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1.  Control of the mitotic cleavage plane by local epithelial topology 
Cell  2011;144(3):427-438.
SUMMARY
For nearly 150 years, it has been recognized that cell shape strongly influences the orientation of the mitotic cleavage plane (e.g. Hofmeister, 1863). However, we still understand little about the complex interplay between cell shape and cleavage plane orientation in epithelia, where polygonal cell geometries emerge from multiple factors, including cell packing, cell growth, and cell division itself. Here, using mechanical simulations, we show that the polygonal shapes of individual cells can systematically bias the long axis orientations of their adjacent mitotic neighbors. Strikingly, analysis of both animal epithelia and plant epidermis confirm a robust and nearly identical correlation between local cell topology and cleavage plane orientation in vivo. Using simple mathematics, we show that this effect derives from fundamental packing constraints. Our results suggest that local epithelial topology is a key determinant of cleavage plane orientation, and that cleavage plane bias may be a widespread property of polygonal cell sheets in plants and animals.
doi:10.1016/j.cell.2010.12.035
PMCID: PMC3491649  PMID: 21295702
2.  LRRK2 exonic variants and susceptibility to Parkinson’s disease 
Lancet neurology  2011;10(10):898-908.
Background
Leucine-rich repeat kinase 2 (LRRK2) is known to harbor highly penetrant mutations linked to familial parkinsonism. However, its full polymorphic variability in relationship to Parkinson’s disease (PD) risk has not been systematically assessed.
Methods
We examined the frequency pathogenicity of 121 exonic LRRK2 variants in three ethnic series (Caucasian [N=12,590], Asian [N=2,338] and Arab-Berber [N=612]) consisting of 8,611 patients and 6,929 control subjects from 23 separate sites of the Genetic Epidemiology of Parkinson’s Disease Consortium.
Findings
Excluding carriers of previously known pathogenic mutations, new independent risk associations were found for polymorphic variants in Caucasian (p.M1646T, OR: 1.43, 95% CI: 1.15 – 1.78, P=0.0012) and Asian (p.A419V, OR: 2.27, 95% CI: 1.35 – 3.83, P=0.0011) populations. In addition, a protective haplotype was observed at >5% frequency (p.N551K-p.R1398H-p.K1423K) in the Caucasian and Asian series’, with a similar finding in the small Arab-Berber series that requires further study (combined 3-series OR: 0.82, 95% CI: 0.72 – 0.94, P=0.0043). Of the two previously reported Asian risk variants p.G2385R was found to be associated with disease (OR: 1.73, 95% CI: 1.20 – 2.49, P=0.0026) but no association was observed for p.R1628P (OR: 0.62, 95% CI: 0.36 – 1.07, P=0.087). Also in the Arab-Berber series, p.Y2189C showed potential evidence of risk association with PD (OR: 4.48, 95% CI: 1.33 – 15.09, P=0.012). Of note, two variants (p.I1371V and p.T2356I) which have been previously proposed as pathogenic were observed in patient and control subjects at the same frequency.
Interpretation
LRRK2 offers an example where multiple rare and common genetic variants in the same gene have independent effects on disease risk. Lrrk2, and the pathway in which it functions, is important in the etiology and pathogenesis of a greater proportion of patients with PD than previously believed.
Funding
The present study and original funding for the GEO-PD Consortium was supported by grants from Michael J. Fox Foundation. Studies at individual sites were supported by a number of funding agencies world-wide.
doi:10.1016/S1474-4422(11)70175-2
PMCID: PMC3208320  PMID: 21885347
Parkinson disease; LRRK2; genetics
3.  Modeling and Inferring Cleavage Patterns in Proliferating Epithelia 
PLoS Computational Biology  2009;5(6):e1000412.
The regulation of cleavage plane orientation is one of the key mechanisms driving epithelial morphogenesis. Still, many aspects of the relationship between local cleavage patterns and tissue-level properties remain poorly understood. Here we develop a topological model that simulates the dynamics of a 2D proliferating epithelium from generation to generation, enabling the exploration of a wide variety of biologically plausible cleavage patterns. We investigate a spectrum of models that incorporate the spatial impact of neighboring cells and the temporal influence of parent cells on the choice of cleavage plane. Our findings show that cleavage patterns generate “signature” equilibrium distributions of polygonal cell shapes. These signatures enable the inference of local cleavage parameters such as neighbor impact, maternal influence, and division symmetry from global observations of the distribution of cell shape. Applying these insights to the proliferating epithelia of five diverse organisms, we find that strong division symmetry and moderate neighbor/maternal influence are required to reproduce the predominance of hexagonal cells and low variability in cell shape seen empirically. Furthermore, we present two distinct cleavage pattern models, one stochastic and one deterministic, that can reproduce the empirical distribution of cell shapes. Although the proliferating epithelia of the five diverse organisms show a highly conserved cell shape distribution, there are multiple plausible cleavage patterns that can generate this distribution, and experimental evidence suggests that indeed plants and fruitflies use distinct division mechanisms.
Author Summary
Cell division is one of the key mechanisms driving organismal growth and morphogenesis. Yet many aspects of the relationship between local cell division (how a cell chooses an orientation to divide) and global tissue architecture (e.g., regular versus irregular cells) remain poorly understood. We present a computational framework for studying topological networks that are created by cell division; this framework reveals how certain tissue statistics can be used to infer properties of the cell division model. Recently it has been observed that five diverse organisms show almost identical cell shape distributions in their proliferating epithelial tissues, yet how this conservation arises is not understood. Using our model we show that the low variation observed in nature requires a strong correlation between how neighboring cells divide and that although the statistics of plants and fruitflies are almost identical, it is likely that they have evolved distinct cell division methods.
doi:10.1371/journal.pcbi.1000412
PMCID: PMC2688032  PMID: 19521504
5.  Potential early intermediates in anaerobic benzoate degradation by Rhodopseudomonas palustris. 
Alkali-treated extracts of Rhodopseudomonas palustris growing photosynthetically on benzoate were examined by gas chromatography/mass spectrometry for partially reduced benzoate derivatives. Two cyclic dienes, cyclohexa-2,5-diene-1-carboxylate and cyclohexa-1,4-diene-1-carboxylate, were detected. Either compound supported cell growth as effectively as benzoate. These results suggest that these cyclohexadienecarboxylates, probably as their coenzyme A esters, are the initial reduction products formed during anaerobic benzoate metabolism by R. palustris.
PMCID: PMC195304  PMID: 1610191
6.  Seatone in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1985;44(9):645-646.
PMCID: PMC1001730  PMID: 4037890
7.  Seatone in arthritis. 
PMCID: PMC1507599  PMID: 6797585
8.  Seatone in arthritis. 
PMCID: PMC1505733  PMID: 6786626
9.  An Encouraging Report * 
PMCID: PMC1830210  PMID: 13585296
10.  A Human Infection with Actinomyces Caprae 
British Medical Journal  1938;1(4028):612-614.
PMCID: PMC2086000  PMID: 20781325
11.  Site-specific acylation changes in the lipid A of Escherichia coli lpxL mutants grown at high temperatures 
Innate immunity  2013;20(3):269-282.
LPS is a major component of the outer membrane of Gram-negative bacteria. The lipid A region of LPS mediates stimulation of the immune system. In E. coli, the gene (formerly htrB) codes for a late lauroyltransferase (LpxL) in lipid A biosynthesis. E. coli lpxL mutants have been described previously with impaired growth above 33°C in rich media. However, we were able to grow lpxL mutants at 30°C, 37°C and 42°C, and investigate their lipid A moieties to gain insight into changes and regulatory effects in lipid A biosynthesis. Multiple-stage mass spectrometry was used to decipher unusual lipid A structures produced by lpxL mutant bacteria at high temperatures that rescue the temperature-sensitive phenotype. At 37°C and 42°C, E. coli lpxL mutants appear to activate different acyltransferases or biosynthetic pathways that generate atypical penta- and hexaacyl lipid A structures by incorporating longer fatty acids, such as a secondary palmitoleic acid (2′-O-position, distal) and a secondary palmitic acid (2-O-position, proximal) respectively. However, we observed no changes in these structures through various growth curve stages. This study indicates that E. coli (lpxL) lipid A biosynthesis, and specifically the ‘late’ acylation of lipid A, is temperature dependent, thus suggesting a highly regulated process.
doi:10.1177/1753425913490534
PMCID: PMC3983921  PMID: 23812252
Late acylation; lipopolysaccharide; lpxL; mass spectrometry; temperature regulation
12.  Protein Quantitative Trait Loci Identify Novel Candidates Modulating Cellular Response to Chemotherapy 
PLoS Genetics  2014;10(4):e1004192.
Annotating and interpreting the results of genome-wide association studies (GWAS) remains challenging. Assigning function to genetic variants as expression quantitative trait loci is an expanding and useful approach, but focuses exclusively on mRNA rather than protein levels. Many variants remain without annotation. To address this problem, we measured the steady state abundance of 441 human signaling and transcription factor proteins from 68 Yoruba HapMap lymphoblastoid cell lines to identify novel relationships between inter-individual protein levels, genetic variants, and sensitivity to chemotherapeutic agents. Proteins were measured using micro-western and reverse phase protein arrays from three independent cell line thaws to permit mixed effect modeling of protein biological replicates. We observed enrichment of protein quantitative trait loci (pQTLs) for cellular sensitivity to two commonly used chemotherapeutics: cisplatin and paclitaxel. We functionally validated the target protein of a genome-wide significant trans-pQTL for its relevance in paclitaxel-induced apoptosis. GWAS overlap results of drug-induced apoptosis and cytotoxicity for paclitaxel and cisplatin revealed unique SNPs associated with the pharmacologic traits (at p<0.001). Interestingly, GWAS SNPs from various regions of the genome implicated the same target protein (p<0.0001) that correlated with drug induced cytotoxicity or apoptosis (p≤0.05). Two genes were functionally validated for association with drug response using siRNA: SMC1A with cisplatin response and ZNF569 with paclitaxel response. This work allows pharmacogenomic discovery to progress from the transcriptome to the proteome and offers potential for identification of new therapeutic targets. This approach, linking targeted proteomic data to variation in pharmacologic response, can be generalized to other studies evaluating genotype-phenotype relationships and provide insight into chemotherapeutic mechanisms.
Author Summary
The central dogma of biology explains that DNA is transcribed to mRNA that is further translated into protein. Many genome-wide studies have implicated genetic variation that influences gene expression and that ultimately affect downstream complex traits including response to drugs. However, because of technical limitations, few studies have evaluated the contribution of genetic variation on protein expression and ensuing effects on downstream phenotypes. To overcome this challenge, we used a novel technology to simultaneously measure the baseline expression of 441 proteins in lymphoblastoid cell lines and compared them with publicly available genetic data. To further illustrate the utility of this approach, we compared protein-level measurements with chemotherapeutic induced apoptosis and cell-growth inhibition data. This study demonstrates the importance of using protein information to understand the functional consequences of genetic variants identified in genome-wide association studies. This protein data set will also have broad utility for understanding the relationship between other genome-wide studies of complex traits.
doi:10.1371/journal.pgen.1004192
PMCID: PMC3974641  PMID: 24699359
13.  Human Cartilage Repair with a Photoreactive Adhesive-Hydrogel Composite 
Science translational medicine  2013;5(167):167ra6.
Surgical options for cartilage resurfacing may be significantly improved by advances and application of biomaterials that direct tissue repair. A poly(ethylene glycol) diacrylate (PEGDA) hydrogel was designed to support cartilage matrix production, with easy surgical application. A model in vitro system demonstrated deposition of cartilage-specific extracellular matrix in the hydrogel biomaterial and stimulation of adjacent cartilage tissue development by mesenchymal stem cells. For translation to the joint environment, a chondroitin sulfate adhesive was applied to covalently bond and adhere the hydrogel to cartilage and bone tissue in articular defects. After preclinical testing in a caprine model, a pilot clinical study was initiated where the biomaterials system was combined with standard microfracture surgery in 15 patients with focal cartilage defects on the medial femoral condyle. Control patients were treated with microfracture alone. Magnetic resonance imaging showed that treated patients achieved significantly higher levels of tissue fill compared to controls. Magnetic resonance spin-spin relaxation times (T2) showed decreasing water content and increased tissue organization over time. Treated patients had less pain compared with controls, whereas knee function [International Knee Documentation Committee (IKDC)] scores increased to similar levels between the groups over the 6 months evaluated. No major adverse events were observed over the study period. With further clinical testing, this practical biomaterials strategy has the potential to improve the treatment of articular cartilage defects.
doi:10.1126/scitranslmed.3004838
PMCID: PMC3972413  PMID: 23303605
14.  Association of Single-Nucleotide Polymorphisms of the Tau Gene With Late-Onset Parkinson Disease 
Context
The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease.
Objective
To investigate whether the tau gene is involved in idiopathic PD.
Design, Setting, and Participants
Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene.
Main Outcome Measure
Family-based tests of association, calculated using asymptotic distributions.
Results
Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P = .03; SNP 9i, P = .04; and SNP 11, P = .04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P = .11, and SNP 9iii, P = .87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P = .009) and a negative association with another haplotype (P = .007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3,9i, 9ii, and 11).
Conclusions
This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.
PMCID: PMC3973175  PMID: 11710889
15.  LOSS OF DENTIN SIALOPHOSPHOPROTEIN (DSPP) LEADS TO PERIODONTAL DISEASES IN MICE 
Journal of periodontal research  2012;48(2):221-227.
Background and Objective
Dentin sialophosphoprotein (DSPP) and its cleaved products, dentin phosphoprotein (DPP) and dentin sialoprotein (DSP), play important roles in biomineralization. Recently, we observed that DSPP is highly expressed in the alveolar bone and cementum, indicating that this molecule may play an important role in the formation and maintenance of a healthy periodontium, and its deletion may cause increased susceptibility to periodontal diseases. The objective of this investigation was to study the effects of Dspp ablation on periodontal tissues by analyzing Dspp null mice.
Methods
Newborn to 6-month-old Dspp null mice were examined, and the 3-month and 6-month-old Dspp null mice were characterized in detail using X-ray radiography, histology and scanning electron microscopy (backscattered as well as resin-infiltrating). Wild-type mice of the same age groups served as the normal controls.
Results
The Dspp null mice showed a significant loss of alveolar bone and cementum, particularly in the furcation and the interproximal regions of the molars. The alveolar bone appeared more porous while the quantity of cementum was reduced in the apical region. The canalicular systems and osteocytes in the alveolar bone were abnormal, with reduced numbers of canaliculi and an altered osteocyte morphology. The loss of alveolar bone and cementum along with the detachment of the periodontal ligaments (PDL) led to the apical migration of the epithelial attachment and the formation of periodontal pockets.
Conclusion
Inactivation of DSPP leads to the loss of the alveolar bone and cementum and increased susceptibility to bacterial infections in the PDL of Dspp null mice. The fact that the loss of DSPP results in periodontal diseases indicates that this molecule plays a vital role in maintaining the health of the periodontium.
doi:10.1111/j.1600-0765.2012.01523.x
PMCID: PMC3514631  PMID: 22934831
16.  Role of NH2-terminal fragment of Dentin Sialophosphoprotein (DSPP) in dentinogenesis 
DSPP is a large precursor protein that is proteolytically processed into three fragments: a NH2-terminal fragment [dentin sialoprotein (DSP), a proteoglycan form (DSP-PG)] and a COOH-terminal fragment [dentin phosphoprotein (DPP)]. In vitro studies indicate that DPP is a strong initiator and regulator of hydroxyapatite crystal formation and growth, but the role(s) of the NH2-terminal fragment of DSPP (i.e., DSP and DSP-PG) in dentinogenesis remain unclear. This study focuses on the function of the NH2-terminal fragment of DSPP in dentinogenesis. Here, transgenic mouse lines expressing the NH2-terminal fragment of DSPP driven by 3.6-kb type I collagen promoter (Col 1a1) were generated and crossbred with Dspp null mice to obtain mice that express the transgene but lack the endogenous Dspp (Dspp KO/DSP Tg). We found dentin from the Dspp KO/DSP Tg mice was much thinner; more poorly mineralized and remarkably disorganized compared to the Dspp KO mice. The fact that Dspp KO/DSP Tg mice exhibited more severe dentin defects than the Dspp null mice indicates that the NH2-terminal fragment of DSPP may inhibit dentin mineralization or may serve as an antagonist against the accelerating action of DPP and serve to prevent predentin from being mineralized too rapidly during dentionogenesis.
doi:10.1111/eos.12020
PMCID: PMC3602929  PMID: 23489896
DSPP; Proteolytic processing; Posttranslational modification; biomineralization; dentin
17.  Burkitt lymphoma risk in U.S. solid organ transplant recipients 
American journal of hematology  2013;88(4):245-250.
Case reports of Burkitt lymphoma (BL) in transplant recipients suggest that the risk is markedly elevated. Therefore, we investigated the incidence of BL in 203,557 solid organ recipients in the U.S. Transplant Cancer Match Study (1987–2009) and compared it to the general population using standardized incidence ratios (SIRs). We also assessed associations with demographic and clinical characteristics, and treatments used to induce therapeutic immunosuppression. BL incidence was 10.8 per 100,000 person-years, representing 23-fold (95%CI 19–28) greater risk than in the general population, and it peaked 3–8 years after the time of transplantation. In adjusted analyses, BL incidence was higher in recipients transplanted when <18 vs. ≥35 years (incidence rate ratio [IRR] 3.49, 95% CI 2.08–5.68) and in those transplanted with a liver (IRR 2.91, 95% CI 1.68–5.09) or heart (IRR 2.39, 95% CI 1.30–4.31) compared to kidney. BL incidence was lower in females than males (IRR 0.45, 95% CI 0.28–0.71), in blacks than whites (IRR 0.33, 95% CI 0.12–0.74), in those with a baseline Epstein-Barr virus (EBV)-seropositive versus EBV-seronegative status (IRR 0.34, 95% CI 0.13–0.93), and in those treated with azathioprine (IRR 0.56, 95% CI 0.34–0.89) or corticosteroids (IRR 0.48, 95% CI 0.29–0.82). Tumors were EBV-positive in 69% of 32 cases with results. EBV positivity was 90% in those aged <18 years and 59% in those aged 18+ years. In conclusion, BL risk is markedly elevated in transplant recipients, and it is associated with certain demographic and clinical features. EBV infection was present in most but not all BL cases.
doi:10.1002/ajh.23385
PMCID: PMC3608801  PMID: 23386365
Burkitt lymphoma; transplantation; immunosuppression; Epstein-Barr virus; non-Hodgkin lymphoma
18.  The neural correlates of passively viewed sequences of true and false beliefs 
The ability to infer other people's mental states such as desires, emotions, intentions and beliefs is essential for successful social interactions, and it is usually referred to as theory of mind (ToM). In particular, the ability to detect and understand that people have beliefs about reality that may be false is considered an important hallmark of ToM. This experiment reports on the results of 18 participants who viewed photographic sequences of an actress performing actions as a consequence of true and false beliefs. Consistent with prior work, results from the passive viewing of stimuli depicting true belief indicated an increased response over frontal, central and parietal regions when compared with the amplitude for the false belief condition. These results show that (i) frontal activity is required for processing false belief tasks and (ii) parietal effects reported in previous studies to reflect specific cognitive process of monitoring others' beliefs can be elicited in the absence of an explicit instruction for mentalizing.
doi:10.1093/scan/nss015
PMCID: PMC3624954  PMID: 22317745
ERP; false belief; passive paradigms; frontal activity; parietal activity; social cognition
19.  Evaluation of a web-based asthma management intervention program for urban teenagers: Reaching the hard to reach 
Purpose
Asthma interventions targeting urban adolescents are rare, despite a great need. Motivating adolescents to achieve better self-management of asthma is challenging, and the literature suggests that certain subgroups are more resistant than others. We conducted a school-based, randomized controlled trial to evaluate Puff City, a web-based, tailored asthma intervention, which included a referral coordinator, and incorporated theory-based strategies to target urban teens with characteristics previously found to be associated with lack of behavior change.
Methods
To identify eligible teens, questionnaires on asthma diagnoses and symptoms were administered to 9–12th graders of participating schools during a scheduled English class. Eligible, consenting students were randomized to Puff City (treatment) or generic asthma education (control).
Results
422 students were randomized (98% African-American, mean age=15.6 years). At 12 month follow-up, adjusted Odds Ratios (95% Confidence Intervals) indicated intervention benefit for treatment teens for symptom-days and restricted activity days (analyzed as categorical variables) aOR=0.49 (0.24–0.79), p=0.006 and 0.53 (0.32–0.86), p=0.010, respectively. Among teens meeting baseline criteria for rebelliousness, treatment teens reported fewer symptom-days, symptom-nights, school absences and restricted activity days, aOR=0.30 (0.11–0.80), 0.29 (0.14–0.64), 0.40 (0.20–0.78), and 0.23 (0.10–0.55); all p<0.05. Among teens reporting low perceived emotional support, treatment students reported only fewer symptom-days than controls, aOR=0.23 (0.06 – 0.88), p=0.031. Statistically significant differences in medical care use were not observed.
Conclusions
Results suggest a theory-based, tailored approach, with a referral coordinator, can improve asthma management in urban teens. Puff City represents a viable strategy for disseminating an effective intervention to high risk and hard-to-reach populations.
doi:10.1016/j.jadohealth.2012.07.009
PMCID: PMC3632347  PMID: 23299008
20.  Cetuximab-activated natural killer (NK) and dendritic cells (DC) collaborate to trigger tumor antigen-specific T cell immunity in head and neck cancer patients 
Purpose
Tumor antigen (TA)-specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcγ receptor (FcγR)-mediated cytotoxicity. However, the role of CD8+ cytotoxic T lymphocyte (CTL) and FcγR in initiating innate and adaptive immune responses in mAb-treated human cancer patients is still emerging.
Experimental Design
FcγRIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated head and neck cancer (HNC) patients. Flow cytometry was performed to quantify EGFR-specific T cells in cetuximab-treated HNC patients. The effect of cetuximab on NK cell, dendritic cell (DC), and T cell activation was measured using IFN-γ release assays and flow cytometry.
Results
FcγR IIIa polymorphism did not predict clinical outcome in cetuximab-treated HNC patients, however elevated circulating EGFR -specific CD8+ 853-861 T cells were found in cetuximab-treated HNC patients (p<0.005). Cetuximab promoted EGFR-specific cellular immunity through the interaction of EGFR+ tumor cells and FcγRIIIa on NK cells, but not on the polymorphism per se. Cetuximab-activated NK cells induced IFN-γ dependent expression of DC maturation markers, antigen presentation machinery (APM) components such as TAP-1/2, and Th1 chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK-cell induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another TA, MAGE-3.
Conclusion
Cetuximab-activated NK cells promote DC maturation and CD8+ T cell priming, leading to TA spreading and Th1 cytokine release through ‘NK-DC cross-talk.’ FcγRIIIa polymorphism did not predict clinical response to cetuximab, but was necessary for NK-DC interaction and mAb induced cross-presentation. EGFR-specific T cells in cetuximab treated HNC patients may contribute to clinical response.
doi:10.1158/1078-0432.CCR-12-2426
PMCID: PMC3640274  PMID: 23444227
Cetuximab; Panitumumab; EGFR; ADCC; CTL; cross-presentation; head and neck cancer; immunotherapy
21.  ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR CHEMOTHERAPY-UNRESPONSIVE MANTLE CELL LYMPHOMA: A COHORT ANALYSIS FROM THE CIBMTR 
Patients with chemorefractory mantle cell lymphoma (MCL) have poor prognosis. We used the CIBMTR database to study the outcome of 202 patients with refractory MCL who underwent allogeneic hematopoietic cell transplantation (allo-HCT) using either myeloablative (MA) or reduced intensity/non-myeloablative conditioning (RIC/NST), during 1998–2010. We analyzed non-relapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS). Seventy-four patients received MA, and 128 underwent RIC/NST. Median ages are 54 and 59 years for MA and RIC/NST allo-HCT recipients, respectively. Median follow-up after MA and RIC/NST allo-HCT is 35 months and 43 months, respectively. At 3 years, comparing MA with RIC/NST allo-HCT, no significant differences were found in terms of NRM (47% vs. 43%; p-value=0.68), relapse/progression (33% vs. 32%; p-value=0.89), PFS (20% vs. 25%; p=0.53), and OS (25% vs. 30%; p-value=0.45). On multivariate analysis no significant differences were observed in NRM, relapse, PFS and OS between MA and RIC/NST allo-HCT; however, receiving a bone marrow or T-cell depleted allograft was associated with an increased risk of NRM and inferior PFS and OS. Despite a refractory disease state, approximately a fourth of MCL patients can attain durable remissions after allo-HCT. Conditioning regimen intensity did not influence the outcomes of patients after allo HCT.
doi:10.1016/j.bbmt.2013.01.009
PMCID: PMC3640440  PMID: 23333532
Mantle cell lymphoma; allogeneic transplantation; chemotherapy unresponsive; graft-versus-host disease
22.  Patients with Idiopathic Pulmonary Fibrosis with Antibodies to Heat Shock Protein 70 Have Poor Prognoses 
Rationale: Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations.
Objectives: To identify clinically relevant, antigen-specific immune responses in patients with IPF.
Methods: Autoantibodies were detected by immunoblots and ELISA. Intrapulmonary immune processes were evaluated by immunohistochemistry. Anti–heat shock protein 70 (HSP70) IgG was isolated from plasma by immunoaffinity. Flow cytometry was used for leukocyte functional studies.
Measurements and Main Results: HSP70 was identified as a potential IPF autoantigen in discovery assays. Anti-HSP70 IgG autoantibodies were detected by immunoblots in 3% of 60 control subjects versus 25% of a cross-sectional IPF cohort (n = 122) (P = 0.0004), one-half the patients with IPF who died (P = 0.008), and 70% of those with acute exacerbations (P = 0.0005). Anti-HSP70 autoantibodies in patients with IPF were significantly associated with HLA allele biases, greater subsequent FVC reductions (P = 0.0004), and lesser 1-year survival (40 ± 10% vs. 80 ± 5%; hazard ratio = 4.2; 95% confidence interval, 2.0–8.6; P < 0.0001). HSP70 protein, antigen–antibody complexes, and complement were prevalent in IPF lungs. HSP70 protein was an autoantigen for IPF CD4 T cells, inducing lymphocyte proliferation (P = 0.004) and IL-4 production (P = 0.01). IPF anti-HSP70 autoantibodies activated monocytes (P = 0.009) and increased monocyte IL-8 production (P = 0.049). ELISA confirmed the association between anti-HSP70 autoreactivity and IPF outcome. Anti-HSP70 autoantibodies were also found in patients with other interstitial lung diseases but were not associated with their clinical progression.
Conclusions: Patients with IPF with anti-HSP70 autoantibodies have more near-term lung function deterioration and mortality. These findings suggest antigen-specific immunoassays could provide useful clinical information in individual patients with IPF and may have implications for understanding IPF progression.
doi:10.1164/rccm.201203-0506OC
PMCID: PMC3678112  PMID: 23262513
B cells; T cells; adaptive immunity; interstitial lung disease
23.  Genetic Variation in PEAR1 is Associated with Platelet Aggregation and Cardiovascular Outcomes 
Background
Aspirin or dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard therapy for patients at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known.
Methods and Results
We measured ex-vivo platelet aggregation before and after DAPT in individuals (n=565) from the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study and conducted a genome-wide association study (GWAS) of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in two independent aspirin-treated cohorts: 227 percutaneous coronary intervention (PCI) patients, and 1,000 patients of the International VErapamil SR/trandolapril Study (INVEST) GENEtic Substudy (INVEST-GENES). GWAS revealed a strong association between single nucleotide polymorphisms on chromosome 1q23 and post-DAPT platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with DAPT response (P=7.66×10−9). In Caucasian and African American patients undergoing PCI, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared to GG homozygotes (hazard ratio = 2.62, 95%CI 0.96-7.10, P=0.059 and hazard ratio = 3.97, 95%CI 1.10-14.31, P=0.035 respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared to GG homozygotes (OR=2.03, 95%CI 1.01-4.09, P=0.048).
Conclusions
Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin, alone and in combination with clopidogrel.
Clinical Trial Registration Information
clinicaltrials.gov; Identifiers: NCT00799396 and NCT00370045
doi:10.1161/CIRCGENETICS.111.964627
PMCID: PMC3715320  PMID: 23392654
pharmacogenomics; platelets; percutaneous coronary intervention; PEAR1; CYP2C19
24.  The Role of Single-Cell Analyses in Understanding Cell Lineage Commitment 
Biotechnology journal  2013;8(4):397-407.
The study of cell lineage commitment is critical to improving our understanding of tissue development and regeneration and to enhancing stem cell-based therapies and engineered tissue replacements. Recently, the discovery of an unanticipated degree of variability in fundamental biological processes, including divergent responses of genetically identical cells to various stimuli, has provided mechanistic insight into cellular decision making and the collective behavior of cell populations. Therefore the study of lineage commitment with single-cell resolution could provide greater knowledge of cellular differentiation mechanisms and the influence of noise on cell processes. This will require the adoption of new technologies for single-cell analysis, in contrast to traditional methods that typically measure average values of bulk population behavior. This review discusses the recent development of methods for analyzing the behavior of individual cells and how these approaches are leading to deeper understanding and better control of cellular decision making.
doi:10.1002/biot.201200201
PMCID: PMC3753774  PMID: 23520130
single-cell; stochastic; single-molecule; lineage commitment; cellular heterogeneity; noise; gene expression; cell differentiation
25.  Size matters: How age and reaching experiences shape infants’ preferences for different sized objects 
Infant behavior & development  2013;36(2):189-198.
Looking and reaching preferences for different-sized objects were examined in 4–5- and 5–6-month-old infants. Infants were presented with pairs of different sized cylinders and preferences were analyzed by age and reaching status. Outcome variables included looking and touching time for each object, first look, and first touch. Significant three-way interactions with age and reaching status were found for both infants’ looking and touching duration. Four–5- and 5–6-month-olds with less reaching experience spent more time visually and manually exploring larger objects. In contrast, 5–6-month-olds with more reaching experience spent more time looking at and touching smaller objects, despite a first look and first touch preference for the largest object. Initially, looking and reaching preferences seem to be driven by mechanisms responding to general visual salience independent of an object’s potential for manual action. Once reaching skills emerge, infants begin to use visual information to selectively choose smaller, more graspable objects as exploration targets.
doi:10.1016/j.infbeh.2013.01.006
PMCID: PMC3757549  PMID: 23454420
Infant; Motor development; Reaching; Preferential looking; Object selection; Grasping

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