLC diagnosis and treatment.

miR-106a* inhibits the proliferation of esophageal carcinoma cells by targeting CDK2-associated Cullin 1 (CACUL1).

Previous studies suggest that aberrant microRNA expression is common in plenty of cancers. The expression of miR-106a* was decreased in follicular lymphoma, but the expression and functions of miR-106a* in esophageal carcinoma (EC) remain unclear. In this study, we explored the expression and anti-oncogenic roles of miR-106a* in human EC. The expression of miR-106a* is significantly decreased in EC tissues and EC cell lines. Overexpression of miR-106a* suppressed EC cell proliferation, clonogenicity, G1/S transition, and induced apoptosis in vitro, but inhibition of miR-106a* facilitated cell proliferation, clonogenicity, G1/S transition. Luciferase reporter assay results showed that CDK2-associated Cullin 1 (CACUL1) was a direct target of miR-106a* in EC cells. Moreover, silencing CACUL1 resulted in the same biologic effects of miR-106a* overexpression in EC cells, which included suppressed EC cell proliferation, clonogenicity, and blocked G1/S transition through CDK2 pathway by inhibiting cell cycle regulators (Cyclin A, Cyclin E). Our data indicate that miR-106a* might play an anti-oncogenic role in EC by regulating CACUL1 expression, which suggest miR-106a* as a new potential diagnostic and therapeutic target for EC.

Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100.

BACKGROUND: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension. METHODS: A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100. RESULTS: When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10(-8); OR=3.3) and in the cumulative dose model (P=4.7 × 10(-8); HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4). CONCLUSIONS: A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials.

Validation of genetic polymorphisms on BTA14 associated with carcass trait in a commercial Hanwoo population.

The objective of this study was to validate the association of significant SNPs identified from a previous genome-wide association study with carcass weight (CWT) in a commercial Hanwoo population. We genotyped 13 SNPs located on BTA14 in 867 steers from Korea Hanwoo feedlot bulls. Of these 13 SNPs, five SNPs, namely rs29021868, rs110061498, rs109546980, rs42404006 and rs42303720, were found to be significantly associated (P < 0.001) with CWT. These five significant markers spanned the 24.3 to 29.4 Mb region of BTA14. The most significant marker (rs29021868) for CWT in this study had a 13.07 kg allele substitution effect and accounted for 2.4% of the additive genetic variance in the commercial Hanwoo population. The SNP marker rs109546980 was found to be significantly associated with both CWT (P < 0.001) and eye muscle area (P < 0.001) and could potentially be exploited for marker-assisted selection in Hanwoo cattle. We also genotyped the ss319607402 variation, which maps to intron2 of PLAG1 gene and which is already reported to be associated with height, to identify any significant association with carcass weight; however, no such association was observed in this Hanwoo commercial population.

Genome-wide Association Study for Warner-Bratzler Shear Force and Sensory Traits in Hanwoo (Korean Cattle).

Significant SNPs associated with Warner-Bratzler (WB) shear force and sensory traits were confirmed for Hanwoo beef (Korean cattle). A Bonferroni-corrected genome-wide significant association (p<1.3×10(-6)) was detected with only one single nucleotide polymorphism (SNP) on chromosome 5 for WB shear force. A slightly higher number of SNPs was significantly (p<0.001) associated with WB shear force than with other sensory traits. Further, 50, 25, 29, and 34 SNPs were significantly associated with WB shear force, tenderness, juiciness, and flavor likeness, respectively. The SNPs between p = 0.001 and p = 0.0001 thresholds explained 3% to 9% of the phenotypic variance, while the most significant SNPs accounted for 7% to 12% of the phenotypic variance. In conclusion, because WB shear force and sensory evaluation were moderately affected by a few loci and minimally affected by other loci, further studies are required by using a large sample size and high marker density.

Phylogenetic analyses of vector mosquito basic helix-loop-helix transcription factors.

Basic helix-loop-helix (bHLH) transcription factors play critical roles in the regulation of a wide range of developmental processes in higher organisms and have been identified in more than 20 organisms. Mosquitoes are important vectors of certain human diseases. In this study, Aedes aegypti, Anopheles gambiae str. PEST and Culex quinquefasciatus genomes were found to encode 55, 55 and 57 bHLH genes, respectively. Further phylogenetic analyses and OrthoDB and Kyoto encyclopedia of genes and genomes orthology database searches led us to define orthology for all the identified mosquito bHLHs successfully. This provides useful information with which to update annotations to 40 Ae. aegypti, 55 An. gambiae and 38 C. quinquefasciatus bHLH genes in VectorBase. The mosquito lineage has more bHLH genes in the Atonal, neurogenin (Ngn) and Hes-related with YRPW motif (Hey) families than do other insect species, suggesting that mosquitoes have evolved to be more sensitive to vibration, light and chemicals. Mosquito bHLH genes generally have higher evolutionary rates than other insect species. However, no pervasive positive selection occurred in the evolution of insect bHLH genes. Only episodic positive selection was found to affect evolution of bHLH genes in 11 families. Besides, coding regions of several Ae. aegypti bHLH motifs have unusually long introns in which multiple copies of transposable elements have been identified. These data provide a solid basis for further studies on structures and functions of bHLH proteins in the regulation of mosquito development and for prevention and control of mosquito-mediated human diseases.

Further evidence for the contribution of the BRCA1-interacting protein-terminal helicase 1 (BRIP1) gene in breast cancer susceptibility.

BRCA1-interacting protein C-terminal helicase 1 (BRIP1) is a DNA helicase that influences the DNA repair ability and tumor suppressor function of BRCA1. Truncating BRIP1 mutations have been described as cancer susceptibility alleles. To evaluate BRIP1 polymorphisms as risk factors for breast cancer, we performed a detailed analysis of possible single nucleotide polymorphisms (rs2048718, rs4988344, rs8077088, rs6504074, rs4986764, rs4986763, rs11079454, rs7213430, rs34289250, rs4988345, and rs12937080) using the MassARRAY system. A total of 319 patients with breast cancer and 306 healthy control females from the Chinese Han population enrolled in the study. A weak association was found between the rs4986764 allele (exon 18) and breast cancer. The frequency of the rs4986764 C allele was significantly higher in breast cancer patients than in healthy controls [χ(2) = 4.089, P = 0.043, odds ratio (OR) = 0.781, 95% confidence interval (CI) = 0.614-0.992]. Additionally, our study is the first to identify a significant association between rs7213430 and breast cancer. Compared to healthy controls, patients with breast cancer had a higher frequency of the rs7213430 A allele (χ(2) = 8.865, P = 0.003, OR = 0.700, 95%CI = 0.553-0.886). Furthermore, linkage disequilibrium was observed in two blocks (D' > 0.9). While significantly more T-A-C haplotypes (P = 0.001, block 1) were found in breast cancer patients, the frequency of T-T haplotypes (P = 0.008, block 2) was significantly higher in healthy controls. The possible association among rs4986764, rs7213430, and breast cancer risk merits further validation in an independent case-control study.

Using GIS Remote Sensing Image Data for Wetland Monitoring and Environmental Simulation.

Through a comprehensive theoretical basis and actual test analysis of the application system design and functional efficiency of the cloud platform, this paper puts forward an artificial intelligence environmental data monitoring and wetland environmental simulation method based on GIS remote sensing images. First, the basic storage and computing functions have been enhanced at the physical layer. Second, the middleware layer is more flexible in the use of management methods and strategies. There are many strategies and methods that can be used in combination. Finally, based on this, the application system design framework is more convenient and faster so that you can focus on business logic, and the strategic advantages of certain functions are very obvious. The method of object-oriented classification and visual interpretation using UAV image data and satellite remote sensing images from the typical recovery area and treatment area of wetland from 2016 to 2020 is given in detail together to extract wetland information and use GIS software for dynamic calculation. Using the wetland transmission matrix method, the distribution map of the characteristic types of the survey areas in the four periods and the conversion status of the characteristic types at each stage were obtained, and the effect of wetland treatment was quantitatively studied.

A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer.

BACKGROUND: SRC plays an important role in the pathogenesis of metastatic breast cancer (MBC). In preclinical models, paclitaxel and the oral SRC inhibitor dasatinib showed greater antitumor activity than either agent. To determine the maximum tolerated dose of this combination, we conducted a phase I study. PATIENTS AND METHODS: Patients with MBC; Eastern Cooperative Oncology Group performance status of zero to one; normal hepatic, renal and marrow function were eligible. Paclitaxel 80 mg/m(2) was given 3 weeks of 4. The starting dasatinib dose was 70 mg and was increased, using a standard 3 + 3 dose-escalation scheme. RESULTS: Fifteen patients enrolled (median age 54 years, range 35-74). No dose-limiting toxic effects (DLTs) occurred at dasatinib doses of 70-120 mg. One DLT (grade 3 fatigue) occurred in the dasatinib 150-mg cohort, which was expanded (six patients) with no further DLTs. However, due to cumulative toxic effects (rash, fatigue, diarrhea), the recommended phase II dose is dasatinib 120 mg. Of 13 assessable patients, a partial response was seen in 4 patients (31%), including 2 patients previously treated with taxanes; all received ≥120 mg dasatinib. An additional five patients (29%) had stable disease. CONCLUSION: In combination with weekly paclitaxel, the recommended phase II dose of dasatinib is 120 mg daily and preliminary activity has been seen in patients with MBC.

Effect of L-arginine on the microcirculation in the neuropathic diabetic foot in Type 2 diabetes mellitus: a double-blind, placebo-controlled study.

OBJECTIVE: To investigate the effect of L-arginine on endothelial function, transcutaneous oxygen and clinical neuropathy in patients with peripheral neuropathy as a result of diabetes. RESEARCH DESIGN AND METHODS: Thirty diabetic patients with peripheral neuropathy were randomized to receive L-arginine (3 g three times daily) or placebo (3 g three times daily) for 3 months. All patients had foot microcirculation and foot transcutaneous oxygen pressure (TcPO(2)), neuropathy disability score (NDS) and vibration perception threshold (VPT) assessed at baseline and follow-up. RESULTS: No difference was observed in endothelium-dependent and -independent vasodilation, TcPO(2), NDS and VPT. CONCLUSIONS: L-arginine has no effect on endothelial dysfunction, TcPO(2) and clinical neuropathy.

RUNX1-activated upregulation of lncRNA RNCR3 promotes cell proliferation, invasion, and suppresses apoptosis in colorectal cancer via miR-1301-3p/AKT1 axis in vitro and in vivo.

PURPOSE: Long non-coding RNAs (lncRNAs) have participated in progression of colorectal cancer. This study aims to study the role of RUNX1/RNCR3/miR-1301-3p/AKT1 axis in colorectal cancer. METHODS: The cancer tissues were from patients with colorectal cancer. The qRT-PCR was used to determine expression of lncRNA RNCR3, miR-1301-3p, and AKT1. Both dual-luciferase reporter assay and ChIP assay were conducted to investigate the binding sites of RUNX1 on RNCR3 promoter. Western blot was performed to analyze expression of AKT1 protein. Both dual-luciferase reporter assay and RIP assay were performed to detect the interacting sites between RNCR3 and miR-1301-3p. The CCK-8 assay, soft agar assay, transwell assay, and annexin-V-FITC/PI staining were applied to analyze the cell growth, invasion, and apoptosis, respectively. RESULTS: The data demonstrated that RNCR3 was elevated in colorectal cancer, and it was negatively correlated with expression of miR-1301-3p which was decreased in cancers. Then, RNCR3 could interact with and suppress miR-1301-3p expression in HCT116 and SW480. Knockdown of RNCR3 or miR-1301-3p overexpression significantly inhibited cell growth, invasion, and increased apoptosis through suppressing expression of Cyclin A1, PCNA, N-cadherin, Bcl-2, and promoting expression of E-cadherin, Bax in vitro and in vivo. RUNX1 was directly bound to RNCR3 promoter to activate RNCR3 expression. Furthermore, overexpression of RNCR3 blocked tumor inhibitory effects of miR-1301-3p on proliferation, colony formation, invasion, and apoptosis in vitro and in vivo. Additionally, RNCR3 and miR-1301-3p synergistically modulated AKT1 expression. CONCLUSION: RUNX1-activated upregulation of RNCR3 promoted colorectal cancer progression by sponging miR-1301-3p to elevate AKT1 levels in vitro and in vivo.

Association of methionyl-tRNA synthetase with detergent-insoluble components of the rough endoplasmic reticulum.

Using fluorescent antibody staining, we have established the association of methionyl-tRNA synthetase with the endoplasmic reticulum in PtK2 cells. After Triton X-100 extraction, 70% of the recovered aminoacyl-tRNA synthetase activity was found in the detergent-insoluble fraction. This fraction of the enzyme remained localized with insoluble endoplasmic reticulum antigens and with ribosomes, which were stained with acridine orange. By both fluorescence microscopy and electron microscopy the organization of the detergent-insoluble residue was found to depend on the composition of the extracting solution. After extraction with a microtubule-stabilizing buffer containing EGTA, Triton X-100, and polyethylene glycol (Osburn, M., and K. Weber, 1977, Cell, 12:561-571) the ribosomes were aggregated in large clusters with remnants of membranes. After extraction with a buffer containing Triton X-100, sucrose, and CaCl2 (Fulton, A. B., K. M. Wang, and S. Penman, 1980, Cell, 20:849-857), the ribosomes were in small clusters and there were few morphologically recognizable membranes. In both cases the methionyl-tRNA synthetase and some endoplasmic reticulum antigens retained approximately their normal distribution in the cell. Double fluorochrome staining showed no morphological association of methionyl-tRNA synthetase with the microtubule, actin, or cytokeratin fiber systems of PtK2 cells. These observations demonstrate that detergent-insoluble cellular components, sometimes referred to as "cytoskeletal" preparations, contain significant amounts of nonfilamentous material including ribosomes, and membrane residue. Caution is required in speculating about intermolecular associations in such a complex cell fraction.