Citations

Abstract CXCR4, like other G protein-coupled receptors, signals via heterotrimeric guanine nucleotide-binding proteins (G proteins) to regulate gene transcription, migration, development, growth, and transformation. We describe a formerly uncharacterized function of a G protein: a role in receptor trafficking. We previously showed that CXCR4 and the TCR physically associate and form a heterodimer upon stromal cell-derived factor-1 or CXCL12 (SDF-1) stimulation in human T cells to prolong ERK activation and, thereby, lead to gene upregulation and cytokine secretion. The CXCR4–TCR heterodimers occur on the cell surface and in an intracellular compartment in response to SDF-1. Neither the intracellular compartment to which the CXCR4–TCR heterodimers localize nor the mechanism for localization has been elucidated. In this article, we characterize molecular mechanisms required for postendocytic trafficking of CXCR4. Upon SDF-1 stimulation, CXCR4 localizes to Rab11+ vesicles, a recycling compartment near the microtubule organizing center and Golgi apparatus. This trafficking requires the CXCR4 C-terminal tail domain but not the CXCR4 ubiquitination sites. The TCR also constitutively localizes to this Rab11+ compartment. Trafficking of CXCR4 into the Rab11+, TCR-containing endosomes requires actin polymerization. Furthermore, inhibiting Rho activation or depleting Gα13 prevented trafficking of CXCR4 into the Rab11+ endosomes without hindering the ability of CXCR4 to endocytose. These results indicated that, upon SDF-1 treatment, Gα13 and Rho mediate the actin polymerization necessary for trafficking CXCR4 into the Rab11+, recycling endosomal compartment, which also contains constitutively recycling TCR and, thus, CXCR4–TCR heterodimers. To our knowledge, this is the first report of Gα13 as a mediator of receptor trafficking.

Background— Heart failure (HF) care constitutes an increasing economic burden on the health care system, and has become a key focus in the health care debate. However, there are limited data on the lifetime health care costs for individuals with HF after initial diagnosis. Methods and Results— Olmsted County residents with incident HF from 1987 to 2006 were identified. Direct medical costs incurred from the time of HF diagnosis until death or last follow-up were obtained using population-based administrative data through 2007. Costs were inflated to 2008 US dollars using the general Consumer Price Index. Inpatient, outpatient, and total costs were estimated using a 2-part model with adjustment for right censoring of data. Predictors of total costs were examined using a similar model. A total of 1054 incident HF patients were identified (mean age, 76.8 years; 46.1% men). After a mean follow-up of 4.6 years, 765 (72.6%) patients had died. The estimated total lifetime costs were $109 541 (95% confidence interval, $100 335 to 118 946) per person, with the majority accumulated during hospitalizations (mean, $83 980 per person). After adjustment for age, year of diagnosis, and comorbidity, diabetes mellitus and preserved ejection fraction (≥50%) were associated with 24.8% ( P =0.003) and 23.6% ( P =0.041) higher lifetime costs, respectively. Higher costs were observed at initial HF diagnosis and in the months immediately before death in those surviving >12 months after diagnosis. Conclusions— HF imposes a significant economic burden, primarily related to hospitalizations. Variations in cost over a lifetime can help identify strategies for efficient management of patients, particularly at the end of life.

With favorable regenerative and immunotolerant profiles, patient-derived human mesenchymal stem cells (hMSCs) are increasingly considered in cell therapy. Derived from bone marrow (BM) and standardized with culture in fetal bovine serum (FBS), translation of hMSC-based approaches is impeded by protracted expansion times, risk of xenogenic response, and exposure to zoonoses. Here, human platelet lysate adherent to good manufacturing practices (GMP-hPL) provided a nonzoonotic adjuvant that enhanced the capacity of BM-hMSC to proliferate. The nurturing benefit of GMP-hPL was generalized to hMSC from adipose tissue evaluated as an alternative to bone marrow. Long-term culture in GMP-hPL maintained the multipotency of hMSC, while protecting against clonal chromosomal instability detected in the FBS milieu. Proteomic dissection identified TGF-β, VEGF, PDGF, FGF, and EGF as highly ranked effectors of hPL activity, revealing a paradigm of healing that underlies platelet lysate adjuvancy. Thus, GMP-adherent human platelet lysate accelerates hMSC proliferation with no chromosomal aberrancy, through an innate repair paradigm.

Purpose There are scant data regarding the effects of prophylactic cranial irradiation (PCI) on neurocognitive function (NCF) and quality of life (QOL). Radiation Therapy Oncology Group trial 0214 showed no overall survival (OS) benefit for PCI in stage III non–small-cell lung cancer (NSCLC) at 1 year. However, there was a significant decrease in brain metastases (BM). This analysis focuses on the impact of PCI on NCF and QOL. Patients and Methods Patients with stage III NSCLC who completed definitive therapy without progression were randomly assigned to PCI or observation. NCF was assessed with Mini-Mental Status Examination (MMSE), Activities of Daily Living Scale (ADLS), and Hopkins Verbal Learning Test (HVLT). QOL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) core tool (QOL Questionnaire-QLQC30) and brain module (QLQBN20). Results There were no statistically significant differences at 1 year between the two arms in any component of the EORTC-QLQC30 or QLQBN20 (P > .05), although a trend for greater decline in patient-reported cognitive functioning with PCI was noted. There were no significant differences in MMSE (P = .60) or ADLS (P = .88). However, for HVLT, there was greater decline in immediate recall (P = .03) and delayed recall (P = .008) in the PCI arm at 1 year. Conclusion PCI in stage III NSCLC significantly decreases the risk of BM without improving 1-year OS. There were no significant differences in global cognitive function (MMSE) or QOL after PCI, but there was a significant decline in memory (HVLT) at 1 year. This study provides prospective data regarding the relative risks and benefits of PCI in this setting and the need to use sensitive cognitive assessments.

PurposeThis study was conducted to determine if prophylactic cranial irradiation (PCI) improves survival in locally advanced non–small-cell lung cancer (LA-NSCLC).Patients and MethodsPatients with stage III NSCLC without disease progression after treatment with surgery and/or radiation therapy (RT) with or without chemotherapy were eligible. Participants were stratified by stage (IIIA v IIIB), histology (nonsquamous v squamous), and therapy (surgery v none) and were randomly assigned to PCI or observation. PCI was delivered to 30 Gy in 15 fractions. The primary end point of the study was overall survival (OS). Secondary end points were disease-free survival (DFS), neurocognitive function (NCF), and quality of life. Kaplan-Meier and log-rank analyses were used for OS and DFS. The incidence of brain metastasis (BM) was evaluated with the logistic regression model.ResultsOverall, 356 patients were accrued of the targeted 1,058. The study was closed early because of slow accrual; 340 of the 356 patients were eligible. The 1-year OS (P = .86; 75.6% v 76.9% for PCI v observation) and 1-year DFS (P = .11; 56.4% v 51.2% for PCI v observation) were not significantly different. The hazard ratio for observation versus PCI was 1.03 (95% CI, 0.77 to 1.36). The 1-year rates of BM were significantly different (P = .004; 7.7% v 18.0% for PCI v observation). Patients in the observation arm were 2.52 times more likely to develop BM than those in the PCI arm (unadjusted odds ratio, 2.52; 95% CI, 1.32 to 4.80).ConclusionIn patients with stage III disease without progression of disease after therapy, PCI decreased the rate of BM but did not improve OS or DFS.

AbstractIntroductionRoux‐en‐Y gastric bypass is increasingly performed in the United States. In addition, liver transplantation and other complex hepatobiliary surgeries are increasingly performed with creation of a Roux‐en‐Y hepaticojejunostomy. Consequently, endoscopists more frequently need to carry out endoscopic procedures in patients with Roux‐en‐Y anatomy.Materials and methodsThe present article discusses the techniques and instruments available to therapeutic endoscopists who are faced with the challenge of performing endoscopic retrograde cholangiopancreatography (ERCP) in patients with long‐ or short‐limb Roux‐en‐Y anatomy.ConclusionEndoscopists can successfully perform ERCP in patients with Roux‐en‐Y anatomy by making use of appropriate techniques and instruments.

Primary progressive multiple sclerosis (PPMS), relapsing remitting MS (RRMS) and acute disseminated encephalomyelitis (ADEM) are clinically and immunopathogenetically distinct phenotypes of inflammatory demyelinating disorders of the central nervous system. Progression following RRMS is well described as secondary progressive MS. We report a patient with unexpected transition from long established PPMS to clinically and radiologically active RRMS after an ADEM-like fulminant demyelinating episode despite an immunosuppressive treatment preceding relapses. We note clearly accelerated brain atrophy after the RRMS course ensues. The unique disease course in this patient illustrates the dissociation of the biology and disability impact of relapses and progression.

Abstract Recently, we detected that chronic lymphocytic leukemia (CLL) B-cell–derived microvesicles in CLL plasma carry a constitutively phosphorylated novel receptor tyrosine kinase (RTK), Axl, indicating that Axl was acquired from the leukemic B cells. To examine Axl status in CLL, we determined the expression of phosphorylated-Axl (P-Axl) in freshly isolated CLL B cells by Western blot analysis. We detected differential levels of P-Axl in CLL B cells, and further analysis showed that expression of P-Axl was correlated with the other constitutively phosphorylated kinases, including Lyn, phosphoinositide-3 kinase, SyK/ζ-associated protein of 70 kDa, phospholipase C γ2 in CLL B cells. We found that these intracellular signaling molecules were complexed with P-Axl in primary CLL B cells. When Axl and Src kinases were targeted by a Src/Abl kinase inhibitor, bosutinib (SKI-606), or a specific-inhibitor of Axl (R428), robust induction of CLL B-cell apoptosis was observed in both a dose- and time-dependent manner. Therefore, we have identified a novel RTK in CLL B cells which appears to work as a docking site for multiple non-RTKs and drives leukemic cell survival signals. These findings highlight a unique target for CLL treatment.