Citations

Waldenström Macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is often differentiated from myeloma based on the presence of lytic bone lesions (LBL). However, WM/LPL can present with LBL and management is poorly understood. We describe a case of an 81-year-old woman with LPL who presented with LBL and was successfully treated with chemoimmunotherapy.

Abstract Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by cyclical niraparib treatment in vivo. PH039 acquired PARPi resistance by the third treatment cycle and grew through subsequent treatment with either niraparib or rucaparib. Transcriptional profiling throughout the course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of ovarian cancer samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated an association between loss of RAD51C methylation prior to on-study biopsy and limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide a model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.

Abstract Introduction Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD‐MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD‐MC and could help predict risk for dementia during trial enrollment. Methods We created a dementia risk score by entering standardized gray‐matter volumes from 231 DIAD‐MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD‐MC followed longitudinally. Results Our risk score separated asymptomatic versus demented DIAD‐MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%–98.2%]) and improved prediction beyond established methods based on familial age of onset. Discussion Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD‐MC participants for prevention trials.

Vascular permeability factor/vascular endothelial growth factor A (VEGF) is a central regulator of angiogenesis and potently promotes vascular permeability. VEGF plays a key role in the pathologies of heart disease, stroke, and cancer. Therefore, understanding the molecular regulation of VEGF signaling is an important pursuit. Rho GTPase proteins play various roles in vasculogenesis and angiogenesis. While the functions of RhoA and RhoB in these processes have been well defined, little is known about the role of RhoC in VEGF-mediated signaling in endothelial cells and vascular development. Here, we describe how RhoC modulates VEGF signaling to regulate endothelial cell proliferation, migration and permeability. We found VEGF stimulation activates RhoC in human umbilical vein endothelial cells (HUVECs), which was completely blocked after VEGF receptor 2 (VEGFR-2) knockdown indicating that VEGF activates RhoC through VEGFR-2 signaling. Interestingly, RhoC knockdown delayed the degradation of VEGFR-2 compared to control siRNA treated HUVECs, thus implicating RhoC in VEGFR-2 trafficking. In light of our results suggesting VEGF activates RhoC through VEGFR-2, we sought to determine whether RhoC regulates vascular permeability through the VEGFR-2/phospholipase Cγ (PLCγ) /Ca 2+ /eNOS cascade. We found RhoC knockdown in VEGF-stimulated HUVECs significantly increased PLC-γ1 phosphorylation at tyrosine 783, promoted basal and VEGF-stimulated eNOS phophorylation at serine 1177, and increased calcium flux compared with control siRNA transfected HUVECs. Taken together, our findings suggest RhoC negatively regulates VEGF-induced vascular permeability. We confirmed this finding through a VEGF-inducible zebrafish model of vascular permeability by observing significantly greater vascular permeability in RhoC morpholino (MO)-injected zebrafish than control MO-injected zebrafish. Furthermore, we showed that RhoC promotes endothelial cell proliferation and negatively regulates endothelial cell migration. Our data suggests a scenario in which RhoC promotes proliferation by upregulating -catenin in a Wnt signaling-independent manner, which in turn, promotes Cyclin D1 expression and subsequently drives cell cycle progression.

Background: Participation in cardiac rehabilitation (CR) has been shown to decrease mortality following acute myocardial infarction (MI), but its impact on rehospitalizations requires examination. Methods: We included patients who were hospitalized with first-ever MI in Olmsted County Minnesota from 1987-2010 and survived to hospital discharge. Participation in CR within the first 30 days following MI was determined using billing data and was analyzed as a time-dependent covariate. The association between CR participation and all-cause rehospitalization was analyzed using Andersen-Gill models to account for repeated events. As CR participation is a non-randomized intervention, we adjusted for propensity to participate after fitting a logistic regression model using 13 factors significantly associated with participation on univariate analysis. Patients were censored at the time of death or last follow-up. Results: Among 2991 patients (mean age 67 years, 59% male, 31% ST elevation MI), 1480 (49%) participated in CR following acute MI hospital discharge (first session occurred at a mean of 9 days post-discharge). Most patients (75%) were rehospitalized at least once during a mean follow-up of 7.6 years, and CR participation was associated with reduced risk of rehospitalization. The rehospitalization rates were 39% and 59% at one year for participants and non-participants, respectively. In unadjusted analysis, CR participation was associated with a markedly decreased risk of rehospitalization (HR 0.51, 95% CI 0.49-0.53, p<0.001). After adjusting for propensity to participate, the association between CR participation and all-cause rehospitalization persisted (HR 0.70, 95% CI 0.67-0.73, p<0.001). Conclusions: CR participation is associated with a markedly reduced risk of rehospitalization after incident MI. In addition to reducing mortality, improving CR participation rates may have a large impact post-MI healthcare resource use.

Introduction: Cardiac rehabilitation (CR) is an effective but highly underutilized therapy for heart disease. Efforts are underway to increase CR referral and enrollment, but little is known about the potential capacity for growth in CR utilization in the United States. To address this concern, we estimated the current national capacity of CR programs across the United States and assessed obstacles to potential growth. Methods: We surveyed all CR Program Directors listed in the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) database in November of 2012. Respondents reported current enrollment levels, current program capacity, program capacity given reasonable expansion, and obstacles to growth. Results: Of 812 Program Directors in the AACVPR database, 290 (36%) completed the full survey. Respondents represented somewhat larger programs compared to non-respondents (4.0 vs. 4.6 full time employees, p = 0.01), but were otherwise similar. Current enrollment levels demonstrated a median [IQ range] of 140 [75,232] patients per year and a current estimated capacity of 192 [100,300] patient per year. Respondents estimated that programs could expand services by 25% to 240 [141,380] patients annually, assuming a significant increase in patient demand and a feasible increase in resources. We estimate that if programs filled to their current capacity, national CR utilization rates would increase from 34.7% to 46.4% (95% CI, 43.9 to 48.9) of eligible US patients each year. Given feasible program expansion, utilization could increase to a maximum of 58.4% (95% CI, 55.2 to 61.6) of qualifying patients. Capacity projections based upon absolute patient numbers and national statistics revealed concordant results. The most commonly cited obstacles to increasing patient participation are shown in the figure. As seen, the majority (88%) are controllable system-related factors unrelated to patient behavior. Conclusions: Even with substantial expansion of all existing CR programs, there is currently insufficient capacity in current CR programs to meet national service needs. Solutions to this problem will likely include the creation of new CR programs, and new policies that improve reimbursement for CR and also embrace new models of CR delivery.

AbstractBackgroundMucosal‐associated invariant T (MAIT) cells are unconventional T cells which recognize microbial metabolites presented by the major histocompatibility complex class I‐related molecule MR1. Although MAIT cells have been shown to reside in human and murine skin, their contribution to atopic dermatitis (AD), an inflammatory skin disease associated with barrier dysfunction and microbial translocation, has not yet been determined.MethodsGenetic deletion of MR1 and topical treatment with inhibitory MR1 ligands, which result in the absence and functional inhibition of MAIT cells, respectively, were used to investigate the role of MR1‐dependent immune surveillance in a MC903‐driven murine model of AD.ResultsThe absence or inhibition of MR1 arrested AD disease progression through the blockade of both eosinophil activation and recruitment of IL‐4‐ and IL‐13‐producing cells. In addition, the therapeutic efficacy of phototherapy against MC903‐driven AD could be increased with prior application of folate, which photodegrades into the inhibitory MR1 ligand 6‐formylpterin.ConclusionWe identified MAIT cells as sentinels and mediators of cutaneous type 2 immunity. Their pathogenic activity can be inhibited by topical application or endogenous generation, via phototherapy, of inhibitory MR1 ligands.

Paraganglioma (PGL) is a rare form of neuroendocrine cancer for which the underlying molecular basis is poorly understood. A mysterious hallmark of many PGL tumors is the inactivation of succinate dehydrogenase (SDH), a mitochondrial enzyme of the TCA cycle. Why does SDH loss induce cancer in certain cells? As a result of SDH loss, PGL tumor cells accumulate succinate, which may have epigenetic consequences. For example, certain lysine residues on histone proteins in nucleosomes are subject to succinylation by succinyl‐CoA as a post translational modification (PTM) that converts the lysine cation to an anion. We hypothesize that the structure and stability of the nucleosome core particle (NCP) is affected by succinylation PTMs through weakening of electrostatic histone‐DNA and histone‐histone interactions. Proteomic analysis of an SDH‐loss cell line model of PGL previously demonstrated that the greatest increase in nucleosomal lysine succinylation maps to H4K79 when compared to a control cell line. The mammalian H4K79 residue lies within the nucleosome core near wrapped DNA. We specifically hypothesize that the charge inversion conferred by H4K79 succinylation, destabilizes the NCP. Point mutations at H4K79 have been generated as lysine succinylation mimics at this site. Biophysical and in vitro transcription assays are being utilized to validate the assembly of NCPs incorporating lysine succinylation mimics at this site and to interrogate their resulting stabilities. Analyses of alterations in NCP dynamics in variant NCP will help to elucidate the role of lysine succinylation of histones in the altered chromatin landscape observed during PGL oncogenesis. Support or Funding Information GM75148‐09‐10 PREP This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

There are multiple conditions that can make children prone to having a sudden cardiac arrest (SCA) or sudden cardiac death (SCD). Efforts have been made by multiple organizations to screen children for cardiac conditions, but the emphasis has been on screening before athletic competition. This article is an update of the previous American Academy of Pediatrics policy statement of 2012 that addresses prevention of SCA and SCD. This update includes a comprehensive review of conditions that should prompt more attention and cardiology evaluation. The role of the primary care provider is of paramount importance in the evaluation of children, particularly as they enter middle school or junior high. There is discussion about whether screening should find any cardiac condition or just those that are associated with SCA and SCD. This update reviews the 4 main screening questions that are recommended, not just for athletes, but for all children. There is also discussion about how to handle post-SCA and SCD situations as well as discussion about genetic testing. It is the goal of this policy statement update to provide the primary care provider more assistance in how to screen for life-threatening conditions, regardless of athletic status.