Chemotherapy was not associated with cognitive decline in older adults with breast and colorectal cancer: findings from a prospective cohort study

OBJECTIVES: : This study tested 2 hypotheses: (1) chemotherapy increases the rate of cognitive decline in breast and colorectal cancer patients beyond what is typical of normal aging and (2) chemotherapy results in systematic cognitive declines when compared with breast and colorectal cancer patients who did not receive chemotherapy. SUBJECTS: : Data came from personal interviews with a prospective cohort of patients with breast (n=141) or colorectal cancer (n=224) with incident disease drawn from the nationally representative Health and Retirement Study (1998-2006) with linked Medicare claims. MEASURES: : The 27-point modified Telephone Interview for Cognitive Status was used to assess cognitive functioning, focusing on memory and attention. We defined the smallest clinically significant change as 0.4 points per year. RESULTS: : We used Bayesian hierarchical linear models to test the hypotheses, adjusting for multiple possible confounders. Eighty-eight patients were treated with chemotherapy; 277 were not. The mean age at diagnosis was 75.5. Patients were followed for a median of 3.1 years after diagnosis, with a range of 0 to 8.3 years. We found no differences in the rates of cognitive decline before and after diagnosis for patients who received chemotherapy in adjusted models (P=0.86, one-sided 95% posterior intervals lower bound: 0.09 worse after chemotherapy), where patients served as their own controls. Moreover, the rate of cognitive decline after diagnosis did not differ between patients who had chemotherapy and those who did not (P=0.84, one-sided 95% posterior intervals lower bound: 0.11 worse for chemotherapy group in adjusted model). CONCLUSIONS: : There was no evidence of cognitive decline associated with chemotherapy in this sample of older adults with breast and colorectal cancer.NIH K08Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93627/1/12.Shaffer.MedCare.Chemo.Brain.pd

Function of von Willebrand factor after crossed bone marrow transplantation between normal and von Willebrand disease pigs: effect on arterial thrombosis in chimeras.

von Willebrand factor (vWF) is essential for the induction of occlusive thrombosis in stenosed and injured pig arteries and for normal hemostasis. To separate the relative contribution of plasma and platelet vWF to arterial thrombosis, we produced chimeric normal and von Willebrand disease pigs by crossed bone marrow transplantation; von Willebrand disease (vWD) pigs were engrafted with normal pig bone marrow and normal pigs were engrafted with vWD bone marrow. Thrombosis developed in the chimeric normal pigs that showed normal levels of plasma vWF and an absence of platelet vWF; but no thrombosis occurred in the chimeric vWD pigs that demonstrated normal platelet vWF and an absence of plasma vWF. The ear bleeding times of the chimeric pigs were partially corrected by endogenous plasma vWF but not by platelet vWF. Our animal model demonstrated that vWF in the plasma compartment is essential for the development of arterial thrombosis and that it also contributes to the maintenance of bleeding time and hemostasis

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro, however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects