During CNS autoimmunity, brain endothelial cell CXCR7 internalizes CXCL12 from the perivascular space, thereby permitting leukocyte migration into the CNS parenchyma.

IntroductionConstitutive activation of the class III receptor tyrosine kinase, FLT3, plays important roles in leukemogenesis. [1][2][3][4] Internal tandem duplications in the juxtamembrane region (FLT3-ITD) or point mutations in the kinase domain (FLT3-PM) lead to constitutively activated FLT3. [5][6][7] FLT3 is also activated by coexpression of FLT3 ligand (FL) through intracrine, paracrine, and/or autocrine pathways. [8][9][10] The presence of FLT3-ITD mutations is associated with a poor prognosis in acute myelogenous leukemia (AML). 11-14 Activated FLT3 mediates signaling through at least 3 major downstream signaling pathways: signal transducers and activators of transcription (STAT5), PI3K/Akt, and Ras/mitogen-activated protein (MAP) kinase. [15][16][17][18][19][20][21][22][23][24][25] These signaling pathways have overlapping roles in cell differentiation, proliferation, and survival. FLT3 is expressed in most acute leukemias, including 94% of B-lineage acute lymphoblastic leukemia (ALL), 34% of T-lineage ALL, and 89% of AML cases. [26][27][28] These observations strongly suggest FLT3 as a candidate for molecularly targeted therapy.In fact, a number of FLT3 tyrosine kinase inhibitors (TKIs) have been developed. Some of the best studied to date include CEP-701 (lestaurtinib), PKC412, MLN518, SU11248 (sunitinib malate), and AG1295. 23,[29][30][31][32][33] Although these inhibitors vary in their potency and selectivity for FLT3, all are able to induce cytotoxicity in FLT3-expressing cells in vitro and/or in vivo. Furthermore, clinical trials with some of these inhibitors have demonstrated their ability to decrease peripheral blood and bone marrow blast counts in some patients. [34][35][36] CEP-701 is currently being tested on relapsed patients with FLT3 mutant AML in a randomized phase 2 clinical trial in combination with chemotherapy.Although FLT3 inhibitors demonstrate preclinical and clinical activity, they possess a number of limitations. Clinical trials have revealed that FLT3 TKIs used as single agents are able to significantly reduce peripheral blood and bone marrow blasts only in a minority of patients, and the effect is transitory. [34][35][36] This may be due to achieving insufficient levels of FLT3 inhibition in these patients, a lack of dependence of these cells on FLT3 signaling for proliferation and survival, and/or selection of resistant cell populations. Furthermore, most cases of AML and ALL do not express mutant FLT3, and it is unclear to what degree these cells depend on FLT3 signaling for sustaining the leukemic phenotype. At drug concentrations necessary to inhibit FLT3 phosphorylation past a critical threshold required to induce cytotoxicity, a varying spectrum of other kinases are frequently also inhibited, which can lead to toxicities.Even when cells are dependent on FLT3 signaling for survival and proliferation, prolonged exposure to TKIs are likely to select for resistant clones, as has been seen with imatinib mesylate (Gleevec), a TKI targeting BCR-ABL in chronic myelogenous leukemia...

Background The complex interrelationship among physical health, mental health, and social health has gained the attention of the medical community in recent years. Poor social health, also called social deprivation, has been linked to more disease and a more-negative impact from disease across a wide variety of health conditions. However, it remains unknown how social deprivation is related to physical and mental health in patients presenting for orthopaedic care. Questions/purposes (1) Do patients living in zip codes with higher social deprivation report lower levels of physical function and higher levels of pain interference, depression, and anxiety as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) at initial presentation to an orthopaedic provider than those from less deprived areas; and if so, is this relationship independent of other potentially confounding factors such as age, sex, and race? (2) Does the relationship between the level of social deprivation of a patient’s community and that patient’s physical function, pain interference, depression, and anxiety, as measured by PROMIS remain consistent across all orthopaedic subspecialties? (3) Are there differences in the proportion of individuals from areas of high and low levels of social deprivation seen by the various orthopaedic subspecialties at one large, tertiary orthopaedic referral center? Methods This cross-sectional evaluation analyzed 7500 new adult patients presenting to an orthopaedic center between August 1, 2016 and December 15, 2016. Patients completed PROMIS Physical Function-v1.2, Pain Interference-v1.1, Depression-v1.0, and Anxiety-v1.0 Computer Adaptive Tests. The Area Deprivation Index, a composite measure of community-level social deprivation, based on multiple census metrics such as income, education level, and housing type for a given nine-digit zip code was used to estimate individual social deprivation. Statistical analysis determined the effect of disparate area deprivation (based on most- and least-deprived national quartiles) for the entire sample as well as for patients categorized by the orthopaedic subspecialty providing care. Comparisons of PROMIS scores among these groups were based on an MCID of 5 points for each PROMIS domain (Effect size 0.5). Results Patients living in zip codes with the highest levels of social deprivation had worse mean scores across all four PROMIS domains when compared with those living in the least-deprived quartile (physical function 38 +/- 9 versus 43 +/- 9, mean difference 4, 95% CI, 3.7–5.0; p < 0.001; pain interference 64 +/- 8 versus 60+/-8, mean difference -4, 95% CI, -4.8 to -3.7; p < 0.001; depression 50+/-11 versus 45+/-8, mean difference -5, 95% CI, -6.0 to -4.5; p < 0.001; anxiety 56+/-11 versus 50 +/-10, mean difference -6, 95% CI, -6.9 to -5.4; p < 0.001). There were no differences in physical function, pain interference, depression, or anxiety PROMIS scores between patients from the most- and least-deprived quartiles who presented to the subspecialties of spine (physical function, mean 35+/-7 versus 35+/-7; p = 0.872; pain interference, 67+/-7 versus 66+/-7; p = 0.562; depression, 54+/-12 versus 51 +/-10; p = 0.085; and anxiety, 60+/-11 versus 58 +/-9; p = 0.163), oncology (physical function, mean 33+/-9 versus 38 +/-13; p = 0.105; pain interference, 68+/-9 versus 64+/-10; p = 0.144; depression, 51+/-10 versus 52+/-13; p = 0.832; anxiety, 59+/-11 versus 59+/-10 p = 0.947); and trauma (physical function, 35+/-11 versus 32+/-10; p = 0.268; pain interference, 66+/-7 versus 67+/-6; p = 0.566; depression, 52+/-12 versus 53+/-11; p = 0.637; and anxiety, 59+/-12 versus 60+/-9 versus; p = 0.800). The social deprivation-based differences in all PROMIS domains remained for the subspecialties of foot/ankle, where mean differences ranged from 3 to 6 points on the PROMIS domains (p < 0.001 for all four domains), joint reconstruction where mean differences ranged from 4 to 7 points on the PROMIS domains (p < 0.001 for all four domains), sports medicine where mean differences in PROMIS scores ranged from 3 to 5 between quartiles (p < 0.001 for all four domains), and finally upper extremity where mean differences in PROMIS scores between the most- and least-deprived quartiles were five points for each PROMIS domain (p < 0.001 for all four domains). The proportion of individuals from the most- and least-deprived quartiles was distinct when looking across all seven subspecialty categories; only 11% of patients presenting to sports medicine providers and 17% of patients presenting to upper extremity providers were from the most-deprived quartile, while 39% of trauma patients were from the most-deprived quartile (p < 0.001). Conclusions Orthopaedic patients must be considered within the context of their social environment because it influences patient-reported physical and mental health as well as has potential implications for treatment and prognosis. Social deprivation may need to be considered when using patient-reported outcomes to judge the value of care delivered between practices or across specialties. Further studies should examine potential interventions to improve the perceived health of patients residing in communities with greater social deprivation and to determine how social health influences ultimate orthopaedic treatment outcomes. Level of Evidence Level II, prognostic study.

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