Improved Survival of Young Adults with Cancer Following the Passage of the Affordable Care Act

BackgroundCompared with their ensured counterparts, uninsured adolescents and young adults (AYAs) with cancer are more likely to present with advanced disease and have poor prognoses. The Patient Protection and Affordable Care Act (ACA), enacted in 2010, provided health care coverage to millions of uninsured young adults by allowing them to remain on their parents’ insurance until age 26 years (the Dependent Care Expansion, DCE). The impact of the expansion of insurance coverage on survival outcomes for young adults with cancer has not been assessed.ParticipantsUtilizing the Surveillance, Epidemiology, and End Results database, we identified all patients aged 12-16 (younger-AYAs), 19-23 (middle-AYAs), and 26-30 (older-AYAs) who were diagnosed with cancer between 2006-2008 (pre-ACA) and 2011-2013 (post-ACA).MethodsIn this population-based cohort study, we used an accelerated failure time model to assess changes in survival rates before and after the enactment of the ACA DCE.ResultsMiddle-AYAs ages 19-23 (thus eligible to remain on their parents’ insurance) experienced significantly increased 2-year survival after the enactment of the ACA DCE (survival time ratio 1.25, 95% confidence interval: 0.75-2.43, P = .029) and that did not occur in younger-AYAs (ages 12-16). Patients with sarcoma and acute myeloid leukemia accounted for the majority of improvement in survival. Middle-AYAs of hispanic ethnicity and those with low socioeconomic status experienced trends of improved survival after the ACA DCE was enacted.ConclusionSurvival outcomes improved for young adults with cancer following the expansion of health insurance coverage. Efforts are needed to expand coverage for the millions of young adults who do not have health insurance.     

前后路联合手术治疗髋臼双柱骨折疗效分析

目的:探讨前后路联合手术治疗髋臼双柱骨折的效果并分析影响疗效的相关因素。方法:2007年8月至2009年7月收治髋臼双柱骨折患者19例,男13例,女6例;年龄27～52岁,平均39.6岁。高位双柱骨折11例,低位双柱骨折8例,双柱骨折累及骶髂关节1例。受伤至手术时间4～11 d,平均5.8 d。患者均采用前后联合入路手术,重建钢板和螺钉内固定。结果:除1例死亡外本组全部获随访,随访时间12～18个月,平均13.6个月。关节功能根据Harris评分标准,术后功能优9例,良7例,可2例。结论:经前后路联合切开复位内固定治疗髋臼双柱骨折疗效满意。     

Blood Pressure Control Provides Less Cardiovascular Protection in Adults With Than Without Apparent Treatment‐Resistant Hypertension

Hypertension control may offer less protection from incident cardiovascular disease (CVD_i) in adults with than without apparent treatment‐resistant hypertension (aTRH), ie, blood pressure uncontrolled while taking three or more antihypertensive medications or controlled to <140/<90 mm Hg while taking four or more antihypertensive medications. Electronic health data were matched to health claims for 2006–2012. Patients with CVD_i in 2006–2007 or with untreated hypertension were excluded, leaving 118,356 treated hypertensives, including 40,690 with aTRH, and 460,599 observation years. Blood pressure and medication number were determined by all clinic visit means from 2008 to CVD_i or end of study. Primary outcome was first CVD_i (stroke, coronary heart disease, heart failure) from hospital and emergency department claims. Controlling for age, race, sex, diabetes, chronic kidney disease, and statin use, hypertension control afforded less CVD_i protection in patients with aTRH (hazard ratio, 0.87; 95% confidence interval, 0.82–0.93) than without aTRH (hazard ratio, 0.69; 95% confidence interval, 0.65–0.74; P<.001). Strategies beyond hypertension control may prevent more CVD_i in patients with aTRH.     

Transfected leukocyte integrin CD11b/CD18 (Mac-1) mediates phorbol ester-activated, homotypic cell:cell adherence in the K562 cell line

The CD11b/CD18 leukocyte integrin molecule mediates diverse neutrophil adherence-related functions, including cell:cell and cell:extracellular matrix attachments. To study the individual role of this leukocyte integrin in cell adherence in hematopoietic cells, we expressed the CD11b/CD18 complex on the surface of K562 cells, a cell line derived from an individual with chronic myelogenous leukemia in blast crisis. We used an amphotrophic retroviral vector designated LCD18SN, harboring the complete coding sequence for the CD18 subunit, to transfer the CD18 cDNA into K562 cells and select stable cell lines. The CD11b subunit in the expression plasmid pREP4 was transfected into these K562/CD18 cells by electroporation and stable cell clones were selected. These K562 cells possessed RNA and intracellular protein for each subunit, and they expressed the CD11b/CD18 heterodimer on the cell surface. When CD11b/CD18 expressing K562 cells were stimulated with phorbol myristate acetate (50 ng/mL) for 24 to 48 hours, these K562 cells formed dense cell:cell aggregates. This homotypic aggregation required both activation of the CD11b/CD18 complex and the induction of the counter- receptor for CD11b/CD18 on the conjugate cell. This cell line will (1) enable the structure-function relationships between cell activation and homotypic adherence to be assessed, (2) provide the opportunity to identify accessory molecules required for activation of the CD11b/CD18 complex, and (3) facilitate the identification of novel ligands for the CD11b/CD18 complex.     

Function of C3 in a humoral response: iC3b/C3dg bound to an immune complex generated with natural antibody and a primary antigen promotes antigen uptake and the expression of co-stimulatory molecules by all B cells,but only stimulates immunoglobulin synthesis by antigen-specific B cells

Previous studies have shown that an optimal humoral response to a primary protein antigen requires C3 and CR2 (CD21). Sera from non-immunized donors contain natural IgM and IgG antibodies to the primary antigen keyhole limpet haemocyanin (KLH), and these have been previously shown to form immune complexes (IC) that activate the classical pathway of C, fixing iC3b/C3dg onto the KLH antigen. Such KLH IC bind to CR2 on KLH-non-specific B lymphocytes, resulting in antigen processing and MHC class II-dependent presentation to KLH-specific helper T cells. KLH IC also induce B lymphocytes to express the CD80 co-stimulatory molecule via simultaneous CR2 ligation with C3 and FcγRII (CD32) stimulation by IgG natural antibody. The current study demonstrated that KLH IC ligation to either CR2 or FcγRII resulted in activation of a second co-stimulatory molecule, LFA-1 (CD11a, CD18). The possibility of polyclonal B cell stimulation by the presentation of KLH-iC3b/C3dg by antigen-non-specific B cells was excluded by demonstration that in vitro cultivation of peripheral blood mononuclear cells (PBMC) with KLH-iC3b/C3dg elicited only anti-KLH, and did not stimulate synthesis of antibodies to hepatitis C virus (HCV) or tetanus toxoid (TT). Of greatest significance, a specific anti-KLH response was only detectable in cultures stimulated with KLH-iC3b/C3dg and not in cultures stimulated with KLH alone or KLH-IgG. Thus, iC3b/C3dg that was bound to a primary protein antigen enhanced recognition and specific immunoglobulin synthesis by antigen-specific B cells, even though the antigen was taken up and processed via CR2 by both antigen-specific and non-specific B cells.     

Existing Antilisterial Immunity Does Not Inhibit the Development of a Listeria monocytogenes-Specific Primary Cytotoxic T-Lymphocyte Response

Infection of BALB/c mice with Listeria monocytogenes stimulates an antilisterial immune response evident by the appearance of H2-K^d-restricted CD8⁺ cytotoxic T lymphocytes (CTLs) specific for the nanomer peptides amino acids (aa) 91 to 99 of listeriolysin O (LLO 91–99) and aa 217 to 225 of the p60 molecule (p60 217–225). We have introduced point mutations at anchor residues within LLO 91–99 (92F) or p60 217–225 (218F), and BALB/c mice infected with L. monocytogenes strains containing these point mutations do not develop CTLs specific for LLO 91–99 or p60 217–225, respectively. We have used these strains to test whether primary CTL responses against L. monocytogenes-derived determinants can be stimulated within an environment of existing antilisterial immunity. We found that the development of a primary L. monocytogenes-specific CTL response is not altered by existing immunity to L. monocytogenes. For example, primary immunization with the p60 218F strain of L. monocytogenes followed by a secondary immunization with wild-type L. monocytogenes results in stimulation of p60 217–225-specific CTLs at primary response levels and LLO 91–99-specific effectors at levels consistent with a memory CTL response. Similarly, primary immunization with the 92F strain of L. monocytogenes followed by a secondary immunization with wild-type L. monocytogenes results in stimulation of LLO 91–99-specific CTLs at primary response levels and p60 217–225-specific effectors at levels consistent with a memory CTL response. These results provide additional support for the use of L. monocytogenes as a recombinant vaccine vector and show that antivector immunity does not inhibit the development of a primary CTL response when the epitope is delivered by L. monocytogenes as the vaccine strain.     

Regulation of CR3 (CD11b/CD18)-dependent natural killer (NK) cell cytotoxicity by tumour target cell MHC class I molecules

Phagocyte and NK cell CR3 functions as both an adhesion molecule and an iC3b receptor mediating cytotoxic responses to microorganisms. Cytotoxic activation of iC3b receptor function requires ligation of both a CD11b I-domain site for iC3b and a lectin site located in the C-terminus of CD11b. Because tumours lack the CR3-binding polysaccharides of bacteria and fungi, iC3b-opsonized tumours do not stimulate CR3-dependent cytotoxicity. Previous studies showed that NK cells could be induced to kill iC3b-opsonized tumours with small soluble β-glucans that bound with high affinity to CR3, bypassing the absence of similar polysaccharides on tumour membranes. Because CR3 signalling requires several tyrosine phosphorylation events, it appeared possible that CR3-dependent killing of autologous tumour cells might be suppressed by NK cell inhibitory receptors for MHC class I (KIR and CD94/NKG2) whose action involves recruitment of SHP-1 and SHP-2 tyrosine phosphatases. In the current study, Epstein–Barr virus (EBV)-transformed B cells were used as targets following opsonization with iC3b. Soluble β-glucan primed CR3 for killing of iC3b-coated B cells, but autologous class I-bearing targets were 84% more resistant than class I-deficient Daudi cells. Blockade of target cell class I with a MoAb specific for a domain recognized by both KIR and CD94/NKG2 resulted in comparable killing of class I⁺ B cells. By contrast, another MoAb to class II had no effect on cytotoxicity. These data suggest that NK cell recognition of class I suppresses CR3/tyrosine kinase-dependent cytotoxicity in the same way as it suppresses cytotoxicity mediated by other tyrosine kinase-linked receptors such as FcγRIIIA (CD16).     

Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome

Champion KJ, Bunag C, Estep AL, Jones JR, Bolt CH, Rogers RC, Rauen KA, Everman DB. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio‐facio‐cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild‐type BRAF but is less strongly activating than the cancer‐associated p.V600E mutation.     

Computer simulation and geometric design of endarterectomized carotid artery bifurcations

The main goal of this computational study is to establish surgical guidelines for optimal geometries of carotid endarterectomy reconstructions that may measurably reduce postoperative complications, that is, thrombosis, stroke, and/or restenosis. The underlying hypotheses are that nonuniform hemodynamics, or "disturbed flows," are linked to arterial diseases and consequently that minimization of "disturbed flow" indicators leads to geometric bifurcation designs that lower postoperative complication rates. Considering transient 3-D laminar blood flow in partially occluded, in-plane, rigid-wall carotid artery bifurcations, the results presented include time-averaged indicators of "disturbed flow", such as the wall shear stress, spatial wall shear stress gradient, and wall shear stress angle deviation. In addition, trajectories and deposition patterns of critical blood particles (i.e., monocytes) are shown and evaluated. Within given physiological constraints, the vessel geometry was then changed in order to reduce the magnitudes of key indicators associated with thrombosis (i.e., blood clot formation) or restenosis (e.g., renewed atherosclerosis and/or hyperplasia). The quantitative results and knowledge base generated will be crucial for future clinical trials.     

Immunoglobulin E (IgE) Responses to Paramyosin Predict Resistance to Reinfection with Schistosoma japonicum and Are Attenuated by IgG4

Schistosomiasis remains a public health concern in developing countries, and rapid reinfection fostered by continued exposure to contaminated water sources necessitates a vaccine to augment current mass treatment-based control strategies. We report isotype-specific (immunoglobulin A [IgA], IgE, IgG1, IgG4, and IgG) antibody responses to soluble worm antigen preparation and the recombinant vaccine candidates rSj97, rSj67, and rSj22 from a Schistosoma japonicum-infected cohort in Leyte, the Philippines, where schistosomiasis is endemic. Sera were collected from infected individuals 1 month posttreatment with praziquantel, and antibody responses were measured using a bead-based multiplex platform. Reinfection was monitored by stool sampling every 3 months, and data up to 1 year were included in the analysis (n = 553). In repeated-measures models, individuals with detectible IgE responses to rSj97 had a 26% lower intensity of reinfection at 12 months posttreatment compared to nonresponders after adjusting for age, gender, village, exposure, pretreatment infection intensity, and clustering by household (P = 0.018). In contrast, IgG4 responses to rSj97 as well as rSj67 and rSj22 were associated with markedly increased reinfection intensity. When stratified by IgG4 and IgE responder status, individuals with IgE but not IgG4 responses to rSj97 (n = 16) had a 77% lower intensity of reinfection at 12 months compared to individuals with IgG4 responses but not IgE responses (n = 274), even after adjusting for potential confounders (P = 0.016). Together with our previously described protective cytokine responses, these data further support paramyosin as a leading vaccine candidate for human schistosomiasis japonica and underscore the importance of careful adjuvant selection to avoid the generation of blocking IgG4 antibody responses.Schistosomiasis, caused by parasitic helminths of the genus Schistosoma, remains a major public health concern and currently infects 200 million individuals with 600 million individuals at risk of infection in 74 developing countries (19). National control strategies focusing on mass chemotherapy with praziquantel have significantly reduced severe liver and urinary tract pathology; however, rapid reinfection with consequent subtle morbidities such as anemia, malnutrition, and cognitive impairment persist despite years of annual treatment (30). Continued exposure to contaminated water sources mandates alternative control strategies such as vaccine-linked chemotherapy (3).In vitro studies have demonstrated that schistosome larvae are susceptible to damage in the presence of sera from infected individuals together with leukocytes from uninfected donors, suggesting that parasite-specific antibody-dependent cellular cytotoxicity (ADCC) plays a key role in parasite elimination (8). Subsequent investigations identified the role of protective immunoglobulin E (IgE), IgA, and IgG antibody isotypes (11, 23, 29) and the participation of eosinophils and mast cells in orchestrating this attack (7, 12). However, several studies have also demonstrated the presence of inhibitory antibodies which block schistosomular killing (22, 28). In particular, the antibody isotype IgG4 is a poor initiator of ADCC and blocks killing by competing with protective isotypes (29). These data suggest that schistosomes induce both protective and antagonistic antibody responses, which may alter the balance between parasite elimination and immune evasion (3).Consonant with in vitro studies, several immunoepidemiologic surveys conducted in areas where schistosomiasis is endemic have demonstrated associations between antibody responses to crude parasite antigens and reinfection outcomes in humans. Protective IgE responses to worm (17, 24) and egg (43) antigens have been described across schistosome species, as well as IgA responses mediating antifecundity effects (23). These cohort studies have also described antiparasite IgG4 (16, 24, 32), IgM, and IgG2 (5, 22, 28) as isotypes associated with susceptibility.Based on a model of antibody-mediated protection, the antigenic targets of both protective antibody isotypes and protective monoclonal antibodies have been identified in parasite extracts and genomic libraries. Numerous candidates have been identified (4), and a panel of the most promising of these was evaluated in immunoepidemiologic studies in Egypt (2), Brazil (35), and to a limited extent in China and the Philippines (1, 32). Despite this progress (3), only one vaccine candidate (Schistosoma haematobium glutathione S-transferase) has advanced to early-phase clinical trials (10).We have previously described cytokine responses to crude antigen preparations (soluble worm antigen preparation [SWAP], SEA) and defined vaccine candidates (Sj97, Sj67, and Sj22) in a cohort of schistosomiasis-infected individuals between 7 and 30 years old and residing in Leyte, the Philippines (31). Here, we extend this work by measuring isotype-specific (IgA, IgE, IgG1, IgG4, and total IgG, henceforth referred to as IgG) antibody responses to these antigens in the same cohort and evaluating their association with resistance to reinfection over 12 months of posttreatment follow-up. We report that IgE responses to rSj97 are associated with resistance to reinfection and are attenuated by IgG4.