Dual energy CT - a possible new method to assess regression of rectal cancers after neoadjuvant treatment

BACKGROUND AND OBJECTIVES: The measurement of tumor regression after neoadjuvant oncological treatment has gained increasing interest because it has a prognostic value and because it may influence the method of treatment in rectal cancer. The assessment of tumor regression remains difficult and inaccurate with existing methods. Dual Energy Computed Tomography (DECT) enables qualitative tissue differentiation by simultaneous scanning with different levels of energy. We aimed to assess the feasibility of DECT in quantifying tumor response to neoadjuvant therapy in loco-advanced rectal cancer.METHODS: We enrolled 11 patients with histological and MRI verified loco-advanced rectal adenocarcinoma and followed up on them prospectively. All patients had one DECT scanning before neoadjuvant treatment and one 12 weeks after using the spectral imaging scan mode. DECT analyzing tools were used to determine the average quantitative parameters; effective-Z, water- and iodine-concentration, Dual Energy Index (DEI), and Dual Energy Ratio (DER). These parameters were compared to the regression in the resection specimen as measured by the pathologist.RESULTS: Changes in the quantitative parameters differed significantly after treatment in comparison with pre-treatment, and the results were different in patients with different CRT response rates.CONCLUSION: DECT might be helpful in the assessment of rectal cancer regression grade after neoadjuvant treatment.</p

Prognostic Value of Serum NPY Hypermethylation in Neoadjuvant Chemoradiotherapy for Rectal Cancer: Secondary Analysis of a Randomized Trial

Objectives: Long-term prevention of metastatic disease remains a challenge in locally advanced rectal cancer, and robust pretreatment prognostic factors for metastatic progression are lacking. We hypothesized that detecting circulating tumor-specific DNA (ctDNA) based on hypermethylation of the neuropeptide Y gene (meth-ctDNA) could be a prognostic marker in the neoadjuvant setting; we examined this in a secondary, explorative analysis of a prospective trial. Materials and Methods: Serum samples were prospectively collected in a phase III trial for locally advanced rectal cancer. Positivity for and fractional abundance of meth-ctDNA in baseline samples were estimated. Overall survival (OS) and the rate of distant metastases were compared between meth-ctDNA positive and negative patients; other prognostic factors were controlled for in multivariate Cox regression. Importance of quantitative load was examined by considering the fractional abundance of meth-ctDNA relative to total circulating DNA. Results: Baseline serum samples were available for 146 patients. In total, 30 patients had presence of meth-ctDNA, with no correlation with cT (P=0.8) or cN (P=0.6) stages. Median follow-up was 10.6 years for OS and 5.1 years for freedom from distant metastases. Patients with meth-ctDNA had significantly worse 5-year OS (47% vs. 69%), even when controlling for other prognostic factors (hazard ratio=2.08; 95% confidence interval, 1.23-1.51). This seemed mainly driven by disparity in the rate of distant metastases (55% vs. 72% at 5 y, P=0.01); hazard ratio=2.20 (95% confidence interval, 1.19-4.07, P=0.01) in multivariate analysis. Increased quantitative load was highly significant for worse outcomes. Conclusions: Meth-ctDNA could be a potential prognostic marker in the neoadjuvant setting and may, if validated, identify patients at increased risk of distant metastases

Astrocytes Infected with Chlamydia pneumonia Alter Amyloid Processing Implicated in Alzheimer’s Disease

Alzheimer’s Disease (AD) is a chronic, progressive neurodegenerative disease whose pathogenesis centers around the abnormal processing of amyloid precursor protein (APP) by proteases, resulting in the formation of neuritic plaques composed of toxic, insoluble fragments of amyloid protein (Aβ), including Aβ1-40 and Aβ1-42. Previously, our laboratory identified Chlamydia pneumoniae (Cpn) in autopsied sporadic AD brains. Additionally, an infection based animal model was developed using BALB/c mice that were intranasally inoculated with Cpn, in which the deposition of amyloid was consistent with that observed in the human AD brain. These studies have led to the pathogen hypothesis of AD that implicates Cpn as a trigger for the cleavage of APP into Aβ1-40 and Aβ1-42. Objective: Several studies have demonstrated the presence of astrocytes surrounding neuritic plaques within the AD brain; therefore, we speculate that astrocytes may be specifically involved in the pathological processes leading to Aβ deposition. This investigation addresses if an in vitro Cpn infection of human astrocytes affects processing of the ß amyloid precursor protein (ßAPP) and the enzyme ß APP cleaving enzyme-1 (BACE1), a type 1 transmembrane aspartyl protease directly involved in the processing of APP to Aβ and implicated in numerous neurodegenerative diseases, such as traumatic brain injury. Methods: Human astrocytes (CCF-STTG1) were infected in vitro with the respiratory strain AR39 Cpn (MOI=1). Analysis of protein levels for Aβ and the enzyme BACE1 post-infection was detected by immunocytochemistry and captured with the Olympus Confocal FV1000 microscope. Results: Amyloid processing in infected astrocytes was altered relative to that of uninfected astrocytes. BACE1 immunolabeling appeared more diffuse in the infected astrocytes as compared to membrane-localized BACE1 in the uninfected astrocytes. Conclusions: Neurons have been presumed to be the primary source of beta-amyloid peptides in AD brains; however, when astrocytes are activated, as occurs during infection with Cpn, astrocytic beta-amyloid generation may contribute to amyloid plaque formation. These data imply that infection of human astrocytes with Cpn affects the processing of ßAPP through altering the localization of BACE1 protein from the membrane to the cytoplasm. These data suggest an activation of BACE1 in the processing of amyloid by astrocytes as a major contributor to the neurotoxic amyloid deposition linked to pathology observed in AD

Astrocytes Infected with Chlamydia Pneumoniae Demonstrate Altered Expression and Activity of Secretases Involved in the Generation of Β-amyloid Found in Alzheimer Disease

BACKGROUND: Epidemiologic studies strongly suggest that the pathophysiology of late-onset Alzheimer disease (AD) versus early-onset AD has environmental rather than genetic causes, thus revealing potentially novel therapeutic targets to limit disease progression. Several studies supporting the pathogen hypothesis of AD demonstrate a strong association between pathogens and the production of β-amyloid, the pathologic hallmark of AD. Although the mechanism of pathogen-induced neurodegeneration of AD remains unclear, astrocytes, a key player of the CNS innate immune response and producer/metabolizer of β-amyloid, have been implicated. We hypothesized that Chlamydia pneumoniae infection of human astrocytes alters the expression of the amyloid precursor protein (APP)-processing secretases, ADAM10, BACE1, and PSEN1, to promote β-amyloid formation. Utilizing immunofluorescent microscopy, molecular, and biochemical approaches, these studies explore the role of an intracellular respiratory pathogen, Chlamydia pneumoniae, as an environmental trigger for AD pathology. Human astrocytoma cells in vitro were infected with Chlamydia pneumoniae over the course of 6-72 h. The gene and protein expression, as well as the enzymatic activity of non-amyloidogenic (ADAM10), and pro-amyloidogenic (BACE1 and PSEN1) secretases were qualitatively and quantitatively assessed. In addition, the formation of toxic amyloid products as an outcome of pro-amyloidogenic APP processing was evaluated through various modalities. RESULTS: Chlamydia pneumoniae infection of human astrocytoma cells promoted the transcriptional upregulation of numerous genes implicated in host neuroinflammation, lipid homeostasis, microtubule function, and APP processing. Relative to that of uninfected astrocytes, BACE1 and PSEN1 protein levels were enhanced by nearly twofold at 48-72 h post-Chlamydia pneumoniae infection. The processing of APP in Chlamydia pneumoniae-infected astrocytes favors the pro-amyloidogenic pathway, as demonstrated by an increase in enzymatic activity of BACE1, while that of ADAM10 was decreased. Fluorescence intensity of β-amyloid and ELISA-quantified levels of soluble-APP by products revealed temporally similar increases, confirming a BACE1/PSEN1-mediated processing of APP. CONCLUSIONS: Our findings suggest that Chlamydia pneumoniae infection of human astrocytes promotes the pro-amyloidogenic pathway of APP processing through the upregulation of expression and activity of β-secretase, upregulated expression of γ-secretase, and decreased activity of α-secretase. These effects of astrocyte infection provide evidence for a direct link between Chlamydia pneumoniae and AD pathology

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT\ubcT0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4\u20138 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (Po0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73\u20130.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10\u20134.11)-fold and 4.55 (95% CI 1.48\u201313.95)-fold higher, respectively, than those with undetectable plasma TERT levels. Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy

Upsilon (1S+2S+3S) production in d+Au and p+p collisions at sqrt(s_NN)=200 GeV and cold-nuclear matter effects

The three Upsilon states, Upsilon(1S+2S+3S), are measured in d+Au and p+p collisions at sqrt(s_NN)=200 GeV and rapidities 1.2<|y|<2.2 by the PHENIX experiment at the Relativistic Heavy-Ion Collider. Cross sections for the inclusive Upsilon(1S+2S+3S) production are obtained. The inclusive yields per binary collision for d+Au collisions relative to those in p+p collisions (R_dAu) are found to be 0.62 +/- 0.26 (stat) +/- 0.13 (syst) in the gold-going direction and 0.91 +/- 0.33 (stat) +/- 0.16 (syst) in the deuteron-going direction. The measured results are compared to a nuclear-shadowing model, EPS09 [JHEP 04, 065 (2009)], combined with a final-state breakup cross section, sigma_br, and compared to lower energy p+A results. We also compare the results to the PHENIX J/psi results [Phys. Rev. Lett. 107, 142301 (2011)]. The rapidity dependence of the observed Upsilon suppression is consistent with lower energy p+A measurements.Comment: 495 authors, 11 pages, 9 figures, 5 tables. Submitted to Phys. Rev. C. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Double Spin Asymmetry of Electrons from Heavy Flavor Decays in p+p Collisions at sqrt(s)=200 GeV

We report on the first measurement of double-spin asymmetry, A_LL, of electrons from the decays of hadrons containing heavy flavor in longitudinally polarized p+p collisions at sqrt(s)=200 GeV for p_T= 0.5 to 3.0 GeV/c. The asymmetry was measured at mid-rapidity (|eta|<0.35) with the PHENIX detector at the Relativistic Heavy Ion Collider. The measured asymmetries are consistent with zero within the statistical errors. We obtained a constraint for the polarized gluon distribution in the proton of |Delta g/g(log{_10}x= -1.6^+0.5_-0.4, {mu}=m_T^c)|^2 < 0.033 (1 sigma), based on a leading-order perturbative-quantum-chromodynamics model, using the measured asymmetry.Comment: 385 authors, 17 pages, 15 figures, 5 tables. Submitted to Phys. Rev. D. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Measurements of elliptic and triangular flow in high-multiplicity 3^{3}He++Au collisions at sNN=200\sqrt{s_{_{NN}}}=200 GeV

We present the first measurement of elliptic ($v_2$) and triangular ($v_3$) flow in high-multiplicity $^{3}$He$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV. Two-particle correlations, where the particles have a large separation in pseudorapidity, are compared in $^{3}$He$+$Au and in $p$$+$$p$ collisions and indicate that collective effects dominate the second and third Fourier components for the correlations observed in the $^{3}$He$+$Au system. The collective behavior is quantified in terms of elliptic $v_2$ and triangular $v_3$ anisotropy coefficients measured with respect to their corresponding event planes. The $v_2$ values are comparable to those previously measured in $d$$+$Au collisions at the same nucleon-nucleon center-of-mass energy. Comparison with various theoretical predictions are made, including to models where the hot spots created by the impact of the three $^{3}$He nucleons on the Au nucleus expand hydrodynamically to generate the triangular flow. The agreement of these models with data may indicate the formation of low-viscosity quark-gluon plasma even in these small collision systems.Comment: 630 authors, 9 pages, 4 figures, 2 tables. v2 is the version accepted for publication by Physical Review Letters. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm