Older Breast Cancer Survivors: Geriatric Assessment Domains Are Associated With Poor Tolerance of Treatment Adverse Effects and Predict Mortality Over 7 Years of Follow-Up

Purpose To evaluate geriatric assessment (GA) domains in relation to clinically important outcomes in older breast cancer survivors. Methods Six hundred sixty women diagnosed with primary breast cancer in four US geographic regions (Los Angeles, CA; Minnesota; North Carolina; and Rhode Island) were selected with disease stage I to IIIA, age ≥ 65 years at date of diagnosis, and permission from attending physician to contact. Data were collected over 7 years of follow-up from consenting patients' medical records, telephone interviews, physician questionnaires, and the National Death Index. Outcomes included self-reported treatment tolerance and all-cause mortality. Four GA domains were described by six individual measures, as follows: sociodemographic by adequate finances; clinical by Charlson comorbidity index (CCI) and body mass index; function by number of physical function limitations; and psychosocial by the five-item Mental Health Index (MHI5) and Medical Outcomes Study Social Support Survey (MOS-SSS). Associations were evaluated using t tests, χ2 tests, and regression analyses. Results In multivariable regression including age and stage, three measures from two domains (clinical and psychosocial) were associated with poor treatment tolerance; these were CCI ≥ 1 (odds ratio [OR] = 2.49; 95% CI, 1.18 to 5.25), MHI5 score less than 80 (OR = 2.36; 95% CI, 1.15 to 4.86), and MOS-SSS score less than 80 (OR = 3.32; 95% CI, 1.44 to 7.66). Four measures representing all four GA domains predicted mortality; these were inadequate finances (hazard ratio [HR] = 1.89; 95% CI, 1.24 to 2.88; CCI ≥ 1 (HR = 1.38; 95% CI, 1.01 to 1.88), functional limitation (HR = 1.40; 95% CI, 1.01 to 1.93), and MHI5 score less than 80 (HR = 1.34; 95% CI, 1.01 to 1.85). In addition, the proportion of women with these outcomes incrementally increased as the number of GA deficits increased. Conclusion This study provides longitudinal evidence that GA domains are associated with poor treatment tolerance and predict mortality at 7 years of follow-up, independent of age and stage of disease.

Macroevolutionary patterns in the diversification of parrots: effects of climate change, geological events and key innovations

Aim Parrots are thought to have originated on Gondwana during the Cretaceous. The initial split within crown group parrots separated the New Zealand taxa from the remaining extant species and was considered to coincide with the separation of New Zealand from Gondwana 82-85 Ma, assuming that the diversification of parrots was mainly shaped by vicariance. However, the distribution patterns of several extant parrot groups cannot be explained without invoking transoceanic dispersal, challenging this assumption. Here, we present a temporal and spatial framework for the diversification of parrots using external avian fossils as calibration points in order to evaluate the relative importance of the influences of past climate change, plate tectonics and ecological opportunity. Location Australasian, African, Indo-Malayan and Neotropical regions. Methods Phylogenetic relationships were investigated using partial sequences of the nuclear genes c-mos, RAG-1 and Zenk of 75 parrot and 21 other avian taxa. Divergence dates and confidence intervals were estimated using a Bayesian relaxed molecular clock approach. Biogeographic patterns were evaluated taking temporal connectivity between areas into account. We tested whether diversification remained constant over time and if some parrot groups were more species-rich than expected given their age. Results Crown group diversification of parrots started only about 58 Ma, in the Palaeogene, significantly later than previously thought. The Australasian lories and possibly also the Neotropical Arini were found to be unexpectedly species-rich. Diversification rates probably increased around the Eocene/Oligocene boundary and in the middle Miocene, during two periods of major global climatic aberrations characterized by global cooling. Main conclusions The diversification of parrots was shaped by climatic and geological events as well as by key innovations. Initial vicariance events caused by continental break-up were followed by transoceanic dispersal and local radiations. Habitat shifts caused by climate change and mountain orogenesis may have acted as a catalyst to the diversification by providing new ecological opportunities and challenges as well as by causing isolation as a result of habitat fragmentation. The lories constitute the only highly nectarivorous parrot clade, and their diet shift, associated with morphological innovation, may have acted as an evolutionary key innovation, allowing them to explore underutilized niches and promoting their diversification.

Blocking of LFA-1 enhances expansion of Th17 cells induced by human CD14(+) CD16(++) nonclassical monocytes.

Among human peripheral blood (PB) monocyte (Mo) subsets, the classical CD14(++) CD16(-) (cMo) and intermediate CD14(++) CD16(+) (iMo) Mos are known to activate pathogenic Th17 responses, whereas the impact of nonclassical CD14(+) CD16(++) Mo (nMo) on T-cell activation has been largely neglected. The aim of this study was to obtain new mechanistic insights on the capacity of Mo subsets from healthy donors (HDs) to activate IL-17(+) T-cell responses in vitro, and assess whether this function was maintained or lost in states of chronic inflammation. When cocultured with autologous CD4(+) T cells in the absence of TLR-2/NOD2 agonists, PB nMos from HDs were more efficient stimulators of IL-17-producing T cells, as compared to cMo. These results could not be explained by differences in Mo lifespan and cytokine profiles. Notably, however, the blocking of LFA-1/ICAM-1 interaction resulted in a significant increase in the percentage of IL-17(+) T cells expanded in nMo/T-cell cocultures. As compared to HD, PB Mo subsets of patients with rheumatoid arthritis were hampered in their T-cell stimulatory capacity. Our new insights highlight the role of Mo subsets in modulating inflammatory T-cell responses and suggest that nMo could become a critical therapeutic target against IL-17-mediated inflammatory diseases.