155 research outputs found
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Analysis of delay in adjuvant chemotherapy in locally advanced rectal cancer
BackgroundAdjuvant chemotherapy (AC) after neoadjuvant chemoradiation and surgical resection has been the standard of care for locally advanced rectal cancer. However, there are no evidence-based guidelines regarding the optimal timing of AC for rectal cancer. The objective of this study was to evaluate the effect of AC timing on overall survival for rectal cancer.MethodsThe National Cancer Database (NCDB) from 2004 to 2016 was queried for primary clinical stage II or III rectal cancer patients who had undergone neoadjuvant chemoradiation followed by surgery and AC. Patients were grouped based on AC initiation: early ≤ 4 weeks, intermediate 4-8 weeks, and delayed ≥ 8 weeks. The primary outcome was overall survival.ResultsWe identified 8722 patients, of which 905 (10.4%) received early AC, 4621 (53.0%) intermediate AC, and 3196 (36.6%) delayed AC. Pathological lymph-node metastasis (ypN +) was positive in 73% of early AC, 74% intermediate AC, and 63% delayed AC (p < 0.05). The 5-year survival probability was 71.1% (95% CI 68-74%) for early AC, 73.2% (95% CI 72-75%) intermediate AC, and 65.8% (95% CI 64-68%) delayed AC (p < 0.001). Using Cox proportional hazard modeling, patients undergoing delayed AC had an associated decreased survival compared to patients receiving early AC (HR 1.18; 95% CI 1.028-1.353, p = 0.018) or intermediate AC (HR 1.28; 95% CI 1.179-1.395, p < 0.01).ConclusionsDelay in AC administration may be associated with decreased 5-year survival. Compared to early or intermediate AC, patients in the delayed AC group were observed to have increased risk of death, despite having lower proportions with ypN + disease. Patients with higher socioeconomic and education status were more likely to receive early chemotherapy
Computational analysis and design of an aerofoil with morphing tail for improved aerodynamic performance in transonic regime
This article focuses on the aerodynamic design of a morphing aerofoil at cruise conditions using computational fluid dynamics (CFD). The morphing aerofoil has been analysed at a Mach number of 0.8 and Reynolds number of 3×106 , which represents the transonic cruise speed of a commercial aircraft. In this research, the NACA0012 aerofoil has been identified as the baseline aerofoil where the analysis has been performed under steady conditions at a range of angles of attack between 0∘ and 3.86∘ . The performance of the baseline case has been compared to the morphing aerofoil for different morphing deflections ( wte/c=[0.005−0.1] ) and start of the morphing locations ( xs/c=[0.65−0.80] ). Further, the location of the shock wave on the upper surface has also been investigated due to concerns about the structural integrity of the morphing part of the aerofoil. Based upon this investigation, a most favourable morphed geometry has been presented that offers both, a significant increase in the lift-to-drag ratio against its un-morphed counterpart and has a shock location upstream of the start of the morphing part
Averaged Differential Expression for the Discovery of Biomarkers in the Blood of Patients with Prostate Cancer
<div><h3>Background</h3><p>The identification of a blood-based diagnostic marker is a goal in many areas of medicine, including the early diagnosis of prostate cancer. We describe the use of averaged differential display as an efficient mechanism for biomarker discovery in whole blood RNA. The process of averaging reduces the problem of clinical heterogeneity while simultaneously minimizing sample handling.</p> <h3>Methodology/Principal Findings</h3><p>RNA was isolated from the blood of prostate cancer patients and healthy controls. Samples were pooled and subjected to the averaged differential display process. Transcripts present at different levels between patients and controls were purified and sequenced for identification. Transcript levels in the blood of prostate cancer patients and controls were verified by quantitative RT-PCR. Means were compared using a t-test and a receiver-operating curve was generated. The Ring finger protein 19A (RNF19A) transcript was identified as having higher levels in prostate cancer patients compared to healthy men through the averaged differential display process. Quantitative RT-PCR analysis confirmed a more than 2-fold higher level of RNF19A mRNA levels in the blood of patients with prostate cancer than in healthy controls (p = 0.0066). The accuracy of distinguishing cancer patients from healthy men using RNF19A mRNA levels in blood as determined by the area under the receiving operator curve was 0.727.</p> <h3>Conclusions/Significance</h3><p>Averaged differential display offers a simplified approach for the comprehensive screening of body fluids, such as blood, to identify biomarkers in patients with prostate cancer. Furthermore, this proof-of-concept study warrants further analysis of RNF19A as a clinically relevant biomarker for prostate cancer detection.</p> </div
Current perspectives on bone metastases in castrate-resistant prostate cancer
Prostate cancer is the most frequent noncutaneous cancer occurring in men. On average, men with localized prostate cancer have
a high 10-year survival rate, and many can be cured. However, men with metastatic castrate-resistant prostate cancer have
incurable disease with poor survival despite intensive therapy. This unmet need has led to recent advances in therapy aimed at
treating bone metastases resulting from prostate cancer. The bone microenvironment lends itself to metastases in castrate-resistant
prostate cancer, as a result of complex interactions between the microenvironment and tumor cells. The development of 223radium
dichloride (Ra-223) to treat symptomatic bone metastases has improved survival in men with metastatic castrate-resistant
prostate cancer. Moreover, Ra-223 may have effects on the tumor microenvironment that enhance its activity. Ra-223 treatment
has been shown to prolong survival, and its effects on the immune system are under investigation. Because prostate cancer affects
a sizable portion of the adult male population, understanding how it metastasizes to bone is an important step in advancing
therapy. Clinical trials that are underway should yield new information on whether Ra-223 synergizes effectively with immunotherapy
agents and whether Ra-223 has enhancing effects on the immune system in patients with prostate cancer
Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia
Although KIT mutations are present in 20–25% of cases of t(8;21)(q22;q22) acute myeloid leukemia (AML), concurrent development of systemic mastocytosis (SM) is exceedingly rare. We examined the clinicopathologic features of SM associated with t(8;21)(q22;q22) AML in ten patients (six from our institutions and four from published literature) with t(8;21) AML and SM. In the majority of these cases, a definitive diagnosis of SM was made after chemotherapy, when the mast cell infiltrates were prominent. Deletion 9q was an additional cytogenetic abnormality in four cases. Four of the ten patients failed to achieve remission after standard chemotherapy and seven of the ten patients have died of AML. In the two patients who achieved durable remission after allogeneic hematopoietic stem cell transplant, recipient-derived neoplastic bone marrow mast cells persisted despite leukemic remission. SM associated with t(8;21) AML carries a dismal prognosis; therefore, detection of concurrent SM at diagnosis of t(8;21) AML has important prognostic implications
GILZ inhibits the mTORC2/AKT pathway in BCR-ABL+ cells
The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the BCR-ABL oncoprotein, which signals several downstream cell survival pathways, including phosphoinositide 3-kinase/AKT, signal transducer and activator of transcription 5 and extracellular signal-regulated kinase 1/2. In patients with CML, tyrosine kinase inhibitors (TKIs) are used to suppress the BCR-ABL tyrosine kinase, resulting in impressive response rates. However, resistance can occur, especially in acute-phase CML, through various mechanisms. Here, we show that the glucocorticoid-induced leucine zipper protein (GILZ) modulates imatinib and dasatinib resistance and suppresses tumor growth by inactivating the mammalian target of rapamycin complex-2 (mTORC2)/AKT signaling pathway. In mouse and human models, GILZ binds to mTORC2, but not to mTORC1, inhibiting phosphorylation of AKT (at Ser473) and activating FoxO3a-mediated transcription of the pro-apoptotic protein Bim; these results demonstrate that GILZ is a key inhibitor of the mTORC2 pathway. Furthermore, CD34+ stem cells isolated from relapsing CML patients underwent apoptosis and showed inhibition of mTORC2 after incubation with glucocorticoids and imatinib. Our findings provide new mechanistic insights into the role of mTORC2 in BCR-ABL+ cells and indicate that regulation by GILZ may influence TKI sensitivity
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